{"gene":"ATF5","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2016,"finding":"ATF5 is a mammalian transcription factor that mediates the mitochondrial unfolded protein response (UPRmt). Like C. elegans ATFS-1, ATF5 is regulated by organelle partitioning: it normally accumulates in mitochondria, but during mitochondrial stress a fraction traffics to the nucleus to activate UPRmt target genes. ATF5 expression rescues UPRmt signaling in atfs-1-deficient worms requiring the same UPRmt promoter element identified in C. elegans, and mammalian cells require ATF5 to maintain mitochondrial activity during stress.","method":"Cellular fractionation, ATF5 expression in atfs-1-deficient C. elegans (genetic complementation), siRNA knockdown in mammalian cells, reporter assays","journal":"Current Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (fractionation, cross-species genetic rescue, reporter, loss-of-function), widely replicated across subsequent studies","pmids":["27426517"],"is_preprint":false},{"year":2008,"finding":"ATF5 translation is preferentially induced during stress by a mechanism requiring eIF2α phosphorylation. The 5'-leader of ATF5 mRNA contains two uORFs analogous to ATF4: uORF1 is positive-acting (allows reinitiation), and uORF2 is inhibitory under normal conditions. eIF2α phosphorylation during stress delays reinitiation, causing ribosomes to bypass uORF2 and instead translate the ATF5 coding region. Additionally, ATF4 contributes to basal ATF5 transcription.","method":"Polyribosome fractionation, luciferase reporter assays with uORF mutations, ATF4-/- mouse embryo fibroblasts, pharmacological eIF2 kinase activation","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of uORFs in reporter system plus polyribosome fractionation; replicated by independent lab (PMID:18055463)","pmids":["18195013","18055463"],"is_preprint":false},{"year":2007,"finding":"ATF5 mRNA translation is regulated by alternative 5'-UTRs (5'-UTRα and 5'-UTRβ). 5'-UTRα represses basal translation via uORF2, but this repression is released by amino acid limitation or arsenite exposure through eIF2α phosphorylation. 5'-UTRβ does not confer stress-responsive translational upregulation. Mutation of uAUG2 in uORF2 restored basal expression and abolished stress-induced upregulation.","method":"Reporter assays with 5'-UTR variants and uORF mutations, eIF2α phosphorylation analysis, heme-regulated inhibitor kinase overexpression","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of specific uORFs combined with reporter assays; mechanistically consistent with PMID:18195013","pmids":["18055463"],"is_preprint":false},{"year":2013,"finding":"CHOP directly induces ATF5 transcription as part of a feedforward apoptotic switch during severe proteotoxic stress. ATF4 also directly activates ATF5 transcription. Knockdown of ATF5 increases cell survival during proteasome inhibition. ATF5-dependent transcriptome analysis identified NOXA as an ATF5 target important for cell death.","method":"Chromatin immunoprecipitation, ATF5 knockdown (siRNA), transcriptome profiling, proteasome inhibitor treatment, cell viability assays","journal":"Molecular Biology of the Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP establishing direct transcriptional regulation, loss-of-function with defined phenotype, transcriptome analysis; single lab but multiple orthogonal methods","pmids":["23761072"],"is_preprint":false},{"year":2013,"finding":"The 5'-UTRα of ATF5 mRNA renders it a target of nonsense-mediated mRNA decay (NMD) under normal conditions via translation of uORF2. Knockdown of NMD factors Upf1 and Upf2 stabilized ATF5 mRNA. During amino acid limitation or tunicamycin-induced stress, eIF2α phosphorylation stabilizes ATF5 mRNA by preventing uORF2 translation, thereby linking translational control to mRNA decay regulation.","method":"siRNA knockdown of Upf1/Upf2, uORF2 mutation, mRNA stability assays, stress treatment","journal":"The FEBS Journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis of uAUG2, RNAi of NMD factors with mRNA stability readout, single lab with multiple orthogonal approaches","pmids":["23876217"],"is_preprint":false},{"year":2003,"finding":"ATF5 suppresses neuroprogenitor cell differentiation into neurons. ATF5 is highly expressed in neural stem/progenitor cells and downregulated by NGF. Exogenous ATF5 suppresses NGF-promoted neurite outgrowth and neurogenesis; dominant-negative ATF5 or siRNA accelerates neurogenesis. The inhibitory effect requires repression of CRE sites.","method":"Overexpression and dominant-negative ATF5 in PC12 and telencephalic cells, siRNA knockdown, NGF treatment, neurosphere cultures, CRE luciferase reporter","journal":"Journal of Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain-of-function, loss-of-function (dominant-negative and siRNA), and reporter assays in multiple cell types; replicated in subsequent papers","pmids":["12805299"],"is_preprint":false},{"year":2010,"finding":"In malignant glioma, RAS-MAPK or PI3K signaling activates CREB3L2, which directly activates ATF5 transcription. ATF5 in turn promotes survival by directly stimulating transcription of the anti-apoptotic gene MCL1. The RAF inhibitor sorafenib suppresses ATF5 expression in glioma stem cells.","method":"Genome-wide RNAi screen, ChIP, reporter assays, gene expression analysis in human glioma samples and mouse models","journal":"Nature Medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide unbiased screen followed by ChIP validating direct transcriptional regulation, corroborated in vivo","pmids":["20495567"],"is_preprint":false},{"year":2011,"finding":"BCR-ABL suppresses autophagy through the PI3K/AKT/FOXO4 pathway, which transcriptionally upregulates ATF5; ATF5 in turn directly stimulates transcription of mTOR, a master negative regulator of autophagy. Imatinib-induced autophagy is caused by inhibition of this BCR-ABL/PI3K/AKT/FOXO4/ATF5/mTOR pathway.","method":"Reporter assays, ChIP, ATF5 knockdown, mTOR expression analysis, autophagy assays in BCR-ABL-transformed cells","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct ATF5 binding to mTOR promoter, pathway dissection with multiple inhibitors and knockdowns, single lab","pmids":["21715304"],"is_preprint":false},{"year":2011,"finding":"BCL-2 is a direct transcriptional target of ATF5 that mediates its prosurvival function in glioma and breast cancer cells. ATF5 binds to an ATF5-specific regulatory element downstream of and adjacent to the negative regulatory element in the BCL-2 P2 promoter. BCL-2 expression is not regulated by ATF5 in non-transformed cells, explaining the cancer cell-specific survival function.","method":"ChIP, EMSA, ATF5 overexpression/knockdown, BCL-2 promoter reporter assays, rescue experiments in multiple cell types","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct binding demonstrated by EMSA and ChIP, functional rescue experiments, cell-type specificity established; single lab","pmids":["21212266"],"is_preprint":false},{"year":2011,"finding":"HSP70 interacts with the N-terminal activation domain of ATF5 (which is rich in proline residues) through an ATP-driven process requiring functional ATPase on HSP70. HSP70 binding stabilizes ATF5 protein, which is otherwise subject to rapid proteasome-dependent and caspase-dependent degradation. HSP70 depletion accelerates ATF5 degradation and reduces BCL-2 and EGR-1 expression in glioma cells.","method":"Co-immunoprecipitation, HSP70 overexpression/siRNA knockdown, ATF5 stability assays, proteasome/caspase inhibitors, domain mapping","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ATP-dependence tested, domain mapping, functional consequence on downstream targets; single lab","pmids":["21521685"],"is_preprint":false},{"year":2011,"finding":"p300 acetylates ATF5 at lysine-29 (K29), which enhances the ATF5-p300 interaction and binding of the ATF5/p300 complex to the ATF5 response element (ARE) of the EGR-1 promoter. ARE-bound ATF5/p300 then acetylates histone H3 K14 at both ARE and SRE of EGR-1 promoter, facilitating ERK-phosphorylated Elk-1 binding to the SRE and activating EGR-1 transcription.","method":"Co-IP, in vitro acetylation assays, ChIP, acetylation-site mutagenesis (K29), promoter reporter assays, ERK inhibition","journal":"Molecular and Cellular Biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro acetylation, mutagenesis of specific lysine, ChIP, and functional reporter assays; single lab with multiple orthogonal methods","pmids":["21791614"],"is_preprint":false},{"year":2008,"finding":"ATF5 protein is degraded via the ubiquitin-proteasome pathway through N-terminal ubiquitinylation of the free amino group of the N-terminal methionine. The E2 ubiquitin-conjugating enzyme Cdc34 is involved in ATF5 ubiquitination. Cisplatin blocks ATF5 degradation by promoting nucleus-to-cytoplasm translocation of Cdc34, reducing ATF5-Cdc34 interaction.","method":"Ubiquitination assays, N-terminal methionine mutants, Cdc34 overexpression/co-IP, cisplatin treatment, proteasome inhibitor studies","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ubiquitination assays and Co-IP identifying Cdc34 as E2; N-terminal ubiquitination mechanism inferred from deletion mutants; single lab","pmids":["18458088"],"is_preprint":false},{"year":2009,"finding":"Cadmium interferes with ATF5 degradation at a post-ubiquitination step of the proteasome pathway. Unlike proteasome inhibitors (which increase ubiquitinated ATF5), cadmium does not reduce ATF5 ubiquitination but instead blocks a downstream step in proteasomal degradation, stabilizing ATF5 protein.","method":"Ubiquitination assays, CdCl2/NaAsO3 treatment, proteasome inhibitor comparison, transient transfection of FLAG-ATF5","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, single method (ubiquitination assay) distinguishing cadmium from proteasome inhibitors; mechanistically informative negative finding on ubiquitination","pmids":["19285020"],"is_preprint":false},{"year":2012,"finding":"Nucleophosmin (NPM1/B23) interacts with ATF5 via the ATF5 leucine zipper domain binding to the C-terminal nucleolar localization signal region of NPM1. NPM1 promotes ATF5 degradation through proteasome-dependent and caspase-dependent pathways. NPM1 interaction displaces HSP70 from ATF5 complexes, antagonizing HSP70-mediated ATF5 stabilization. NPM1-c, a mutant defective in nucleolar localization, failed to stimulate ATF5 polyubiquitination.","method":"Tandem affinity purification followed by mass spectrometry, Co-IP, domain mapping, ubiquitination assays, NPM1-c mutant","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — unbiased TAP-MS identification of NPM1, validated by Co-IP, domain mapping, ubiquitination assays, and functional mutant; single lab","pmids":["22528486"],"is_preprint":false},{"year":2015,"finding":"ATF5 forms a characteristic 9-fold symmetrical ring structure in the inner layer of the pericentriolar material (PCM) at the proximal end of the mother centriole. ATF5 interacts with polyglutamylated tubulin (PGT) on the mother centriole and with PCNT in the PCM, functioning as a structural linker required for mother centriole-directed PCM accumulation and PCM-dependent centriole formation. ATF5 depletion causes PCM fragmentation, multi-polar mitotic spindles, and genomic instability.","method":"Super-resolution microscopy (9-fold symmetry), Co-IP with PGT and PCNT, ATF5 depletion/RNAi, centrosome fractionation, cell cycle analysis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — super-resolution structural data combined with Co-IP binding partners, loss-of-function with defined structural and functional phenotypes; high-profile single study","pmids":["26213385"],"is_preprint":false},{"year":2018,"finding":"ATF5 is SUMO2/3-modified at a conserved SUMO-targeting consensus site. SUMOylation of ATF5 is elevated in G1 phase and diminished in G2/M phase. SUMOylation disrupts ATF5 interaction with centrosomal proteins, dislodging ATF5 from the centrosome at the end of M phase. Blockade of ATF5 SUMOylation deregulates the centrosome cycle, impedes ATF5 translocation from the centrosome, and causes genomic instability and G2/M arrest.","method":"SUMO modification assays, cell-cycle-synchronized cells, SUMOylation-site mutant ATF5, Co-IP with centrosomal proteins, genomic instability assays","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — SUMO modification demonstrated biochemically, site mutant used to block SUMOylation with defined centrosome and cell-cycle phenotypes; single lab","pmids":["29326161"],"is_preprint":false},{"year":2012,"finding":"ATF5 is required for terminal differentiation and survival of olfactory sensory neurons (OSNs). In Atf5-/- mice, OSNs fail to differentiate from immature to mature OSNs and undergo apoptosis, leading to neonatal lethality from olfactory defect. Ectopic ATF5 expression in neural progenitor cells induces expression of multiple OSN-specific genes.","method":"Atf5 knockout mice, immunostaining with OSN-specific markers, expression profiling, ectopic ATF5 expression","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout phenotype with defined cellular mechanism, gain-of-function confirming OSN gene induction; replicates and extends prior in vitro findings","pmids":["23090999"],"is_preprint":false},{"year":2005,"finding":"ATF5 promotes oligodendrocyte progenitor expansion and inhibits their differentiation into mature oligodendroglia. Constitutively expressed ATF5 maintains SVZ cells and O4+ precursors in cycle; ATF5 loss-of-function (dominant-negative) accelerates oligodendrocyte differentiation in vitro and in vivo, but results in aberrant migration.","method":"Dominant-negative ATF5 in vitro and in vivo (SVZ cells), constitutive ATF5 expression, BrdU labeling, immunostaining","journal":"Molecular and Cellular Neurosciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — both gain-of-function and loss-of-function in vivo and in vitro; replicates neuroprogenitor findings from PMID:12805299 in oligodendrocyte lineage","pmids":["15950153"],"is_preprint":false},{"year":2019,"finding":"Cardioprotection by pharmacological UPRmt induction (oligomycin or doxycycline) requires ATF5 in vivo. In global Atf5-/- mice, UPRmt induction fails to protect against cardiac ischemia-reperfusion injury, whereas it does in wild-type mice. RNA-Seq revealed an ATF5-dependent gene set induced by UPRmt.","method":"Atf5-/- mice, in vivo UPRmt induction, ex vivo ischemia-reperfusion, cardiac qPCR/western blot, RNA-Seq","journal":"American Journal of Physiology: Heart and Circulatory Physiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo knockout with defined functional phenotype, RNA-Seq for mechanistic gene set; multiple methods in single study","pmids":["31274354"],"is_preprint":false},{"year":2014,"finding":"Nemo-like kinase (NLK) interacts with ATF5 and inhibits proteasome-dependent degradation of ATF5 in a kinase-independent manner, thereby stabilizing ATF5 protein. NLK cooperates with ATF5 to activate C/EBP transcription. TAK1, upstream of NLK in the IL-1β pathway, mimics NLK's ability to stabilize ATF5 and activate C/EBP, establishing a TAK1-NLK-ATF5-C/EBP signaling axis.","method":"Co-IP, luciferase reporter for C/EBP activity, NLK overexpression/knockdown/knockout, ATF5 stability assays, kinase-dead NLK mutant","journal":"Molecular and Cellular Biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, kinase-dead mutant, loss-of-function and gain-of-function, defined pathway; single lab","pmids":["25512613"],"is_preprint":false},{"year":2012,"finding":"The ER stress transducer BBF2H7 transcriptionally activates ATF5 in chondrocytes. ATF5 in turn activates transcription of Mcl1 to suppress ER stress-induced apoptosis in chondrocytes. This BBF2H7-ATF5-MCL1 pathway is specifically activated during chondrogenesis and is required to counteract ER stress from abundant ECM protein synthesis.","method":"Bbf2h7-/- mice, TUNEL staining, ChIP/reporter assays, ATF5 and MCL1 expression analysis in chondrocytes","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo knockout, reporter assays establishing direct transcriptional regulation, defined pathway with genetic validation; single lab","pmids":["22936798"],"is_preprint":false},{"year":2017,"finding":"ATF5 is a transcriptional target of PDX1 in pancreatic β-cells (PDX1 binding confirmed by ChIP-sequencing). ATF5 regulates β-cell survival under stress and is positioned downstream of and parallel to ATF4 in the regulation of 4EBP1, a mTOR pathway component that inhibits protein translation. ATF5 deficiency attenuates stress-induced suppression of global translation, increasing β-cell susceptibility to apoptosis.","method":"Primary islet ChIP-sequencing for PDX1, ATF5 loss-of-function, 4EBP1 reporter/expression, translation assays","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP-seq establishing direct PDX1-ATF5 transcriptional regulation, loss-of-function with defined translational and survival phenotype; single lab","pmids":["28115692"],"is_preprint":false},{"year":2008,"finding":"ATF5 is a liver-enriched transcription factor that cooperates with constitutive androstane receptor (CAR) to transactivate CYP2B6. Adenoviral ATF5 overexpression in HepG2 cells selectively upregulates CYP2B6 mRNA, and ATF5+CAR co-expression causes additive CYP2B6 induction. Under ER stress (amino acid limitation), ATF5 is post-transcriptionally upregulated with parallel CYP2B6 induction.","method":"Adenoviral transduction, co-transfection with CAR, qRT-PCR, primary human hepatocyte cultures","journal":"Drug Metabolism and Disposition","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — gain-of-function in multiple systems, but mechanism of cooperation with CAR not resolved at molecular level; single lab","pmids":["18332083"],"is_preprint":false},{"year":2005,"finding":"ATF5 activates asparagine synthetase (ASNS) promoter transcription via the nutrient-sensing response unit (NSRU). This transactivation is blocked by CHOP, which acts as a shut-off device for nutrient deprivation-induced ATF5-mediated gene transcription. ATF5 does not transactivate CRE-containing reporter genes.","method":"Reporter gene assays with ASNS promoter, ATF5 and CHOP overexpression, deletion/mutation analysis of NSRU","journal":"Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — reporter assays in transfected cells; promoter element identified but not confirmed by ChIP; single lab","pmids":["16164412"],"is_preprint":false},{"year":2009,"finding":"ATF5 suppresses the transactivational activity of p53 and p63 in a luciferase reporter assay. ATF5 overexpression in radiosensitive tumor cells confers resistance to ionizing radiation and Ad-p53-induced apoptosis.","method":"Luciferase reporter assay for p53/p63 transactivation, ATF5 gene transfer, colony assay, flow cytometry","journal":"Cell Structure and Function","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — reporter assay and gene transfer in a single cell line, no direct binding demonstrated; single lab","pmids":["19293535"],"is_preprint":false},{"year":2010,"finding":"ATF5 directly binds the ID1 gene promoter (demonstrated by EMSA) and represses ID1 transcription in hepatocellular carcinoma cells. Restoration of ATF5 in HCC cells causes G2/M cell cycle arrest.","method":"EMSA, reporter assays, flow cytometry cell cycle analysis, ATF5 re-expression in HCC cell lines","journal":"Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct binding shown by EMSA but not ChIP, functional G2/M phenotype in multiple lines; single lab","pmids":["18701499"],"is_preprint":false},{"year":2007,"finding":"ATF5 promotes cell survival against heat shock in H9c2 cells by transcriptionally activating Hsp27. The CRE motif in the Hsp27 gene promoter is important for ATF5-mediated upregulation, and Hsp27 knockdown by RNAi increases cell death in ATF5-expressing cells.","method":"ATF5 overexpression, Hsp27 promoter reporter assays, siRNA knockdown of Hsp27, heat shock survival assay","journal":"Cell Biology International","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — reporter and RNAi rescue in single cell line; direct ATF5 binding to Hsp27 promoter not confirmed by ChIP; single lab","pmids":["17606386"],"is_preprint":false},{"year":2010,"finding":"ATF5 activates the CHOP gene promoter via the amino acid response element 1 (AARE1) site in HepG2 cells. ATF5 knockdown reduces arsenite-induced CHOP protein expression and arsenite-induced cell death.","method":"Reporter gene assays with CHOP promoter deletions and AARE1 point mutations, ATF5 overexpression, siRNA knockdown","journal":"Life Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — reporter mutagenesis identifying AARE1 but no ChIP; knockdown functional validation; single lab","pmids":["20654631"],"is_preprint":false},{"year":2019,"finding":"Dominant-negative ATF5 (DN-ATF5) associates with CEBPB and CEBPD (basic leucine zipper proteins) and coiled-coil protein CCDC6, as identified by unbiased pull-down assays coupled with mass spectrometry. DN-ATF5 interferes with CEBPB and CEBPD transcriptional activity; knockdown of CEBPB or CEBPD promotes apoptosis of cancer cells but not normal astrocytes. Cancer cell death by DN-ATF5 occurs partly through suppression of CEBPB/CEBPD function independent of ATF5 itself.","method":"Pull-down assay followed by mass spectrometry, immunoblotting, CEBPB/CEBPD knockdown, reporter assays for CEBPB/CEBPD transcriptional activity","journal":"Molecular Cancer Research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — unbiased MS identification of interactors, validated by functional knockdown, reporter assays; single lab with multiple orthogonal methods","pmids":["31676720"],"is_preprint":false},{"year":2017,"finding":"HCMV immediate-early protein IE86 physically interacts with ATF5 and acetylates ATF5, thereby promoting glioma cell survival.","method":"Co-IP, immunohistochemistry, ATF5 acetylation assays, IE86 overexpression, glioma xenograft","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and acetylation demonstrated, functional glioma survival phenotype; single lab","pmids":["28473657"],"is_preprint":false},{"year":2013,"finding":"ASGR1 interacts with ATF5 (confirmed by Co-IP) and promotes ATF5 expression through NF-κB/IKBa phosphorylation, which in turn promotes monocyte-to-macrophage differentiation.","method":"Co-IP, ASGR1 knockdown/overexpression, western blot for NF-κB phosphorylation and ATF5 expression, THP-1 and bone marrow-derived macrophage models","journal":"Life Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP establishing physical interaction, pathway activation by loss-of-function; single lab","pmids":["36621538"],"is_preprint":false},{"year":2023,"finding":"TMEM11 directly interacts with METTL1 and enhances m7G methylation of Atf5 mRNA, thereby increasing ATF5 expression. Increased ATF5 then promotes transcription of Inca1 (an inhibitor of CDK-cyclin A1), suppressing cardiomyocyte proliferation. TMEM11 deletion enhances cardiomyocyte proliferation and cardiac regeneration.","method":"Co-IP (TMEM11-METTL1 interaction), m7G-MeRIP sequencing, ATF5 overexpression/knockdown, ChIP for ATF5 at Inca1 promoter, cardiomyocyte proliferation assays, mouse myocardial injury model","journal":"Cell Death and Differentiation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing TMEM11-METTL1 interaction, m7G-MeRIP confirming ATF5 mRNA modification, ChIP for ATF5 binding at Inca1 promoter, in vivo validation; single lab","pmids":["37286744"],"is_preprint":false},{"year":2022,"finding":"In skeletal muscle, ATF5 is required for proper mitochondrial quality control. ATF5 KO mice exhibit a larger but less functional mitochondrial pool, with enhanced biogenesis (increased PGC-1α), attenuated mitophagy, reduced antioxidant proteins, and increased ROS emission. Acute exercise causes ATF5 enrichment in mitochondrial fractions rather than nuclear translocation, and loss of ATF5 blunts the mitophagic and UPRmt gene expression response to exercise.","method":"ATF5 KO mice, fractionation (nuclear/cytosolic/mitochondrial), oxygen consumption, ROS emission, mRNA analysis, exercise challenge","journal":"Molecular Metabolism","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo KO with defined organelle fractionation showing exercise-induced mitochondrial localization, multiple functional readouts; single lab","pmids":["36332794"],"is_preprint":false},{"year":2020,"finding":"PRMT1 promotes neuroblastoma cell survival through ATF5 as a downstream effector. Overexpression of ATF5 rescues cell apoptosis triggered by PRMT1 inhibition genetically or pharmacologically, placing ATF5 downstream of PRMT1 in a prosurvival signaling pathway.","method":"PRMT1 depletion (siRNA/pharmacological), ATF5 overexpression rescue, apoptosis assays, sphere formation assays, in vivo xenograft","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established by ATF5 rescue of PRMT1 depletion phenotype; does not identify direct PRMT1-ATF5 molecular interaction; single lab","pmids":["32415090"],"is_preprint":false},{"year":2024,"finding":"METTL14 facilitates m6A modification of ATF5 mRNA, promoting its degradation. ATF5 overexpression (caused by METTL14 knockdown) increases WDR74 transcription and enhances β-catenin nuclear translocation, promoting cancer stemness in gastric cancer. Histone H3 lactylation at Lys18 upregulates METTL14 expression.","method":"m6A RNA immunoprecipitation (MeRIP), luciferase reporter assays, ChIP (ATF5 binding to WDR74 promoter), western blot for β-catenin, rescue experiments","journal":"Cancer Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP and reporter assays for m6A mechanism, ChIP for ATF5-WDR74 relationship; single lab","pmids":["39497511"],"is_preprint":false},{"year":2021,"finding":"ELF1 transcription factor directly binds and activates the ATF5 gene promoter in glioma cells, as confirmed by luciferase reporter assay and chromatin immunoprecipitation (ChIP). Silencing ELF1 inhibits glioma cell growth and migration with ATF5 involvement.","method":"Luciferase reporter assays, ChIP, ELF1 siRNA knockdown, cell proliferation and migration assays","journal":"ACS Chemical Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP confirming ELF1 at ATF5 promoter and functional knockdown; single lab","pmids":["33720698"],"is_preprint":false},{"year":2024,"finding":"In oocytes, AMPK suppression (by obesity) increases the binding affinity of the ATF5-POLG protein complex to mutated mtDNA D-loop and protein-coding regions, promoting replication of heteroplasmic mtDNA. AMPK activation prevents ATF5-POLG recruitment to mutated mtDNA, improving oocyte mitochondrial quality.","method":"Co-IP (ATF5-POLG interaction), AMPK knockout mice, mtDNA heteroplasmy sequencing, AMPK activator treatment, oocyte maturation assays","journal":"Advanced Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying ATF5-POLG complex, AMPK KO phenotype, pharmacological rescue; single lab","pmids":["38499990"],"is_preprint":false},{"year":2021,"finding":"ATF5 directly binds and stimulates the promoter of DVL1 gene (Wnt pathway component) in bladder cancer cells, activating the Wnt/β-catenin pathway. ATF5 promotes tumor sphere formation and cancer stemness through this mechanism.","method":"ChIP-qPCR, luciferase reporter assays, ATF5 overexpression/knockdown, sphere formation assays","journal":"Cancer Cell International","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP and reporter confirming direct ATF5-DVL1 promoter binding; single lab","pmids":["34895217"],"is_preprint":false},{"year":2019,"finding":"C/EBPγ and ATF5 co-expression (but not either alone) increases Vmn2r66 promoter reporter activity via the C/EBP:ATF response element (CARE), suggesting ATF5 and C/EBPγ act cooperatively as a heterodimer to drive V2r-type vomeronasal sensory neuron differentiation.","method":"Luciferase reporter assays in Neuro2a cells, co-expression experiments with C/EBPγ and ATF5, immunostaining in vomeronasal organ","journal":"Cell and Tissue Research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — reporter assay demonstrating cooperative transcriptional activity; dimerization not confirmed by direct biochemical interaction; single lab","pmids":["31309319"],"is_preprint":false},{"year":2013,"finding":"IL-1β increases ATF5 protein expression in HepG2 cells by two mechanisms: stabilization of ATF5 protein via its N-terminal hydrophobic domain, and increased translational efficiency via 5'-UTRα and eIF2α phosphorylation. ATF5 knockdown upregulates IL-1β-induced SAA1 and SAA2 expression, identifying ATF5 as a negative regulator of acute-phase gene expression.","method":"N-terminal deletion mutants, protein stability assays, 5'-UTR reporter assays, ATF5 siRNA knockdown, SAA1/2 expression analysis","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping and reporter assays for two distinct regulatory mechanisms, loss-of-function for downstream target; single lab","pmids":["24379400"],"is_preprint":false},{"year":2021,"finding":"ATF5 directly binds the CCAAT/enhancer-binding protein (C/EBP)-ATF response element (CARE) in the promoter region of the olfactory chaperone gene Rtp1, as demonstrated by ChIP in ATF5-HA knock-in mice. This establishes Rtp1 as a direct in vivo transcriptional target of ATF5 in olfactory sensory neurons.","method":"CRISPR/Cas9 HA-tag knock-in mice, ChIP with anti-HA antibody, in vivo olfactory epithelium analysis","journal":"Cell and Tissue Research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo ChIP from knock-in mice with endogenous ATF5-HA at specific gene locus; single lab but rigorous in vivo approach","pmids":["33825962"],"is_preprint":false},{"year":2022,"finding":"Intestinal ATF5 promotes a satiety response by transcriptionally regulating the gastrointestinal peptide hormone cholecystokinin (CCK), which promotes leptin secretion, thereby maintaining intestinal barrier function and preventing obesity-associated hyperglycemia and barrier dysfunction during enteric pathogen infection.","method":"Atf5-/- mice, intestinal barrier assays, enteric infection models, CCK reporter/expression analysis, leptin measurements","journal":"Cell Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockout with defined pathway from ATF5 to CCK to leptin to barrier function; transcriptional regulation of CCK by ATF5 shown but ChIP not detailed in abstract; single lab","pmids":["36516750"],"is_preprint":false}],"current_model":"ATF5 is a bZIP transcription factor regulated at multiple levels: its translation is preferentially induced during stress (ER stress, amino acid deprivation, oxidative stress) through eIF2α phosphorylation-dependent bypass of inhibitory uORFs in its 5'-UTRα, while its mRNA is also stabilized by suppression of nonsense-mediated decay; its protein stability is controlled by ubiquitin-proteasome degradation (via E2 enzyme Cdc34 and N-terminal ubiquitination) that is antagonized by HSP70 binding and promoted by NPM1, while NLK kinase and stress signals (cadmium, IL-1β) also stabilize ATF5; ATF5 is acetylated by p300 (at K29) to enhance its transcriptional activity at target gene promoters including EGR-1, BCL-2, MCL1, mTOR, CYP2B6, ASNS, Hsp27, DVL1, Rtp1, and CCK; at the centrosome ATF5 forms a structural ring connecting the mother centriole (via polyglutamylated tubulin) to PCM (via PCNT), regulated by cell-cycle-dependent SUMO2/3 modification; in the mitochondrial UPR, ATF5 traffics from mitochondria to the nucleus during organellar stress to activate a transcriptional program restoring proteostasis; and ATF5 is a key regulator of neural progenitor cell differentiation, olfactory sensory neuron maturation, and cancer cell survival, functioning through direct transcriptional regulation of anti-apoptotic targets including BCL-2 and MCL1, and cooperating with binding partners including CEBPB, CEBPD, and C/EBPγ."},"narrative":{"mechanistic_narrative":"ATF5 is a stress-responsive bZIP transcription factor that governs cell survival, organellar proteostasis, and progenitor cell fate, acting as a convergence point between translational stress signaling and transcriptional cell-fate decisions [PMID:18195013, PMID:18055463, PMID:12805299, PMID:27426517]. Its expression is controlled predominantly at the level of translation: the 5'-UTRα of ATF5 mRNA contains an inhibitory uORF2 that represses basal translation, and eIF2α phosphorylation during amino acid deprivation, ER stress, or oxidative stress causes ribosomes to bypass uORF2 and translate the coding region, a regulatory logic analogous to ATF4 [PMID:18195013, PMID:18055463]. The same uORF2-dependent translation event renders the transcript a substrate of nonsense-mediated decay under basal conditions, so eIF2α phosphorylation simultaneously stabilizes the mRNA, coupling translational and decay control [PMID:23876217]. ATF5 transcription is itself driven by stress effectors including CHOP and ATF4, the ER-stress transducer BBF2H7, and lineage factors such as PDX1, forming feed-forward loops that amplify the stress response [PMID:23761072, PMID:22936798, PMID:28115692]. Protein abundance is set by ubiquitin-proteasome degradation initiated through N-terminal ubiquitination and the E2 enzyme Cdc34, antagonized by HSP70 binding to the N-terminal activation domain and promoted by nucleophosmin (NPM1), which displaces HSP70; NLK and stress signals further stabilize the protein [PMID:18458088, PMID:21521685, PMID:22528486, PMID:25512613]. As a transcription factor ATF5 drives a prosurvival program, directly activating anti-apoptotic targets MCL1 and BCL-2 in cancer cells, mTOR, Hsp27, and ASNS, and its activity is enhanced by p300-mediated acetylation at K29 [PMID:20495567, PMID:21212266, PMID:21715304, PMID:21791614, PMID:16164412]. ATF5 mediates the mitochondrial unfolded protein response, partitioning between mitochondria and nucleus so that during organellar stress a fraction traffics to the nucleus to induce a proteostasis-restoring gene set, a function required for cardioprotection and skeletal-muscle mitochondrial quality control in vivo [PMID:27426517, PMID:31274354, PMID:36332794]. Beyond its transcriptional role, ATF5 is a structural component of the centrosome, forming a 9-fold symmetric ring that links polyglutamylated tubulin on the mother centriole to PCNT in the pericentriolar material, with its centrosomal residence gated by cell-cycle-dependent SUMO2/3 modification [PMID:26213385, PMID:29326161]. In development, ATF5 maintains neural and oligodendrocyte progenitors in an undifferentiated state and is required for terminal differentiation and survival of olfactory sensory neurons, where it directly regulates targets including Rtp1 and cooperates with C/EBP family partners [PMID:12805299, PMID:15950153, PMID:23090999, PMID:33825962, PMID:31309319].","teleology":[{"year":2003,"claim":"Established ATF5 as a brake on neural progenitor differentiation, defining its first developmental role and showing it acts through repression of CRE-dependent transcription.","evidence":"Gain-of-function, dominant-negative, and siRNA manipulation with NGF treatment and CRE reporters in PC12 and telencephalic cells","pmids":["12805299"],"confidence":"High","gaps":["Direct in vivo target genes not identified","Mechanism of CRE repression unresolved"]},{"year":2007,"claim":"Defined how ATF5 abundance is tuned to stress, showing alternative 5'-UTRs and an inhibitory uORF2 confer eIF2α-phosphorylation-dependent translational induction.","evidence":"Reporter assays with 5'-UTR variants and uORF mutations plus eIF2α phosphorylation analysis","pmids":["18055463"],"confidence":"High","gaps":["Did not address mRNA stability layer","Endogenous protein induction quantified only indirectly"]},{"year":2008,"claim":"Resolved the uORF reinitiation logic mechanistically and linked basal expression to ATF4, placing ATF5 in an integrated stress response cascade.","evidence":"Polyribosome fractionation, uORF mutant reporters, ATF4-/- MEFs, and pharmacological eIF2 kinase activation","pmids":["18195013","18055463"],"confidence":"High","gaps":["Quantitative contribution of transcriptional vs translational control in vivo unclear"]},{"year":2008,"claim":"Identified the degradation arm of ATF5 control, showing proteasomal turnover via N-terminal ubiquitination and the E2 enzyme Cdc34.","evidence":"Ubiquitination assays, N-terminal methionine mutants, Cdc34 Co-IP, and cisplatin treatment","pmids":["18458088"],"confidence":"Medium","gaps":["E3 ligase not identified","N-terminal ubiquitination inferred from deletion mutants","Single lab"]},{"year":2010,"claim":"Demonstrated that oncogenic signaling drives ATF5 to enforce cancer cell survival via direct anti-apoptotic transcription, identifying MCL1 as a key target.","evidence":"Genome-wide RNAi screen, ChIP, and reporter assays in glioma samples and mouse models","pmids":["20495567"],"confidence":"High","gaps":["Generality of CREB3L2-ATF5 axis beyond glioma untested","Other survival targets not enumerated here"]},{"year":2011,"claim":"Defined ATF5's prosurvival transcriptional program in detail — direct BCL-2 and mTOR activation — and revealed cancer-cell-specific target regulation.","evidence":"ChIP, EMSA, reporter assays, knockdown/rescue in glioma, breast cancer, and BCR-ABL cells","pmids":["21212266","21715304"],"confidence":"High","gaps":["Basis of cancer-cell-specific BCL-2 regulation not molecularly resolved","In vivo target occupancy not shown"]},{"year":2011,"claim":"Established post-translational control of ATF5 stability and activity, showing HSP70 binding protects it from degradation and p300 acetylation at K29 boosts its transcriptional output.","evidence":"Reciprocal Co-IP, ATP-dependence and domain mapping, in vitro acetylation, K29 mutagenesis, and ChIP","pmids":["21521685","21791614"],"confidence":"High","gaps":["Stoichiometry and dynamics of HSP70/acetylation in vivo unclear","Deacetylase not identified"]},{"year":2012,"claim":"Identified NPM1 as a destabilizer that antagonizes HSP70, and demonstrated ATF5's requirement for olfactory sensory neuron maturation in vivo, unifying its survival and differentiation roles.","evidence":"TAP-MS, Co-IP and domain mapping for NPM1; Atf5-/- mice with OSN markers and ectopic expression","pmids":["22528486","23090999"],"confidence":"High","gaps":["NPM1/HSP70 competition not reconstituted in vitro","Direct OSN target genes not defined in this work"]},{"year":2013,"claim":"Showed ATF5 can act as a pro-apoptotic effector during severe stress and is a substrate of NMD, integrating decay control with the eIF2α translational switch.","evidence":"ChIP, transcriptome profiling, NMD factor (Upf1/Upf2) knockdown, and mRNA stability assays under stress","pmids":["23761072","23876217"],"confidence":"High","gaps":["Determinants of pro-survival vs pro-apoptotic ATF5 outputs unresolved","NOXA induction mechanism not detailed"]},{"year":2015,"claim":"Revealed an unexpected non-transcriptional role: ATF5 is a structural centrosomal protein bridging the mother centriole to the pericentriolar material, required for genome stability.","evidence":"Super-resolution microscopy showing 9-fold symmetry, Co-IP with polyglutamylated tubulin and PCNT, and RNAi depletion phenotypes","pmids":["26213385"],"confidence":"High","gaps":["How the bZIP transcription factor is repurposed structurally unknown","Relationship between centrosomal and nuclear pools unclear"]},{"year":2016,"claim":"Defined ATF5 as the mammalian UPRmt regulator, functionally orthologous to C. elegans ATFS-1, governed by mitochondria-to-nucleus partitioning.","evidence":"Cellular fractionation, cross-species genetic rescue in atfs-1 worms, mammalian siRNA, and reporter assays","pmids":["27426517"],"confidence":"High","gaps":["Molecular sensor controlling mitochondrial import vs nuclear trafficking not defined","Full UPRmt target set incomplete"]},{"year":2018,"claim":"Showed SUMO2/3 modification cyclically gates ATF5's centrosomal residence across the cell cycle, coupling its post-translational state to the centrosome cycle.","evidence":"SUMO modification assays, cell-cycle synchronization, SUMO-site mutant, and Co-IP with centrosomal proteins","pmids":["29326161"],"confidence":"High","gaps":["SUMO E3 ligase and protease not identified","Crosstalk with the transcriptional/UPRmt roles unexplored"]},{"year":2019,"claim":"Validated ATF5's UPRmt and survival functions physiologically, demonstrating it is required for cardioprotection in vivo, and mapped its interface with the C/EBP family.","evidence":"Atf5-/- mice with ischemia-reperfusion and RNA-Seq; pull-down/MS identifying CEBPB, CEBPD, CCDC6 with functional knockdown","pmids":["31274354","31676720"],"confidence":"High","gaps":["Identity of ATF5 dimerization partners in each context not fully resolved","Cardioprotective gene set not mechanistically dissected"]},{"year":2023,"claim":"Extended ATF5 regulation to RNA modification, showing m7G methylation of Atf5 mRNA controls its expression to restrain cardiomyocyte proliferation.","evidence":"Co-IP (TMEM11-METTL1), m7G-MeRIP-seq, ChIP for ATF5 at the Inca1 promoter, and a mouse myocardial injury model","pmids":["37286744"],"confidence":"High","gaps":["Direct effect of m7G on ATF5 translation vs stability not separated","Generality beyond cardiac context untested"]},{"year":null,"claim":"How ATF5 partitions among its mitochondrial, centrosomal, and nuclear pools, and what molecular switch selects between its prosurvival and pro-apoptotic transcriptional outputs, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model linking bZIP and centrosomal functions","Sensor controlling mitochondrial import vs nuclear trafficking unknown","Determinants of survival vs death transcriptional programs undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,5,6,7,8,10,16,20,21,23,40]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[8,10,25,37,40]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[14]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[14]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,10,32]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,32,36]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[14,15]}],"pathway":[{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,1,2,4,18,32]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,6,8,10,16,20,21]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3,6,8,16,24]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[14,15,25,31]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,16,17,38,40]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,2,9,11,13,19]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[14,0,32]}],"complexes":["centrosome/pericentriolar material ring"],"partners":["HSP70","NPM1","CDC34","NLK","PCNT","CEBPB","CEBPD","POLG"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y2D1","full_name":"Cyclic AMP-dependent transcription factor ATF-5","aliases":["Activating transcription factor 5","Transcription factor ATFx"],"length_aa":282,"mass_kda":30.7,"function":"Transcription factor that either stimulates or represses gene transcription through binding of different DNA regulatory elements such as cAMP response element (CRE) (consensus: 5'-GTGACGT[AC][AG]-3'), ATF5-specific response element (ARE) (consensus: 5'-C[CT]TCT[CT]CCTT[AT]-3') but also the amino acid response element (AARE), present in many viral and cellular promoters. Critically involved, often in a cell type-dependent manner, in cell survival, proliferation, and differentiation (PubMed:10373550, PubMed:15358120, PubMed:20654631, PubMed:21212266). Its transcriptional activity is enhanced by CCND3 and slightly inhibited by CDK4 (PubMed:15358120). Important regulator of the cerebral cortex formation, functions in cerebral cortical neuroprogenitor cells to maintain proliferation and to block differentiation into neurons. Must be down-regulated in order for such cells to exit the cycle and differentiate (By similarity). Participates in the pathways by which SHH promotes cerebellar granule neuron progenitor cells proliferation (By similarity). Critical for survival of mature olfactory sensory neurons (OSN), directs expression of OSN-specific genes (By similarity). May be involved in osteogenic differentiation (PubMed:22442021). Promotes cell proliferation and survival by inducing the expression of EGR1 sinergistically with ELK1. Once acetylated by EP300, binds to ARE sequences on target genes promoters, such as BCL2 and EGR1 (PubMed:21791614). Plays an anti-apoptotic role through the transcriptional regulation of BCL2, this function seems to be cell type-dependent (By similarity). Cooperates with NR1I3/CAR in the transcriptional activation of CYP2B6 in liver (PubMed:18332083). In hepatic cells, represses CRE-dependent transcription and inhibits proliferation by blocking at G2/M phase (PubMed:18701499, PubMed:22528486). May act as a negative regulator of IL1B transduction pathway in liver (PubMed:24379400). Upon IL1B stimulus, cooperates with NLK to activate the transactivation activity of C/EBP subfamily members (PubMed:25512613). Besides its function of transcription factor, acts as a cofactor of CEBPB to activate CEBPA and promote adipocyte differentiation (PubMed:24216764). Regulates centrosome dynamics in a cell-cycle- and centriole-age-dependent manner. Forms 9-foci symmetrical ring scaffold around the mother centriole to control centrosome function and the interaction between centrioles and pericentriolar material (PubMed:26213385)","subcellular_location":"Cytoplasm; Nucleus; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/Q9Y2D1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ATF5","classification":"Not Classified","n_dependent_lines":16,"n_total_lines":1208,"dependency_fraction":0.013245033112582781},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ATF5","total_profiled":1310},"omim":[{"mim_id":"615903","title":"COILED-COIL-HELIX-COILED-COIL-HELIX DOMAIN-CONTAINING PROTEIN 10; CHCHD10","url":"https://www.omim.org/entry/615903"},{"mim_id":"606398","title":"ACTIVATING TRANSCRIPTION FACTOR 5; ATF5","url":"https://www.omim.org/entry/606398"},{"mim_id":"605210","title":"DISC1 SCAFFOLD PROTEIN; DISC1","url":"https://www.omim.org/entry/605210"},{"mim_id":"137800","title":"GLIOMA SUSCEPTIBILITY 1; GLM1","url":"https://www.omim.org/entry/137800"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":2375.4}],"url":"https://www.proteinatlas.org/search/ATF5"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9Y2D1","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y2D1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y2D1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y2D1-F1-predicted_aligned_error_v6.png","plddt_mean":67.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATF5","jax_strain_url":"https://www.jax.org/strain/search?query=ATF5"},"sequence":{"accession":"Q9Y2D1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y2D1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y2D1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y2D1"}},"corpus_meta":[{"pmid":"27426517","id":"PMC_27426517","title":"The Transcription Factor ATF5 Mediates a Mammalian Mitochondrial UPR.","date":"2016","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/27426517","citation_count":539,"is_preprint":false},{"pmid":"18195013","id":"PMC_18195013","title":"Phosphorylation of eIF2 directs ATF5 translational control in response to diverse stress conditions.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18195013","citation_count":248,"is_preprint":false},{"pmid":"23761072","id":"PMC_23761072","title":"CHOP induces activating transcription factor 5 (ATF5) to trigger apoptosis in response to perturbations in protein homeostasis.","date":"2013","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/23761072","citation_count":193,"is_preprint":false},{"pmid":"20495567","id":"PMC_20495567","title":"A genome-wide RNA interference screen reveals an essential CREB3L2-ATF5-MCL1 survival pathway in malignant glioma with therapeutic implications.","date":"2010","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/20495567","citation_count":151,"is_preprint":false},{"pmid":"18055463","id":"PMC_18055463","title":"Stress-induced translation of ATF5 mRNA is regulated by the 5'-untranslated region.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18055463","citation_count":119,"is_preprint":false},{"pmid":"21715304","id":"PMC_21715304","title":"BCR-ABL suppresses autophagy through ATF5-mediated regulation of mTOR transcription.","date":"2011","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/21715304","citation_count":119,"is_preprint":false},{"pmid":"12805299","id":"PMC_12805299","title":"Regulated expression of ATF5 is required for the progression of neural progenitor cells to neurons.","date":"2003","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/12805299","citation_count":116,"is_preprint":false},{"pmid":"31274354","id":"PMC_31274354","title":"Cardioprotection by the mitochondrial unfolded protein response requires ATF5.","date":"2019","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/31274354","citation_count":115,"is_preprint":false},{"pmid":"28499833","id":"PMC_28499833","title":"Mitochondrial dysfunction in cancer: Potential roles of ATF5 and the mitochondrial UPR.","date":"2017","source":"Seminars in cancer biology","url":"https://pubmed.ncbi.nlm.nih.gov/28499833","citation_count":95,"is_preprint":false},{"pmid":"17266024","id":"PMC_17266024","title":"The transcription factor ATF5 is widely expressed in carcinomas, and interference with its function selectively kills neoplastic, but not nontransformed, breast cell lines.","date":"2007","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/17266024","citation_count":79,"is_preprint":false},{"pmid":"16170340","id":"PMC_16170340","title":"Selective destruction of glioblastoma cells by interference with the activity or expression of ATF5.","date":"2006","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/16170340","citation_count":77,"is_preprint":false},{"pmid":"21212266","id":"PMC_21212266","title":"BCL-2 is a downstream target of ATF5 that mediates the prosurvival function of ATF5 in a cell type-dependent manner.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21212266","citation_count":77,"is_preprint":false},{"pmid":"19046351","id":"PMC_19046351","title":"The transcription factor ATF5: role in neurodevelopment and neural tumors.","date":"2008","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19046351","citation_count":73,"is_preprint":false},{"pmid":"27126996","id":"PMC_27126996","title":"A Synthetic Cell-Penetrating Dominant-Negative ATF5 Peptide Exerts Anticancer Activity against a Broad Spectrum of Treatment-Resistant Cancers.","date":"2016","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/27126996","citation_count":67,"is_preprint":false},{"pmid":"15950153","id":"PMC_15950153","title":"ATF5 regulates the proliferation and differentiation of oligodendrocytes.","date":"2005","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/15950153","citation_count":63,"is_preprint":false},{"pmid":"28115692","id":"PMC_28115692","title":"ATF5 regulates β-cell survival during stress.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28115692","citation_count":54,"is_preprint":false},{"pmid":"29137451","id":"PMC_29137451","title":"The transcription factor ATF5: role in cellular differentiation, stress responses, and cancer.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29137451","citation_count":54,"is_preprint":false},{"pmid":"21521685","id":"PMC_21521685","title":"HSP70 protein promotes survival of C6 and U87 glioma cells by inhibition of ATF5 degradation.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21521685","citation_count":53,"is_preprint":false},{"pmid":"23518711","id":"PMC_23518711","title":"Protective neuronal induction of ATF5 in endoplasmic reticulum stress induced by status epilepticus.","date":"2013","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/23518711","citation_count":51,"is_preprint":false},{"pmid":"18332083","id":"PMC_18332083","title":"ATF5 is a highly abundant liver-enriched transcription factor that cooperates with constitutive androstane receptor in the transactivation of CYP2B6: implications in hepatic stress responses.","date":"2008","source":"Drug metabolism and disposition: the biological fate of chemicals","url":"https://pubmed.ncbi.nlm.nih.gov/18332083","citation_count":51,"is_preprint":false},{"pmid":"25517360","id":"PMC_25517360","title":"Integrated analyses of DNA methylation and hydroxymethylation reveal tumor suppressive roles of ECM1, ATF5, and EOMES in human hepatocellular carcinoma.","date":"2014","source":"Genome biology","url":"https://pubmed.ncbi.nlm.nih.gov/25517360","citation_count":49,"is_preprint":false},{"pmid":"12213205","id":"PMC_12213205","title":"Mouse Atf5: molecular cloning of two novel mRNAs, genomic organization, and odorant sensory neuron localization.","date":"2002","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/12213205","citation_count":49,"is_preprint":false},{"pmid":"29192290","id":"PMC_29192290","title":"Direct conversion of human fibroblasts into hepatocyte-like cells by ATF5, PROX1, FOXA2, FOXA3, and HNF4A transduction.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29192290","citation_count":48,"is_preprint":false},{"pmid":"36621538","id":"PMC_36621538","title":"ASGR1 promotes liver injury in sepsis by modulating monocyte-to-macrophage differentiation via NF-κB/ATF5 pathway.","date":"2023","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36621538","citation_count":47,"is_preprint":false},{"pmid":"23090999","id":"PMC_23090999","title":"Transcription factor ATF5 is required for terminal differentiation and survival of olfactory sensory neurons.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/23090999","citation_count":47,"is_preprint":false},{"pmid":"21791614","id":"PMC_21791614","title":"p300-Dependent ATF5 acetylation is essential for Egr-1 gene activation and cell proliferation and survival.","date":"2011","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21791614","citation_count":46,"is_preprint":false},{"pmid":"21972289","id":"PMC_21972289","title":"ATF5 polymorphisms influence ATF function and response to treatment in children with childhood acute lymphoblastic leukemia.","date":"2011","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/21972289","citation_count":46,"is_preprint":false},{"pmid":"16164412","id":"PMC_16164412","title":"Regulation of asparagine synthetase gene transcription by the basic region leucine zipper transcription factors ATF5 and CHOP.","date":"2005","source":"Biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16164412","citation_count":46,"is_preprint":false},{"pmid":"37286744","id":"PMC_37286744","title":"TMEM11 regulates cardiomyocyte proliferation and cardiac repair via METTL1-mediated m7G methylation of ATF5 mRNA.","date":"2023","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/37286744","citation_count":44,"is_preprint":false},{"pmid":"22528486","id":"PMC_22528486","title":"Nucleophosmin (NPM1/B23) interacts with activating transcription factor 5 (ATF5) protein and promotes proteasome- and caspase-dependent ATF5 degradation in hepatocellular carcinoma cells.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22528486","citation_count":44,"is_preprint":false},{"pmid":"31676720","id":"PMC_31676720","title":"Dominant-Negative ATF5 Compromises Cancer Cell Survival by Targeting CEBPB and CEBPD.","date":"2019","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/31676720","citation_count":38,"is_preprint":false},{"pmid":"33425220","id":"PMC_33425220","title":"Novel PGC-1α/ATF5 Axis Partly Activates UPRmt and Mediates Cardioprotective Role of Tetrahydrocurcumin in Pathological Cardiac Hypertrophy.","date":"2020","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/33425220","citation_count":37,"is_preprint":false},{"pmid":"17606386","id":"PMC_17606386","title":"ATF5 promotes cell survival through transcriptional activation of Hsp27 in H9c2 cells.","date":"2007","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/17606386","citation_count":37,"is_preprint":false},{"pmid":"23018213","id":"PMC_23018213","title":"ATF5 is overexpressed in epithelial ovarian carcinomas and interference with its function increases apoptosis through the downregulation of Bcl-2 in SKOV-3 cells.","date":"2012","source":"International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists","url":"https://pubmed.ncbi.nlm.nih.gov/23018213","citation_count":37,"is_preprint":false},{"pmid":"17140605","id":"PMC_17140605","title":"Amino acid limitation induces expression of ATF5 mRNA at the post-transcriptional level.","date":"2006","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/17140605","citation_count":36,"is_preprint":false},{"pmid":"35988140","id":"PMC_35988140","title":"ER, Mitochondria, and ISR Regulation by mt-HSP70 and ATF5 upon Procollagen Misfolding in Osteoblasts.","date":"2022","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/35988140","citation_count":35,"is_preprint":false},{"pmid":"18701499","id":"PMC_18701499","title":"Re-expression of transcription factor ATF5 in hepatocellular carcinoma induces G2-M arrest.","date":"2008","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/18701499","citation_count":35,"is_preprint":false},{"pmid":"26679606","id":"PMC_26679606","title":"Hepatic maturation of human iPS cell-derived hepatocyte-like cells by ATF5, c/EBPα, and PROX1 transduction.","date":"2015","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/26679606","citation_count":35,"is_preprint":false},{"pmid":"23060563","id":"PMC_23060563","title":"Interference with ATF5 function enhances the sensitivity of human pancreatic cancer cells to paclitaxel-induced apoptosis.","date":"2012","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/23060563","citation_count":35,"is_preprint":false},{"pmid":"26213385","id":"PMC_26213385","title":"ATF5 Connects the Pericentriolar Materials to the Proximal End of the Mother Centriole.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26213385","citation_count":33,"is_preprint":false},{"pmid":"22936798","id":"PMC_22936798","title":"The endoplasmic reticulum stress transducer BBF2H7 suppresses apoptosis by activating the ATF5-MCL1 pathway in growth plate cartilage.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22936798","citation_count":33,"is_preprint":false},{"pmid":"23876217","id":"PMC_23876217","title":"The 5'-untranslated region regulates ATF5 mRNA stability via nonsense-mediated mRNA decay in response to environmental stress.","date":"2013","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/23876217","citation_count":32,"is_preprint":false},{"pmid":"37095454","id":"PMC_37095454","title":"ATF5 regulates tubulointerstitial injury in diabetic kidney disease via mitochondrial unfolded protein response.","date":"2023","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/37095454","citation_count":31,"is_preprint":false},{"pmid":"28718401","id":"PMC_28718401","title":"Targeting ATF5 in Cancer.","date":"2017","source":"Trends in cancer","url":"https://pubmed.ncbi.nlm.nih.gov/28718401","citation_count":30,"is_preprint":false},{"pmid":"32415090","id":"PMC_32415090","title":"PRMT1 promotes neuroblastoma cell survival through ATF5.","date":"2020","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/32415090","citation_count":30,"is_preprint":false},{"pmid":"21725368","id":"PMC_21725368","title":"Regulated ATF5 loss-of-function in adult mice blocks formation and causes regression/eradication of gliomas.","date":"2011","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/21725368","citation_count":30,"is_preprint":false},{"pmid":"27125458","id":"PMC_27125458","title":"Role of ATF5 in the invasive potential of diverse human cancer cell lines.","date":"2016","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/27125458","citation_count":29,"is_preprint":false},{"pmid":"38626424","id":"PMC_38626424","title":"Engineered Exosomes with ATF5-Modified mRNA Loaded in Injectable Thermogels Alleviate Osteoarthritis by Targeting the Mitochondrial Unfolded Protein Response.","date":"2024","source":"ACS applied materials & interfaces","url":"https://pubmed.ncbi.nlm.nih.gov/38626424","citation_count":28,"is_preprint":false},{"pmid":"20654631","id":"PMC_20654631","title":"Regulation of the human CHOP gene promoter by the stress response transcription factor ATF5 via the AARE1 site in human hepatoma HepG2 cells.","date":"2010","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/20654631","citation_count":26,"is_preprint":false},{"pmid":"30584325","id":"PMC_30584325","title":"Expression of activating transcription factor 5 (ATF5) is increased in astrocytomas of different WHO grades and correlates with survival of glioblastoma patients.","date":"2018","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/30584325","citation_count":24,"is_preprint":false},{"pmid":"26863637","id":"PMC_26863637","title":"Regression/eradication of gliomas in mice by a systemically-deliverable ATF5 dominant-negative peptide.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26863637","citation_count":24,"is_preprint":false},{"pmid":"36831248","id":"PMC_36831248","title":"Targeting Transcription Factors ATF5, CEBPB and CEBPD with Cell-Penetrating Peptides to Treat Brain and Other Cancers.","date":"2023","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/36831248","citation_count":23,"is_preprint":false},{"pmid":"30303867","id":"PMC_30303867","title":"Propofol Regulates Neural Stem Cell Proliferation and Differentiation via Calmodulin-Dependent Protein Kinase II/AMPK/ATF5 Signaling Axis.","date":"2019","source":"Anesthesia and analgesia","url":"https://pubmed.ncbi.nlm.nih.gov/30303867","citation_count":23,"is_preprint":false},{"pmid":"33720698","id":"PMC_33720698","title":"ELF1 Transcription Factor Enhances the Progression of Glioma via ATF5 promoter.","date":"2021","source":"ACS chemical neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/33720698","citation_count":22,"is_preprint":false},{"pmid":"25512613","id":"PMC_25512613","title":"Stabilization of ATF5 by TAK1-Nemo-like kinase critically regulates the interleukin-1β-stimulated C/EBP signaling pathway.","date":"2014","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/25512613","citation_count":22,"is_preprint":false},{"pmid":"18458088","id":"PMC_18458088","title":"Cdc34-mediated degradation of ATF5 is blocked by cisplatin.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18458088","citation_count":22,"is_preprint":false},{"pmid":"36332794","id":"PMC_36332794","title":"ATF5 is a regulator of exercise-induced mitochondrial quality control in skeletal muscle.","date":"2022","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/36332794","citation_count":21,"is_preprint":false},{"pmid":"38913800","id":"PMC_38913800","title":"ATF5-Mediated Mitochondrial Unfolded Protein Response (UPRmt) Protects Neurons Against Oxygen-Glucose Deprivation and Cerebral Ischemia.","date":"2024","source":"Stroke","url":"https://pubmed.ncbi.nlm.nih.gov/38913800","citation_count":19,"is_preprint":false},{"pmid":"34262025","id":"PMC_34262025","title":"ATF5, a putative therapeutic target for the mitochondrial DNA 3243A > G mutation-related disease.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/34262025","citation_count":19,"is_preprint":false},{"pmid":"31551409","id":"PMC_31551409","title":"Dominant-negative ATF5 rapidly depletes survivin in tumor cells.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/31551409","citation_count":19,"is_preprint":false},{"pmid":"22442021","id":"PMC_22442021","title":"ATF5, a possible regulator of osteogenic differentiation in human adipose-derived stem cells.","date":"2012","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22442021","citation_count":19,"is_preprint":false},{"pmid":"39497511","id":"PMC_39497511","title":"METTL14 attenuates cancer stemness by suppressing ATF5/WDR74/β-catenin axis in gastric cancer.","date":"2024","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/39497511","citation_count":18,"is_preprint":false},{"pmid":"16300731","id":"PMC_16300731","title":"ATF5 increases cisplatin-induced apoptosis through up-regulation of cyclin D3 transcription in HeLa cells.","date":"2005","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/16300731","citation_count":18,"is_preprint":false},{"pmid":"38278820","id":"PMC_38278820","title":"CTRP3 alleviates mitochondrial dysfunction and oxidative stress injury in pathological cardiac hypertrophy by activating UPRmt via the SIRT1/ATF5 axis.","date":"2024","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/38278820","citation_count":18,"is_preprint":false},{"pmid":"28861715","id":"PMC_28861715","title":"The neuroprotective transcription factor ATF5 is decreased and sequestered into polyglutamine inclusions in Huntington's disease.","date":"2017","source":"Acta neuropathologica","url":"https://pubmed.ncbi.nlm.nih.gov/28861715","citation_count":17,"is_preprint":false},{"pmid":"28473657","id":"PMC_28473657","title":"Human cytomegalovirus immediate-early protein promotes survival of glioma cells through interacting and acetylating ATF5.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28473657","citation_count":17,"is_preprint":false},{"pmid":"33640883","id":"PMC_33640883","title":"Maf1 suppression of ATF5-dependent mitochondrial unfolded protein response contributes to rapamycin-induced radio-sensitivity in lung cancer cell line A549.","date":"2021","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/33640883","citation_count":17,"is_preprint":false},{"pmid":"26395637","id":"PMC_26395637","title":"Activating transcription factor 5 (ATF5) is essential for the maturation and survival of mouse basal vomeronasal sensory neurons.","date":"2015","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/26395637","citation_count":17,"is_preprint":false},{"pmid":"33980247","id":"PMC_33980247","title":"ATF5 and HIF1α cooperatively activate HIF1 signaling pathway in esophageal cancer.","date":"2021","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/33980247","citation_count":16,"is_preprint":false},{"pmid":"17346882","id":"PMC_17346882","title":"Association analysis of ATF4 and ATF5, genes for interacting-proteins of DISC1, in bipolar disorder.","date":"2007","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/17346882","citation_count":16,"is_preprint":false},{"pmid":"36834738","id":"PMC_36834738","title":"ATF5 Attenuates the Secretion of Pro-Inflammatory Cytokines in Activated Microglia.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36834738","citation_count":15,"is_preprint":false},{"pmid":"34895217","id":"PMC_34895217","title":"Activating transcription factor 5 (ATF5) promotes tumorigenic capability and activates the Wnt/b-catenin pathway in bladder cancer.","date":"2021","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/34895217","citation_count":15,"is_preprint":false},{"pmid":"19285020","id":"PMC_19285020","title":"Cadmium interferes with the degradation of ATF5 via a post-ubiquitination step of the proteasome degradation pathway.","date":"2009","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/19285020","citation_count":15,"is_preprint":false},{"pmid":"38223508","id":"PMC_38223508","title":"ATF5 promotes malignant T cell survival through the PI3K/AKT/mTOR pathway in cutaneous T cell lymphoma.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38223508","citation_count":14,"is_preprint":false},{"pmid":"37847329","id":"PMC_37847329","title":"ATF5-regulated Mitochondrial Unfolded Protein Response Attenuates Neuronal Damage in Epileptic Rat by Reducing Endoplasmic Reticulum Stress Through Mitochondrial ROS.","date":"2023","source":"Neurochemical research","url":"https://pubmed.ncbi.nlm.nih.gov/37847329","citation_count":14,"is_preprint":false},{"pmid":"35939173","id":"PMC_35939173","title":"ATF5 Attenuates Apoptosis in Hippocampal Neurons with Seizures Evoked by Mg2+-Free Medium via Regulating Mitochondrial Unfolded Protein Response.","date":"2022","source":"Neurochemical research","url":"https://pubmed.ncbi.nlm.nih.gov/35939173","citation_count":14,"is_preprint":false},{"pmid":"39153513","id":"PMC_39153513","title":"Salvianolic acid B improves mitochondrial dysfunction of septic cardiomyopathy via enhancing ATF5-mediated mitochondrial unfolded protein response.","date":"2024","source":"Toxicology and applied pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39153513","citation_count":14,"is_preprint":false},{"pmid":"39719538","id":"PMC_39719538","title":"Trimethylamine-N-oxide accelerates osteoporosis by PERK activation of ATF5 unfolding.","date":"2024","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/39719538","citation_count":13,"is_preprint":false},{"pmid":"36516750","id":"PMC_36516750","title":"The mitochondrial UPR regulator ATF5 promotes intestinal barrier function via control of the satiety response.","date":"2022","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/36516750","citation_count":13,"is_preprint":false},{"pmid":"38472656","id":"PMC_38472656","title":"The mitochondrial UPR induced by ATF5 attenuates intervertebral disc degeneration via cooperating with mitophagy.","date":"2024","source":"Cell biology and toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/38472656","citation_count":12,"is_preprint":false},{"pmid":"28480569","id":"PMC_28480569","title":"Expression and targeting of transcription factor ATF5 in dog gliomas.","date":"2017","source":"Veterinary and comparative oncology","url":"https://pubmed.ncbi.nlm.nih.gov/28480569","citation_count":12,"is_preprint":false},{"pmid":"38499990","id":"PMC_38499990","title":"AMPK Suppression Due to Obesity Drives Oocyte mtDNA Heteroplasmy via ATF5-POLG Axis.","date":"2024","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/38499990","citation_count":12,"is_preprint":false},{"pmid":"37913858","id":"PMC_37913858","title":"ATF5 Attenuates Low-magnesium-induced Apoptosis by Inhibiting Endoplasmic Reticulum Stress Via the Regulation of Mitochondrial Reactive Oxygen Species.","date":"2023","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/37913858","citation_count":12,"is_preprint":false},{"pmid":"22095825","id":"PMC_22095825","title":"Reciprocal actions of ATF5 and Shh in proliferation of cerebellar granule neuron progenitor cells.","date":"2012","source":"Developmental neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/22095825","citation_count":12,"is_preprint":false},{"pmid":"29326161","id":"PMC_29326161","title":"SUMO2/3 modification of activating transcription factor 5 (ATF5) controls its dynamic translocation at the centrosome.","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29326161","citation_count":12,"is_preprint":false},{"pmid":"33790322","id":"PMC_33790322","title":"ATF5 deficiency causes abnormal cortical development.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33790322","citation_count":11,"is_preprint":false},{"pmid":"19293535","id":"PMC_19293535","title":"Novel function of transcription factor ATF5: blockade of p53-dependent apoptosis induced by ionizing irradiation.","date":"2009","source":"Cell structure and function","url":"https://pubmed.ncbi.nlm.nih.gov/19293535","citation_count":11,"is_preprint":false},{"pmid":"39283723","id":"PMC_39283723","title":"GDF-15 Predicts Epithelioid Hemangioendothelioma Aggressiveness and Is Downregulated by Sirolimus through ATF4/ATF5 Suppression.","date":"2024","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/39283723","citation_count":10,"is_preprint":false},{"pmid":"24379400","id":"PMC_24379400","title":"N-terminal hydrophobic amino acids of activating transcription factor 5 (ATF5) protein confer interleukin 1β (IL-1β)-induced stabilization.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24379400","citation_count":10,"is_preprint":false},{"pmid":"31309319","id":"PMC_31309319","title":"Co-expression of C/EBPγ and ATF5 in mouse vomeronasal sensory neurons during early postnatal development.","date":"2019","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/31309319","citation_count":9,"is_preprint":false},{"pmid":"20423929","id":"PMC_20423929","title":"Identification and characterization of the promoter of human ATF5 gene.","date":"2010","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20423929","citation_count":9,"is_preprint":false},{"pmid":"40124511","id":"PMC_40124511","title":"Stiff extracellular matrix activates the transcription factor ATF5 to promote the proliferation of cancer cells.","date":"2025","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/40124511","citation_count":8,"is_preprint":false},{"pmid":"36436799","id":"PMC_36436799","title":"ATF5 is a regulator of ER stress and β-cell apoptosis in different mouse models of genetic- and diet-induced obesity and diabetes mellitus.","date":"2022","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/36436799","citation_count":8,"is_preprint":false},{"pmid":"34611283","id":"PMC_34611283","title":"Effect of AAV-mediated overexpression of ATF5 and downstream targets of an integrated stress response in murine skeletal muscle.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/34611283","citation_count":8,"is_preprint":false},{"pmid":"37649699","id":"PMC_37649699","title":"mTORC2 orchestrates monocytic and granulocytic lineage commitment by an ATF5-mediated pathway.","date":"2023","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/37649699","citation_count":7,"is_preprint":false},{"pmid":"32342199","id":"PMC_32342199","title":"ATF5 involved in radioresistance in nasopharyngeal carcinoma by promoting epithelial-to-mesenchymal phenotype transition.","date":"2020","source":"European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery","url":"https://pubmed.ncbi.nlm.nih.gov/32342199","citation_count":7,"is_preprint":false},{"pmid":"37256362","id":"PMC_37256362","title":"Activating transcription factor 5 (ATF5) controls intestinal tuft and goblet cell expansion upon succinate-induced type 2 immune responses in mice.","date":"2023","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/37256362","citation_count":6,"is_preprint":false},{"pmid":"33825962","id":"PMC_33825962","title":"Functional validation of epitope-tagged ATF5 knock-in mice generated by improved genome editing of oviductal nucleic acid delivery (i-GONAD).","date":"2021","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/33825962","citation_count":6,"is_preprint":false},{"pmid":"39547369","id":"PMC_39547369","title":"ATF5-mediated mitochondrial unfolded protein response protects against Pb-induced mitochondria damage in SH-SY5Y cell.","date":"2024","source":"Neurotoxicology","url":"https://pubmed.ncbi.nlm.nih.gov/39547369","citation_count":5,"is_preprint":false},{"pmid":"32603335","id":"PMC_32603335","title":"Expression of activating transcription factor 5 (ATF5) is mediated by microRNA-520b-3p under diverse cellular stress in cancer cells.","date":"2020","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/32603335","citation_count":5,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50859,"output_tokens":11162,"usd":0.160003,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":22179,"output_tokens":5053,"usd":0.11861,"stage2_stop_reason":"end_turn"},"total_usd":0.278613,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"ATF5 is a mammalian transcription factor that mediates the mitochondrial unfolded protein response (UPRmt). Like C. elegans ATFS-1, ATF5 is regulated by organelle partitioning: it normally accumulates in mitochondria, but during mitochondrial stress a fraction traffics to the nucleus to activate UPRmt target genes. ATF5 expression rescues UPRmt signaling in atfs-1-deficient worms requiring the same UPRmt promoter element identified in C. elegans, and mammalian cells require ATF5 to maintain mitochondrial activity during stress.\",\n      \"method\": \"Cellular fractionation, ATF5 expression in atfs-1-deficient C. elegans (genetic complementation), siRNA knockdown in mammalian cells, reporter assays\",\n      \"journal\": \"Current Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (fractionation, cross-species genetic rescue, reporter, loss-of-function), widely replicated across subsequent studies\",\n      \"pmids\": [\"27426517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ATF5 translation is preferentially induced during stress by a mechanism requiring eIF2α phosphorylation. The 5'-leader of ATF5 mRNA contains two uORFs analogous to ATF4: uORF1 is positive-acting (allows reinitiation), and uORF2 is inhibitory under normal conditions. eIF2α phosphorylation during stress delays reinitiation, causing ribosomes to bypass uORF2 and instead translate the ATF5 coding region. Additionally, ATF4 contributes to basal ATF5 transcription.\",\n      \"method\": \"Polyribosome fractionation, luciferase reporter assays with uORF mutations, ATF4-/- mouse embryo fibroblasts, pharmacological eIF2 kinase activation\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis of uORFs in reporter system plus polyribosome fractionation; replicated by independent lab (PMID:18055463)\",\n      \"pmids\": [\"18195013\", \"18055463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ATF5 mRNA translation is regulated by alternative 5'-UTRs (5'-UTRα and 5'-UTRβ). 5'-UTRα represses basal translation via uORF2, but this repression is released by amino acid limitation or arsenite exposure through eIF2α phosphorylation. 5'-UTRβ does not confer stress-responsive translational upregulation. Mutation of uAUG2 in uORF2 restored basal expression and abolished stress-induced upregulation.\",\n      \"method\": \"Reporter assays with 5'-UTR variants and uORF mutations, eIF2α phosphorylation analysis, heme-regulated inhibitor kinase overexpression\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis of specific uORFs combined with reporter assays; mechanistically consistent with PMID:18195013\",\n      \"pmids\": [\"18055463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CHOP directly induces ATF5 transcription as part of a feedforward apoptotic switch during severe proteotoxic stress. ATF4 also directly activates ATF5 transcription. Knockdown of ATF5 increases cell survival during proteasome inhibition. ATF5-dependent transcriptome analysis identified NOXA as an ATF5 target important for cell death.\",\n      \"method\": \"Chromatin immunoprecipitation, ATF5 knockdown (siRNA), transcriptome profiling, proteasome inhibitor treatment, cell viability assays\",\n      \"journal\": \"Molecular Biology of the Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP establishing direct transcriptional regulation, loss-of-function with defined phenotype, transcriptome analysis; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"23761072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The 5'-UTRα of ATF5 mRNA renders it a target of nonsense-mediated mRNA decay (NMD) under normal conditions via translation of uORF2. Knockdown of NMD factors Upf1 and Upf2 stabilized ATF5 mRNA. During amino acid limitation or tunicamycin-induced stress, eIF2α phosphorylation stabilizes ATF5 mRNA by preventing uORF2 translation, thereby linking translational control to mRNA decay regulation.\",\n      \"method\": \"siRNA knockdown of Upf1/Upf2, uORF2 mutation, mRNA stability assays, stress treatment\",\n      \"journal\": \"The FEBS Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis of uAUG2, RNAi of NMD factors with mRNA stability readout, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"23876217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"ATF5 suppresses neuroprogenitor cell differentiation into neurons. ATF5 is highly expressed in neural stem/progenitor cells and downregulated by NGF. Exogenous ATF5 suppresses NGF-promoted neurite outgrowth and neurogenesis; dominant-negative ATF5 or siRNA accelerates neurogenesis. The inhibitory effect requires repression of CRE sites.\",\n      \"method\": \"Overexpression and dominant-negative ATF5 in PC12 and telencephalic cells, siRNA knockdown, NGF treatment, neurosphere cultures, CRE luciferase reporter\",\n      \"journal\": \"Journal of Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain-of-function, loss-of-function (dominant-negative and siRNA), and reporter assays in multiple cell types; replicated in subsequent papers\",\n      \"pmids\": [\"12805299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In malignant glioma, RAS-MAPK or PI3K signaling activates CREB3L2, which directly activates ATF5 transcription. ATF5 in turn promotes survival by directly stimulating transcription of the anti-apoptotic gene MCL1. The RAF inhibitor sorafenib suppresses ATF5 expression in glioma stem cells.\",\n      \"method\": \"Genome-wide RNAi screen, ChIP, reporter assays, gene expression analysis in human glioma samples and mouse models\",\n      \"journal\": \"Nature Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide unbiased screen followed by ChIP validating direct transcriptional regulation, corroborated in vivo\",\n      \"pmids\": [\"20495567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BCR-ABL suppresses autophagy through the PI3K/AKT/FOXO4 pathway, which transcriptionally upregulates ATF5; ATF5 in turn directly stimulates transcription of mTOR, a master negative regulator of autophagy. Imatinib-induced autophagy is caused by inhibition of this BCR-ABL/PI3K/AKT/FOXO4/ATF5/mTOR pathway.\",\n      \"method\": \"Reporter assays, ChIP, ATF5 knockdown, mTOR expression analysis, autophagy assays in BCR-ABL-transformed cells\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct ATF5 binding to mTOR promoter, pathway dissection with multiple inhibitors and knockdowns, single lab\",\n      \"pmids\": [\"21715304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BCL-2 is a direct transcriptional target of ATF5 that mediates its prosurvival function in glioma and breast cancer cells. ATF5 binds to an ATF5-specific regulatory element downstream of and adjacent to the negative regulatory element in the BCL-2 P2 promoter. BCL-2 expression is not regulated by ATF5 in non-transformed cells, explaining the cancer cell-specific survival function.\",\n      \"method\": \"ChIP, EMSA, ATF5 overexpression/knockdown, BCL-2 promoter reporter assays, rescue experiments in multiple cell types\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct binding demonstrated by EMSA and ChIP, functional rescue experiments, cell-type specificity established; single lab\",\n      \"pmids\": [\"21212266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"HSP70 interacts with the N-terminal activation domain of ATF5 (which is rich in proline residues) through an ATP-driven process requiring functional ATPase on HSP70. HSP70 binding stabilizes ATF5 protein, which is otherwise subject to rapid proteasome-dependent and caspase-dependent degradation. HSP70 depletion accelerates ATF5 degradation and reduces BCL-2 and EGR-1 expression in glioma cells.\",\n      \"method\": \"Co-immunoprecipitation, HSP70 overexpression/siRNA knockdown, ATF5 stability assays, proteasome/caspase inhibitors, domain mapping\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ATP-dependence tested, domain mapping, functional consequence on downstream targets; single lab\",\n      \"pmids\": [\"21521685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"p300 acetylates ATF5 at lysine-29 (K29), which enhances the ATF5-p300 interaction and binding of the ATF5/p300 complex to the ATF5 response element (ARE) of the EGR-1 promoter. ARE-bound ATF5/p300 then acetylates histone H3 K14 at both ARE and SRE of EGR-1 promoter, facilitating ERK-phosphorylated Elk-1 binding to the SRE and activating EGR-1 transcription.\",\n      \"method\": \"Co-IP, in vitro acetylation assays, ChIP, acetylation-site mutagenesis (K29), promoter reporter assays, ERK inhibition\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro acetylation, mutagenesis of specific lysine, ChIP, and functional reporter assays; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"21791614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ATF5 protein is degraded via the ubiquitin-proteasome pathway through N-terminal ubiquitinylation of the free amino group of the N-terminal methionine. The E2 ubiquitin-conjugating enzyme Cdc34 is involved in ATF5 ubiquitination. Cisplatin blocks ATF5 degradation by promoting nucleus-to-cytoplasm translocation of Cdc34, reducing ATF5-Cdc34 interaction.\",\n      \"method\": \"Ubiquitination assays, N-terminal methionine mutants, Cdc34 overexpression/co-IP, cisplatin treatment, proteasome inhibitor studies\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ubiquitination assays and Co-IP identifying Cdc34 as E2; N-terminal ubiquitination mechanism inferred from deletion mutants; single lab\",\n      \"pmids\": [\"18458088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Cadmium interferes with ATF5 degradation at a post-ubiquitination step of the proteasome pathway. Unlike proteasome inhibitors (which increase ubiquitinated ATF5), cadmium does not reduce ATF5 ubiquitination but instead blocks a downstream step in proteasomal degradation, stabilizing ATF5 protein.\",\n      \"method\": \"Ubiquitination assays, CdCl2/NaAsO3 treatment, proteasome inhibitor comparison, transient transfection of FLAG-ATF5\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, single method (ubiquitination assay) distinguishing cadmium from proteasome inhibitors; mechanistically informative negative finding on ubiquitination\",\n      \"pmids\": [\"19285020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Nucleophosmin (NPM1/B23) interacts with ATF5 via the ATF5 leucine zipper domain binding to the C-terminal nucleolar localization signal region of NPM1. NPM1 promotes ATF5 degradation through proteasome-dependent and caspase-dependent pathways. NPM1 interaction displaces HSP70 from ATF5 complexes, antagonizing HSP70-mediated ATF5 stabilization. NPM1-c, a mutant defective in nucleolar localization, failed to stimulate ATF5 polyubiquitination.\",\n      \"method\": \"Tandem affinity purification followed by mass spectrometry, Co-IP, domain mapping, ubiquitination assays, NPM1-c mutant\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — unbiased TAP-MS identification of NPM1, validated by Co-IP, domain mapping, ubiquitination assays, and functional mutant; single lab\",\n      \"pmids\": [\"22528486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ATF5 forms a characteristic 9-fold symmetrical ring structure in the inner layer of the pericentriolar material (PCM) at the proximal end of the mother centriole. ATF5 interacts with polyglutamylated tubulin (PGT) on the mother centriole and with PCNT in the PCM, functioning as a structural linker required for mother centriole-directed PCM accumulation and PCM-dependent centriole formation. ATF5 depletion causes PCM fragmentation, multi-polar mitotic spindles, and genomic instability.\",\n      \"method\": \"Super-resolution microscopy (9-fold symmetry), Co-IP with PGT and PCNT, ATF5 depletion/RNAi, centrosome fractionation, cell cycle analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — super-resolution structural data combined with Co-IP binding partners, loss-of-function with defined structural and functional phenotypes; high-profile single study\",\n      \"pmids\": [\"26213385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ATF5 is SUMO2/3-modified at a conserved SUMO-targeting consensus site. SUMOylation of ATF5 is elevated in G1 phase and diminished in G2/M phase. SUMOylation disrupts ATF5 interaction with centrosomal proteins, dislodging ATF5 from the centrosome at the end of M phase. Blockade of ATF5 SUMOylation deregulates the centrosome cycle, impedes ATF5 translocation from the centrosome, and causes genomic instability and G2/M arrest.\",\n      \"method\": \"SUMO modification assays, cell-cycle-synchronized cells, SUMOylation-site mutant ATF5, Co-IP with centrosomal proteins, genomic instability assays\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — SUMO modification demonstrated biochemically, site mutant used to block SUMOylation with defined centrosome and cell-cycle phenotypes; single lab\",\n      \"pmids\": [\"29326161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ATF5 is required for terminal differentiation and survival of olfactory sensory neurons (OSNs). In Atf5-/- mice, OSNs fail to differentiate from immature to mature OSNs and undergo apoptosis, leading to neonatal lethality from olfactory defect. Ectopic ATF5 expression in neural progenitor cells induces expression of multiple OSN-specific genes.\",\n      \"method\": \"Atf5 knockout mice, immunostaining with OSN-specific markers, expression profiling, ectopic ATF5 expression\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout phenotype with defined cellular mechanism, gain-of-function confirming OSN gene induction; replicates and extends prior in vitro findings\",\n      \"pmids\": [\"23090999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ATF5 promotes oligodendrocyte progenitor expansion and inhibits their differentiation into mature oligodendroglia. Constitutively expressed ATF5 maintains SVZ cells and O4+ precursors in cycle; ATF5 loss-of-function (dominant-negative) accelerates oligodendrocyte differentiation in vitro and in vivo, but results in aberrant migration.\",\n      \"method\": \"Dominant-negative ATF5 in vitro and in vivo (SVZ cells), constitutive ATF5 expression, BrdU labeling, immunostaining\",\n      \"journal\": \"Molecular and Cellular Neurosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — both gain-of-function and loss-of-function in vivo and in vitro; replicates neuroprogenitor findings from PMID:12805299 in oligodendrocyte lineage\",\n      \"pmids\": [\"15950153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cardioprotection by pharmacological UPRmt induction (oligomycin or doxycycline) requires ATF5 in vivo. In global Atf5-/- mice, UPRmt induction fails to protect against cardiac ischemia-reperfusion injury, whereas it does in wild-type mice. RNA-Seq revealed an ATF5-dependent gene set induced by UPRmt.\",\n      \"method\": \"Atf5-/- mice, in vivo UPRmt induction, ex vivo ischemia-reperfusion, cardiac qPCR/western blot, RNA-Seq\",\n      \"journal\": \"American Journal of Physiology: Heart and Circulatory Physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockout with defined functional phenotype, RNA-Seq for mechanistic gene set; multiple methods in single study\",\n      \"pmids\": [\"31274354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Nemo-like kinase (NLK) interacts with ATF5 and inhibits proteasome-dependent degradation of ATF5 in a kinase-independent manner, thereby stabilizing ATF5 protein. NLK cooperates with ATF5 to activate C/EBP transcription. TAK1, upstream of NLK in the IL-1β pathway, mimics NLK's ability to stabilize ATF5 and activate C/EBP, establishing a TAK1-NLK-ATF5-C/EBP signaling axis.\",\n      \"method\": \"Co-IP, luciferase reporter for C/EBP activity, NLK overexpression/knockdown/knockout, ATF5 stability assays, kinase-dead NLK mutant\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, kinase-dead mutant, loss-of-function and gain-of-function, defined pathway; single lab\",\n      \"pmids\": [\"25512613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The ER stress transducer BBF2H7 transcriptionally activates ATF5 in chondrocytes. ATF5 in turn activates transcription of Mcl1 to suppress ER stress-induced apoptosis in chondrocytes. This BBF2H7-ATF5-MCL1 pathway is specifically activated during chondrogenesis and is required to counteract ER stress from abundant ECM protein synthesis.\",\n      \"method\": \"Bbf2h7-/- mice, TUNEL staining, ChIP/reporter assays, ATF5 and MCL1 expression analysis in chondrocytes\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockout, reporter assays establishing direct transcriptional regulation, defined pathway with genetic validation; single lab\",\n      \"pmids\": [\"22936798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ATF5 is a transcriptional target of PDX1 in pancreatic β-cells (PDX1 binding confirmed by ChIP-sequencing). ATF5 regulates β-cell survival under stress and is positioned downstream of and parallel to ATF4 in the regulation of 4EBP1, a mTOR pathway component that inhibits protein translation. ATF5 deficiency attenuates stress-induced suppression of global translation, increasing β-cell susceptibility to apoptosis.\",\n      \"method\": \"Primary islet ChIP-sequencing for PDX1, ATF5 loss-of-function, 4EBP1 reporter/expression, translation assays\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq establishing direct PDX1-ATF5 transcriptional regulation, loss-of-function with defined translational and survival phenotype; single lab\",\n      \"pmids\": [\"28115692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ATF5 is a liver-enriched transcription factor that cooperates with constitutive androstane receptor (CAR) to transactivate CYP2B6. Adenoviral ATF5 overexpression in HepG2 cells selectively upregulates CYP2B6 mRNA, and ATF5+CAR co-expression causes additive CYP2B6 induction. Under ER stress (amino acid limitation), ATF5 is post-transcriptionally upregulated with parallel CYP2B6 induction.\",\n      \"method\": \"Adenoviral transduction, co-transfection with CAR, qRT-PCR, primary human hepatocyte cultures\",\n      \"journal\": \"Drug Metabolism and Disposition\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — gain-of-function in multiple systems, but mechanism of cooperation with CAR not resolved at molecular level; single lab\",\n      \"pmids\": [\"18332083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ATF5 activates asparagine synthetase (ASNS) promoter transcription via the nutrient-sensing response unit (NSRU). This transactivation is blocked by CHOP, which acts as a shut-off device for nutrient deprivation-induced ATF5-mediated gene transcription. ATF5 does not transactivate CRE-containing reporter genes.\",\n      \"method\": \"Reporter gene assays with ASNS promoter, ATF5 and CHOP overexpression, deletion/mutation analysis of NSRU\",\n      \"journal\": \"Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — reporter assays in transfected cells; promoter element identified but not confirmed by ChIP; single lab\",\n      \"pmids\": [\"16164412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ATF5 suppresses the transactivational activity of p53 and p63 in a luciferase reporter assay. ATF5 overexpression in radiosensitive tumor cells confers resistance to ionizing radiation and Ad-p53-induced apoptosis.\",\n      \"method\": \"Luciferase reporter assay for p53/p63 transactivation, ATF5 gene transfer, colony assay, flow cytometry\",\n      \"journal\": \"Cell Structure and Function\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — reporter assay and gene transfer in a single cell line, no direct binding demonstrated; single lab\",\n      \"pmids\": [\"19293535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ATF5 directly binds the ID1 gene promoter (demonstrated by EMSA) and represses ID1 transcription in hepatocellular carcinoma cells. Restoration of ATF5 in HCC cells causes G2/M cell cycle arrest.\",\n      \"method\": \"EMSA, reporter assays, flow cytometry cell cycle analysis, ATF5 re-expression in HCC cell lines\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct binding shown by EMSA but not ChIP, functional G2/M phenotype in multiple lines; single lab\",\n      \"pmids\": [\"18701499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ATF5 promotes cell survival against heat shock in H9c2 cells by transcriptionally activating Hsp27. The CRE motif in the Hsp27 gene promoter is important for ATF5-mediated upregulation, and Hsp27 knockdown by RNAi increases cell death in ATF5-expressing cells.\",\n      \"method\": \"ATF5 overexpression, Hsp27 promoter reporter assays, siRNA knockdown of Hsp27, heat shock survival assay\",\n      \"journal\": \"Cell Biology International\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — reporter and RNAi rescue in single cell line; direct ATF5 binding to Hsp27 promoter not confirmed by ChIP; single lab\",\n      \"pmids\": [\"17606386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ATF5 activates the CHOP gene promoter via the amino acid response element 1 (AARE1) site in HepG2 cells. ATF5 knockdown reduces arsenite-induced CHOP protein expression and arsenite-induced cell death.\",\n      \"method\": \"Reporter gene assays with CHOP promoter deletions and AARE1 point mutations, ATF5 overexpression, siRNA knockdown\",\n      \"journal\": \"Life Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — reporter mutagenesis identifying AARE1 but no ChIP; knockdown functional validation; single lab\",\n      \"pmids\": [\"20654631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Dominant-negative ATF5 (DN-ATF5) associates with CEBPB and CEBPD (basic leucine zipper proteins) and coiled-coil protein CCDC6, as identified by unbiased pull-down assays coupled with mass spectrometry. DN-ATF5 interferes with CEBPB and CEBPD transcriptional activity; knockdown of CEBPB or CEBPD promotes apoptosis of cancer cells but not normal astrocytes. Cancer cell death by DN-ATF5 occurs partly through suppression of CEBPB/CEBPD function independent of ATF5 itself.\",\n      \"method\": \"Pull-down assay followed by mass spectrometry, immunoblotting, CEBPB/CEBPD knockdown, reporter assays for CEBPB/CEBPD transcriptional activity\",\n      \"journal\": \"Molecular Cancer Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — unbiased MS identification of interactors, validated by functional knockdown, reporter assays; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31676720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HCMV immediate-early protein IE86 physically interacts with ATF5 and acetylates ATF5, thereby promoting glioma cell survival.\",\n      \"method\": \"Co-IP, immunohistochemistry, ATF5 acetylation assays, IE86 overexpression, glioma xenograft\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and acetylation demonstrated, functional glioma survival phenotype; single lab\",\n      \"pmids\": [\"28473657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ASGR1 interacts with ATF5 (confirmed by Co-IP) and promotes ATF5 expression through NF-κB/IKBa phosphorylation, which in turn promotes monocyte-to-macrophage differentiation.\",\n      \"method\": \"Co-IP, ASGR1 knockdown/overexpression, western blot for NF-κB phosphorylation and ATF5 expression, THP-1 and bone marrow-derived macrophage models\",\n      \"journal\": \"Life Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP establishing physical interaction, pathway activation by loss-of-function; single lab\",\n      \"pmids\": [\"36621538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TMEM11 directly interacts with METTL1 and enhances m7G methylation of Atf5 mRNA, thereby increasing ATF5 expression. Increased ATF5 then promotes transcription of Inca1 (an inhibitor of CDK-cyclin A1), suppressing cardiomyocyte proliferation. TMEM11 deletion enhances cardiomyocyte proliferation and cardiac regeneration.\",\n      \"method\": \"Co-IP (TMEM11-METTL1 interaction), m7G-MeRIP sequencing, ATF5 overexpression/knockdown, ChIP for ATF5 at Inca1 promoter, cardiomyocyte proliferation assays, mouse myocardial injury model\",\n      \"journal\": \"Cell Death and Differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing TMEM11-METTL1 interaction, m7G-MeRIP confirming ATF5 mRNA modification, ChIP for ATF5 binding at Inca1 promoter, in vivo validation; single lab\",\n      \"pmids\": [\"37286744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In skeletal muscle, ATF5 is required for proper mitochondrial quality control. ATF5 KO mice exhibit a larger but less functional mitochondrial pool, with enhanced biogenesis (increased PGC-1α), attenuated mitophagy, reduced antioxidant proteins, and increased ROS emission. Acute exercise causes ATF5 enrichment in mitochondrial fractions rather than nuclear translocation, and loss of ATF5 blunts the mitophagic and UPRmt gene expression response to exercise.\",\n      \"method\": \"ATF5 KO mice, fractionation (nuclear/cytosolic/mitochondrial), oxygen consumption, ROS emission, mRNA analysis, exercise challenge\",\n      \"journal\": \"Molecular Metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO with defined organelle fractionation showing exercise-induced mitochondrial localization, multiple functional readouts; single lab\",\n      \"pmids\": [\"36332794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PRMT1 promotes neuroblastoma cell survival through ATF5 as a downstream effector. Overexpression of ATF5 rescues cell apoptosis triggered by PRMT1 inhibition genetically or pharmacologically, placing ATF5 downstream of PRMT1 in a prosurvival signaling pathway.\",\n      \"method\": \"PRMT1 depletion (siRNA/pharmacological), ATF5 overexpression rescue, apoptosis assays, sphere formation assays, in vivo xenograft\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established by ATF5 rescue of PRMT1 depletion phenotype; does not identify direct PRMT1-ATF5 molecular interaction; single lab\",\n      \"pmids\": [\"32415090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"METTL14 facilitates m6A modification of ATF5 mRNA, promoting its degradation. ATF5 overexpression (caused by METTL14 knockdown) increases WDR74 transcription and enhances β-catenin nuclear translocation, promoting cancer stemness in gastric cancer. Histone H3 lactylation at Lys18 upregulates METTL14 expression.\",\n      \"method\": \"m6A RNA immunoprecipitation (MeRIP), luciferase reporter assays, ChIP (ATF5 binding to WDR74 promoter), western blot for β-catenin, rescue experiments\",\n      \"journal\": \"Cancer Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP and reporter assays for m6A mechanism, ChIP for ATF5-WDR74 relationship; single lab\",\n      \"pmids\": [\"39497511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ELF1 transcription factor directly binds and activates the ATF5 gene promoter in glioma cells, as confirmed by luciferase reporter assay and chromatin immunoprecipitation (ChIP). Silencing ELF1 inhibits glioma cell growth and migration with ATF5 involvement.\",\n      \"method\": \"Luciferase reporter assays, ChIP, ELF1 siRNA knockdown, cell proliferation and migration assays\",\n      \"journal\": \"ACS Chemical Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP confirming ELF1 at ATF5 promoter and functional knockdown; single lab\",\n      \"pmids\": [\"33720698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In oocytes, AMPK suppression (by obesity) increases the binding affinity of the ATF5-POLG protein complex to mutated mtDNA D-loop and protein-coding regions, promoting replication of heteroplasmic mtDNA. AMPK activation prevents ATF5-POLG recruitment to mutated mtDNA, improving oocyte mitochondrial quality.\",\n      \"method\": \"Co-IP (ATF5-POLG interaction), AMPK knockout mice, mtDNA heteroplasmy sequencing, AMPK activator treatment, oocyte maturation assays\",\n      \"journal\": \"Advanced Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying ATF5-POLG complex, AMPK KO phenotype, pharmacological rescue; single lab\",\n      \"pmids\": [\"38499990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ATF5 directly binds and stimulates the promoter of DVL1 gene (Wnt pathway component) in bladder cancer cells, activating the Wnt/β-catenin pathway. ATF5 promotes tumor sphere formation and cancer stemness through this mechanism.\",\n      \"method\": \"ChIP-qPCR, luciferase reporter assays, ATF5 overexpression/knockdown, sphere formation assays\",\n      \"journal\": \"Cancer Cell International\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP and reporter confirming direct ATF5-DVL1 promoter binding; single lab\",\n      \"pmids\": [\"34895217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"C/EBPγ and ATF5 co-expression (but not either alone) increases Vmn2r66 promoter reporter activity via the C/EBP:ATF response element (CARE), suggesting ATF5 and C/EBPγ act cooperatively as a heterodimer to drive V2r-type vomeronasal sensory neuron differentiation.\",\n      \"method\": \"Luciferase reporter assays in Neuro2a cells, co-expression experiments with C/EBPγ and ATF5, immunostaining in vomeronasal organ\",\n      \"journal\": \"Cell and Tissue Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — reporter assay demonstrating cooperative transcriptional activity; dimerization not confirmed by direct biochemical interaction; single lab\",\n      \"pmids\": [\"31309319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IL-1β increases ATF5 protein expression in HepG2 cells by two mechanisms: stabilization of ATF5 protein via its N-terminal hydrophobic domain, and increased translational efficiency via 5'-UTRα and eIF2α phosphorylation. ATF5 knockdown upregulates IL-1β-induced SAA1 and SAA2 expression, identifying ATF5 as a negative regulator of acute-phase gene expression.\",\n      \"method\": \"N-terminal deletion mutants, protein stability assays, 5'-UTR reporter assays, ATF5 siRNA knockdown, SAA1/2 expression analysis\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping and reporter assays for two distinct regulatory mechanisms, loss-of-function for downstream target; single lab\",\n      \"pmids\": [\"24379400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ATF5 directly binds the CCAAT/enhancer-binding protein (C/EBP)-ATF response element (CARE) in the promoter region of the olfactory chaperone gene Rtp1, as demonstrated by ChIP in ATF5-HA knock-in mice. This establishes Rtp1 as a direct in vivo transcriptional target of ATF5 in olfactory sensory neurons.\",\n      \"method\": \"CRISPR/Cas9 HA-tag knock-in mice, ChIP with anti-HA antibody, in vivo olfactory epithelium analysis\",\n      \"journal\": \"Cell and Tissue Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo ChIP from knock-in mice with endogenous ATF5-HA at specific gene locus; single lab but rigorous in vivo approach\",\n      \"pmids\": [\"33825962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Intestinal ATF5 promotes a satiety response by transcriptionally regulating the gastrointestinal peptide hormone cholecystokinin (CCK), which promotes leptin secretion, thereby maintaining intestinal barrier function and preventing obesity-associated hyperglycemia and barrier dysfunction during enteric pathogen infection.\",\n      \"method\": \"Atf5-/- mice, intestinal barrier assays, enteric infection models, CCK reporter/expression analysis, leptin measurements\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockout with defined pathway from ATF5 to CCK to leptin to barrier function; transcriptional regulation of CCK by ATF5 shown but ChIP not detailed in abstract; single lab\",\n      \"pmids\": [\"36516750\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATF5 is a bZIP transcription factor regulated at multiple levels: its translation is preferentially induced during stress (ER stress, amino acid deprivation, oxidative stress) through eIF2α phosphorylation-dependent bypass of inhibitory uORFs in its 5'-UTRα, while its mRNA is also stabilized by suppression of nonsense-mediated decay; its protein stability is controlled by ubiquitin-proteasome degradation (via E2 enzyme Cdc34 and N-terminal ubiquitination) that is antagonized by HSP70 binding and promoted by NPM1, while NLK kinase and stress signals (cadmium, IL-1β) also stabilize ATF5; ATF5 is acetylated by p300 (at K29) to enhance its transcriptional activity at target gene promoters including EGR-1, BCL-2, MCL1, mTOR, CYP2B6, ASNS, Hsp27, DVL1, Rtp1, and CCK; at the centrosome ATF5 forms a structural ring connecting the mother centriole (via polyglutamylated tubulin) to PCM (via PCNT), regulated by cell-cycle-dependent SUMO2/3 modification; in the mitochondrial UPR, ATF5 traffics from mitochondria to the nucleus during organellar stress to activate a transcriptional program restoring proteostasis; and ATF5 is a key regulator of neural progenitor cell differentiation, olfactory sensory neuron maturation, and cancer cell survival, functioning through direct transcriptional regulation of anti-apoptotic targets including BCL-2 and MCL1, and cooperating with binding partners including CEBPB, CEBPD, and C/EBPγ.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ATF5 is a stress-responsive bZIP transcription factor that governs cell survival, organellar proteostasis, and progenitor cell fate, acting as a convergence point between translational stress signaling and transcriptional cell-fate decisions [#1, #5, #0]. Its expression is controlled predominantly at the level of translation: the 5'-UTR\\u03b1 of ATF5 mRNA contains an inhibitory uORF2 that represses basal translation, and eIF2\\u03b1 phosphorylation during amino acid deprivation, ER stress, or oxidative stress causes ribosomes to bypass uORF2 and translate the coding region, a regulatory logic analogous to ATF4 [#1, #2]. The same uORF2-dependent translation event renders the transcript a substrate of nonsense-mediated decay under basal conditions, so eIF2\\u03b1 phosphorylation simultaneously stabilizes the mRNA, coupling translational and decay control [#4]. ATF5 transcription is itself driven by stress effectors including CHOP and ATF4, the ER-stress transducer BBF2H7, and lineage factors such as PDX1, forming feed-forward loops that amplify the stress response [#3, #20, #21]. Protein abundance is set by ubiquitin-proteasome degradation initiated through N-terminal ubiquitination and the E2 enzyme Cdc34, antagonized by HSP70 binding to the N-terminal activation domain and promoted by nucleophosmin (NPM1), which displaces HSP70; NLK and stress signals further stabilize the protein [#11, #9, #13, #19]. As a transcription factor ATF5 drives a prosurvival program, directly activating anti-apoptotic targets MCL1 and BCL-2 in cancer cells, mTOR, Hsp27, and ASNS, and its activity is enhanced by p300-mediated acetylation at K29 [#6, #8, #7, #10, #23]. ATF5 mediates the mitochondrial unfolded protein response, partitioning between mitochondria and nucleus so that during organellar stress a fraction traffics to the nucleus to induce a proteostasis-restoring gene set, a function required for cardioprotection and skeletal-muscle mitochondrial quality control in vivo [#0, #18, #32]. Beyond its transcriptional role, ATF5 is a structural component of the centrosome, forming a 9-fold symmetric ring that links polyglutamylated tubulin on the mother centriole to PCNT in the pericentriolar material, with its centrosomal residence gated by cell-cycle-dependent SUMO2/3 modification [#14, #15]. In development, ATF5 maintains neural and oligodendrocyte progenitors in an undifferentiated state and is required for terminal differentiation and survival of olfactory sensory neurons, where it directly regulates targets including Rtp1 and cooperates with C/EBP family partners [#5, #17, #16, #40, #38].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established ATF5 as a brake on neural progenitor differentiation, defining its first developmental role and showing it acts through repression of CRE-dependent transcription.\",\n      \"evidence\": \"Gain-of-function, dominant-negative, and siRNA manipulation with NGF treatment and CRE reporters in PC12 and telencephalic cells\",\n      \"pmids\": [\"12805299\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct in vivo target genes not identified\", \"Mechanism of CRE repression unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined how ATF5 abundance is tuned to stress, showing alternative 5'-UTRs and an inhibitory uORF2 confer eIF2\\u03b1-phosphorylation-dependent translational induction.\",\n      \"evidence\": \"Reporter assays with 5'-UTR variants and uORF mutations plus eIF2\\u03b1 phosphorylation analysis\",\n      \"pmids\": [\"18055463\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address mRNA stability layer\", \"Endogenous protein induction quantified only indirectly\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved the uORF reinitiation logic mechanistically and linked basal expression to ATF4, placing ATF5 in an integrated stress response cascade.\",\n      \"evidence\": \"Polyribosome fractionation, uORF mutant reporters, ATF4-/- MEFs, and pharmacological eIF2 kinase activation\",\n      \"pmids\": [\"18195013\", \"18055463\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of transcriptional vs translational control in vivo unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified the degradation arm of ATF5 control, showing proteasomal turnover via N-terminal ubiquitination and the E2 enzyme Cdc34.\",\n      \"evidence\": \"Ubiquitination assays, N-terminal methionine mutants, Cdc34 Co-IP, and cisplatin treatment\",\n      \"pmids\": [\"18458088\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase not identified\", \"N-terminal ubiquitination inferred from deletion mutants\", \"Single lab\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated that oncogenic signaling drives ATF5 to enforce cancer cell survival via direct anti-apoptotic transcription, identifying MCL1 as a key target.\",\n      \"evidence\": \"Genome-wide RNAi screen, ChIP, and reporter assays in glioma samples and mouse models\",\n      \"pmids\": [\"20495567\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of CREB3L2-ATF5 axis beyond glioma untested\", \"Other survival targets not enumerated here\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined ATF5's prosurvival transcriptional program in detail \\u2014 direct BCL-2 and mTOR activation \\u2014 and revealed cancer-cell-specific target regulation.\",\n      \"evidence\": \"ChIP, EMSA, reporter assays, knockdown/rescue in glioma, breast cancer, and BCR-ABL cells\",\n      \"pmids\": [\"21212266\", \"21715304\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Basis of cancer-cell-specific BCL-2 regulation not molecularly resolved\", \"In vivo target occupancy not shown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established post-translational control of ATF5 stability and activity, showing HSP70 binding protects it from degradation and p300 acetylation at K29 boosts its transcriptional output.\",\n      \"evidence\": \"Reciprocal Co-IP, ATP-dependence and domain mapping, in vitro acetylation, K29 mutagenesis, and ChIP\",\n      \"pmids\": [\"21521685\", \"21791614\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and dynamics of HSP70/acetylation in vivo unclear\", \"Deacetylase not identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified NPM1 as a destabilizer that antagonizes HSP70, and demonstrated ATF5's requirement for olfactory sensory neuron maturation in vivo, unifying its survival and differentiation roles.\",\n      \"evidence\": \"TAP-MS, Co-IP and domain mapping for NPM1; Atf5-/- mice with OSN markers and ectopic expression\",\n      \"pmids\": [\"22528486\", \"23090999\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"NPM1/HSP70 competition not reconstituted in vitro\", \"Direct OSN target genes not defined in this work\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed ATF5 can act as a pro-apoptotic effector during severe stress and is a substrate of NMD, integrating decay control with the eIF2\\u03b1 translational switch.\",\n      \"evidence\": \"ChIP, transcriptome profiling, NMD factor (Upf1/Upf2) knockdown, and mRNA stability assays under stress\",\n      \"pmids\": [\"23761072\", \"23876217\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of pro-survival vs pro-apoptotic ATF5 outputs unresolved\", \"NOXA induction mechanism not detailed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed an unexpected non-transcriptional role: ATF5 is a structural centrosomal protein bridging the mother centriole to the pericentriolar material, required for genome stability.\",\n      \"evidence\": \"Super-resolution microscopy showing 9-fold symmetry, Co-IP with polyglutamylated tubulin and PCNT, and RNAi depletion phenotypes\",\n      \"pmids\": [\"26213385\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the bZIP transcription factor is repurposed structurally unknown\", \"Relationship between centrosomal and nuclear pools unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined ATF5 as the mammalian UPRmt regulator, functionally orthologous to C. elegans ATFS-1, governed by mitochondria-to-nucleus partitioning.\",\n      \"evidence\": \"Cellular fractionation, cross-species genetic rescue in atfs-1 worms, mammalian siRNA, and reporter assays\",\n      \"pmids\": [\"27426517\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular sensor controlling mitochondrial import vs nuclear trafficking not defined\", \"Full UPRmt target set incomplete\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed SUMO2/3 modification cyclically gates ATF5's centrosomal residence across the cell cycle, coupling its post-translational state to the centrosome cycle.\",\n      \"evidence\": \"SUMO modification assays, cell-cycle synchronization, SUMO-site mutant, and Co-IP with centrosomal proteins\",\n      \"pmids\": [\"29326161\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMO E3 ligase and protease not identified\", \"Crosstalk with the transcriptional/UPRmt roles unexplored\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Validated ATF5's UPRmt and survival functions physiologically, demonstrating it is required for cardioprotection in vivo, and mapped its interface with the C/EBP family.\",\n      \"evidence\": \"Atf5-/- mice with ischemia-reperfusion and RNA-Seq; pull-down/MS identifying CEBPB, CEBPD, CCDC6 with functional knockdown\",\n      \"pmids\": [\"31274354\", \"31676720\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of ATF5 dimerization partners in each context not fully resolved\", \"Cardioprotective gene set not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended ATF5 regulation to RNA modification, showing m7G methylation of Atf5 mRNA controls its expression to restrain cardiomyocyte proliferation.\",\n      \"evidence\": \"Co-IP (TMEM11-METTL1), m7G-MeRIP-seq, ChIP for ATF5 at the Inca1 promoter, and a mouse myocardial injury model\",\n      \"pmids\": [\"37286744\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct effect of m7G on ATF5 translation vs stability not separated\", \"Generality beyond cardiac context untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ATF5 partitions among its mitochondrial, centrosomal, and nuclear pools, and what molecular switch selects between its prosurvival and pro-apoptotic transcriptional outputs, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model linking bZIP and centrosomal functions\", \"Sensor controlling mitochondrial import vs nuclear trafficking unknown\", \"Determinants of survival vs death transcriptional programs undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 5, 6, 7, 8, 10, 16, 20, 21, 23, 40]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [8, 10, 25, 37, 40]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 10, 32]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 32, 36]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [14, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 1, 2, 4, 18, 32]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 6, 8, 10, 16, 20, 21]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3, 6, 8, 16, 24]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [14, 15, 25, 31]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 16, 17, 38, 40]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 2, 9, 11, 13, 19]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [14, 0, 32]}\n    ],\n    \"complexes\": [\"centrosome/pericentriolar material ring\"],\n    \"partners\": [\"HSP70\", \"NPM1\", \"CDC34\", \"NLK\", \"PCNT\", \"CEBPB\", \"CEBPD\", \"POLG\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}