{"gene":"CREB1","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2008,"finding":"Crtc1 (CREB-regulated transcription coactivator-1) is required for Creb1-dependent transcriptional activation of Cartpt and Kiss1 genes in the hypothalamus. Leptin promotes nuclear dephosphorylation of Crtc1, which then co-occupies Cartpt and Kiss1 promoters with Creb1; a dominant-negative Creb1 polypeptide disrupted these effects, establishing Creb1-Crtc1 as the pathway mediating leptin's central effects on energy balance and fertility.","method":"Dominant-negative CREB1 expression, ChIP (chromatin immunoprecipitation) of hypothalamic Crtc1 at target promoters, Crtc1 overexpression/depletion in hypothalamic cells, Crtc1−/− mouse model","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional experiments (dominant-negative, KO mouse, ChIP), multiple orthogonal methods in one study, clear phenotypic readout","pmids":["18758446"],"is_preprint":false},{"year":2010,"finding":"CCDC6 physically interacts with CREB1 and represses its transcriptional activity by recruiting histone deacetylase 1 (HDAC1) and protein phosphatase 1 (PP1) to CRE-containing promoters of CREB1 target genes (including AREG and cyclin A). Loss of CCDC6 via RET/PTC1 fusion leads to increased CREB1 phosphorylation and target gene expression in papillary thyroid carcinoma.","method":"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), reporter assays, expression analysis in PTC tumor specimens","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP identifying complex components, ChIP confirming promoter recruitment, functional reporter assays, with disease-context validation","pmids":["20498639"],"is_preprint":false},{"year":2013,"finding":"Creb1 forms a complex with Mecp2 at methylated CpG sites in the Glut3 gene promoter to transactivate neuronal Glut3 expression. Sequential ChIP showed Creb1 recruitment of Mecp2 to glut3-mCpGs; co-IP confirmed Creb1-Mecp2 association; siRNA depletion of Creb1 or Mecp2 reduced Glut3 expression, establishing a methylation-dependent transactivation mechanism.","method":"Sequential chromatin immunoprecipitation (ChIP), co-immunoprecipitation, siRNA knockdown, luciferase reporter assay, bisulfite sequencing","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (sequential ChIP, Co-IP, siRNA, reporter), single lab but comprehensive mechanistic dissection","pmids":["23493374"],"is_preprint":false},{"year":2013,"finding":"MTOR positively regulates CREB1 activity; impaired autophagy (due to TSC2 or PTEN loss) leads to CREB1 hyperactivation; CREB1 in turn promotes DNA damage and apoptosis in response to etoposide. Silencing Creb1 with siRNA protected MTOR-hyperactive cells from DNA damage-induced apoptosis, placing CREB1 downstream of MTOR and upstream of DNA damage responses.","method":"siRNA knockdown of Creb1, TSC2/PTEN loss-of-function models (MEFs and cancer lines), etoposide treatment, autophagy manipulation, analysis in TSC patient kidney tumor tissue and hepatocyte-specific PTEN-KO mouse livers","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via KO/KD with defined phenotypic readout, multiple cell and in vivo models, single lab","pmids":["24189100"],"is_preprint":false},{"year":2014,"finding":"CREB1 directly binds the TGFB2 gene promoter in cooperation with SMAD3 to mediate TGFβ-induced TGFβ2 transcription, creating an autocrine loop. The PI3K-AKT and RSK pathways regulate this loop through CREB1. Patient-derived glioblastoma in vivo models confirmed that CREB1 levels determine TGFβ2 expression.","method":"ChIP (CREB1 binding at TGFB2 promoter), dominant-negative and overexpression constructs, PI3K/AKT/RSK pathway inhibitors, patient-derived glioblastoma xenograft models","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ChIP establishing direct promoter binding, pathway inhibitor epistasis, in vivo patient-derived models, multiple orthogonal methods in one study","pmids":["25084773"],"is_preprint":false},{"year":2007,"finding":"CREB1 interacts with the transcription factor Lyl1 via the N-terminal domain of Lyl1 and the Q2 and KID domains of CREB1; this interaction recruits histone acetyltransferases p300 and CBP to CREB1-target promoters (including Id1, Id3, cyclin D3, Brca1, Btg2, Egr1) in the absence of CREB1 Ser133 phosphorylation, resulting in transcriptional activation.","method":"Co-immunoprecipitation, domain mapping, ChIP-chip (genome-wide promoter occupancy), reporter assays","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with domain mapping, genome-wide ChIP-chip, functional reporter assays; single lab but multiple orthogonal methods","pmids":["18160048"],"is_preprint":false},{"year":2015,"finding":"CREB1 binds the promoter of miR-320a and activates its transcription during serum starvation; this induces mitophagy by downregulating VDAC1 in cervical cancer cells. Serum starvation sequentially induced CREB1, then miR-320a, then reduced VDAC1 to facilitate mitophagy.","method":"Promoter cloning and deletion mapping, ChIP (CREB1 at miR-320a promoter), overexpression/knockdown experiments, immunoblot for VDAC1 and mitophagy markers","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming direct promoter binding, promoter core region mapped, functional rescue; single lab","pmids":["26472185"],"is_preprint":false},{"year":2011,"finding":"A TSH-CREB1-miRNA loop controls thyroid cell proliferation: thyrotropin (TSH) activates CREB1, which binds the regulatory regions of five specific miRNAs (miR-1, miR-28-A, miR-290-5p, miR-296-3p, miR-297a) and suppresses their expression; three of these miRNAs target CREB1, forming a feedback loop required for TSH-driven thyroid cell growth.","method":"ChIP (CREB1 binding to miRNA regulatory regions), overexpression of miRNAs, reporter assays, TSH stimulation of thyroid cells","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP establishing direct binding, miRNA overexpression phenotype, feedback loop validated; single lab","pmids":["21816899"],"is_preprint":false},{"year":2015,"finding":"E2-induced PI3K/AKT pathway activation drives CREB1 phosphorylation and CREB1-mediated transcriptional activity that controls 17β-estradiol (E2)-induced cell proliferation. ERα residues L429 and A430 are required for E2-induced PI3K/AKT/CREB1 pathway activation; mutation of these residues abolishes E2-induced CREB1 phosphorylation and proliferation.","method":"Stable cell lines expressing L429A,A430G-ERα mutants, PI3K/AKT inhibition, CREB1 reporter assays, proliferation assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structure-function mutagenesis of ERα, pathway inhibitors, CREB1 reporter assays; single lab, multiple orthogonal methods","pmids":["26348925"],"is_preprint":false},{"year":2018,"finding":"CDK5 (PKA/cAMP-independent) maintains CREB1 activation in glioma stem cells (GSCs) to support self-renewal. Pharmacological CDK5 inhibition suppresses CREB1 activation in vitro and in GSC xenograft tumors. A Drosophila genetic suppressor screen identified dCdk5 as a critical regulator, with human CDK5 (79% identity) validated as the ortholog.","method":"Drosophila genetic suppressor screen, CDK5 pharmacological inhibition, GSC self-renewal assays in vitro and xenograft tumors, TCGA data analysis","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic suppressor screen (ortholog validated), in vitro and in vivo pharmacological inhibition; single lab","pmids":["29742423"],"is_preprint":false},{"year":2018,"finding":"SETD2-mediated H3K36 trimethylation (H3K36me3) is required for CREB1 phosphorylation and ERK pathway activation in NSCLC cells; a SETD2 missense mutation (p.T1171K) found in cisplatin-resistant metastatic NSCLC impairs H3K36me3 and CREB1 phosphorylation, conferring cisplatin resistance. Suppression of either SETD2 or CREB1 reduced cisplatin sensitivity.","method":"NGS identification of SETD2 mutation, ectopic expression of mutant SETD2, CREB1 siRNA knockdown, measurement of H3K36me3 and CREB1 phosphorylation, cisplatin cytotoxicity assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (mutant overexpression + siRNA KD), biochemical readouts of H3K36me3 and pCREB1; single lab","pmids":["30093630"],"is_preprint":false},{"year":2019,"finding":"DJ-1 directly interacts with CaMKKβ and modulates CaMKIV/CREB1 (Ser133) phosphorylation to regulate tyrosine hydroxylase (TH) expression. In Dj-1 knockout mouse substantia nigra, CaMKIV phosphorylation, CREB1 Ser133 phosphorylation, and TH levels are all reduced. siRNA knockdown of Creb1 abolishes DJ-1's effect on TH.","method":"Co-immunoprecipitation (DJ-1 with CaMKKβ), Dj-1 knockout mice, siRNA knockdown of Creb1, immunoblot for phospho-CaMKIV and phospho-CREB1 Ser133","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying complex, KO mice, epistasis via Creb1 siRNA; single lab, multiple orthogonal methods","pmids":["31232473"],"is_preprint":false},{"year":2021,"finding":"CREB1 is constitutively active in prostate luminal (but not basal) cells and transcriptionally activates ING4 and its E3 ligase JFK. CREB1-dependent transient ING4 expression is required for luminal cell induction; failure to downregulate ING4 causes luminal cell death. Oncogenic PTEN loss causes constitutive CREB1 activation, which suppresses ING4, disrupting luminal differentiation.","method":"RNA-Seq, CREB1 blocking (pharmacological), overexpression/knockdown constructs, identification of ING4 and JFK as CREB1 transcriptional targets, PTEN-KO oncogenic transformation model, IHC of primary prostate tumors, xenograft tumor growth assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-Seq transcriptomics, pharmacological CREB1 inhibition, in vivo xenograft, IHC of patient tumors; single lab, multiple orthogonal methods","pmids":["33846571"],"is_preprint":false},{"year":2022,"finding":"EBOV VP35 binds human AKIP1, which activates PKA and its downstream transcription factor CREB1. During Ebola infection, CREB1 is recruited into viral ribonucleoprotein complexes in viral inclusion bodies (VIBs) and is required for viral replication. AKIP1 depletion or PKA-CREB1 inhibition dramatically impairs EBOV replication. VP35-dependent CREB1 activation also upregulates coagulation genes THBD and SERPINB2.","method":"Co-immunoprecipitation (VP35-AKIP1), confocal colocalization in VIBs, siRNA depletion of AKIP1, PKA-CREB1 pharmacological inhibition, EBOV replication assays, transcriptomic analysis of CREB1 target genes","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, imaging-based localization in functional viral structures, multiple genetic/pharmacological perturbations, replicated mechanistic chain; single lab but multiple orthogonal methods","pmids":["35474062"],"is_preprint":false},{"year":2023,"finding":"Mettl3 (m6A methyltransferase) modulates the stability of Creb1 mRNA in an m6A-dependent manner in iNKT cells; Mettl3 deficiency decreases Creb1 mRNA stability and reduces Creb1 protein and phosphorylation levels. Conditional ablation of Creb1 in DP thymocytes phenocopies Mettl3 loss; ectopic Creb1 expression rescues developmental defects in Mettl3-deficient iNKT cells.","method":"Conditional KO of Mettl3 and Creb1 in DP thymocytes, transcriptomic and epi-transcriptomic analyses (m6A mapping), ectopic Creb1 expression rescue, flow cytometry, cytokine secretion assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (double KO and rescue), epi-transcriptomic m6A mapping, multiple functional readouts; single lab, multiple orthogonal methods","pmids":["37267102"],"is_preprint":false},{"year":2023,"finding":"Cullin-5 acts as an E3 ubiquitin ligase that ubiquitylates and degrades CREB1 protein, especially under proteotoxic stress. Cullin-5 deficiency leads to CREB1 accumulation and activation of CREB1-CCL2 signaling, promoting monocyte/MDSC accumulation and T-cell reduction in the tumor microenvironment.","method":"CRISPR-Cas9 genome-wide screen and Sleeping Beauty transposon mutagenesis in mice, ubiquitylation assay (Cullin-5 ubiquitylates CREB1), CREB1 inhibitor treatment, immune cell profiling by flow cytometry","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vivo ubiquitylation assay identifying CREB1 as Cullin-5 substrate, two independent genetic screens, pharmacological validation; single lab","pmids":["36662868"],"is_preprint":false},{"year":2021,"finding":"CREB1 directly binds the promoter of CCAT1 lncRNA and activates its transcription to sustain MYC expression and cell proliferation. Additionally, in the absence of CREB1, competition between CREB1 and p65 for CBP/p300 is unbalanced, leading to NF-κB pathway activation and EMT in colorectal cancer cells.","method":"CREB1 CRISPR knockout in HCT116 cells, monitoring of 45 signaling pathways, ChIP (CREB1 at CCAT1 promoter), co-activator competition assay","journal":"Science China. Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming direct promoter binding, CRISPR KO with signaling pathway profiling; single lab, multiple methods","pmids":["35696016"],"is_preprint":false},{"year":2019,"finding":"CREB1 acts as a transcription factor that binds the promoter of the Lin28 gene to activate Lin28 expression; CREB1 also directly binds the VASP promoter. Through this dual transcriptional control, CREB1 activates a CREB1/Lin28/miR-638/VASP interactive network promoting cell proliferation and migration in breast cancer.","method":"ChIP (CREB1 binding at Lin28 and VASP promoters), reporter assays, RNA-binding protein assays, overexpression/knockdown","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming direct promoter binding at two targets; single lab","pmids":["31754343"],"is_preprint":false},{"year":2020,"finding":"Norepinephrine (NE) induces CREB1 phosphorylation, and phosphorylated CREB1 binds to the miR-373 promoter to transcriptionally activate miR-373 expression, which promotes colon cancer cell proliferation and invasion through TIMP2 and APC suppression.","method":"ChIP (pCREB1 at miR-373 promoter), reporter assays, siRNA/overexpression of CREB1 and miR-373, in vitro and in vivo tumor models","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming direct binding, in vivo tumor model; single lab","pmids":["32118353"],"is_preprint":false},{"year":2023,"finding":"CREB1 transcriptionally activates SCD (stearoyl-CoA desaturase) via direct promoter binding; SCD increases monounsaturated fatty acid availability and thereby confers ferroptosis resistance. PKA inhibition reduces CREB1 activity and sensitizes NSCLC cells to ferroptosis inducers; SCD overexpression rescues the effect of CREB1 knockdown.","method":"High-throughput ChIP screening, dual-luciferase assay, CREB1 knockdown, SCD overexpression rescue, lipid peroxidation assays, xenograft tumor experiments","journal":"Respiratory research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase assay confirming direct activation, genetic rescue experiment, in vivo xenograft; single lab","pmids":["37957645"],"is_preprint":false},{"year":2021,"finding":"CREB1 directly binds to the promoter of HLA-E and activates its transcription in multiple myeloma cells. Pharmacological or genomic inhibition of CREB1 reduces HLA-E levels even in the presence of IFN-γ, thereby restoring NK cell-mediated cytotoxicity against MM cells.","method":"ChIP (CREB1 at HLA-E promoter), CREB1 knockdown/knockout and pharmacological inhibition, NK cell cytotoxicity assays, IFN-γ stimulation","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming direct promoter binding, genetic and pharmacological perturbation, functional NK cell assay; single lab","pmids":["38902472"],"is_preprint":false},{"year":2024,"finding":"HTR2B (serotonin receptor) signaling activates S6K1 via Akt/mTOR, which phosphorylates CREB1 at Ser133, promoting CREB1 nuclear translocation. Nuclear phospho-CREB1 then binds the CREB1 half-site (GTCA) in the ZEB1 promoter to transcriptionally activate ZEB1, driving EMT and colorectal cancer metastasis.","method":"Pharmacological blocking and genetic knockdown of HTR2B, ChIP (pCREB1 at ZEB1 promoter), reporter assay with CREB1 half-site, phospho-CREB1 nuclear translocation assay, in vivo metastasis mouse models","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with promoter half-site validation, in vivo metastasis models, pathway epistasis; single lab","pmids":["38381131"],"is_preprint":false},{"year":2021,"finding":"CREB1 directly binds the promoter of SRGN to activate its transcription in nasopharyngeal carcinoma. CREB1 expression is controlled upstream by the FoxO1-miR-148a-5p axis (FoxO1 activates miR-148a-5p transcription; miR-148a-5p targets CREB1). STAT3 suppression upregulates FoxO1, leading to miR-148a-5p-mediated downregulation of CREB1 and SRGN.","method":"EMSA and ChIP (CREB1/FoxO1 binding at SRGN/miR-148a-5p promoters), dual-luciferase reporter assay, RIP assay, xenograft tumor model, siRNA knockdown","journal":"Laboratory investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA and ChIP confirming direct binding, dual-luciferase validation, in vivo xenograft; single lab","pmids":["35562411"],"is_preprint":false},{"year":2022,"finding":"CREB1 binds to the promoter of the lncRNA PVT1 and activates its transcription in cardiac fibroblasts during TGF-β1-induced cardiac fibrosis, as confirmed by ChIP assay.","method":"ChIP assay (CREB1 at PVT1 promoter), luciferase reporter assay, siRNA knockdown, in vitro and in vivo cardiac fibrosis models","journal":"International journal of cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming direct binding, reporter assay validation; single lab","pmids":["35063587"],"is_preprint":false},{"year":2023,"finding":"CREB1 and progesterone receptor (PGR) bind directly to the PTPN11 (SHP2) core promoter (-229 to +1 bp) in response to progesterone and cAMP during uterine stromal decidualization, as confirmed by EMSA and ChIP. Knockdown of either PGR or CREB1 significantly inhibits SHP2 expression induced by medroxyprogesterone acetate and cAMP.","method":"Luciferase reporter with promoter deletion mapping, EMSA, ChIP, siRNA knockdown of PGR and CREB1 in human endometrial stromal cells","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA and ChIP confirming direct binding, functional knockdown; single lab, multiple orthogonal methods","pmids":["37786383"],"is_preprint":false},{"year":2011,"finding":"Striatal CREB1 in medium spiny neurons negatively regulates sensitivity to psychostimulants (cocaine, amphetamine). Postnatal deletion of CREB1 in these neurons increased psychostimulant sensitivity; loss of CREB1 was accompanied by rapid upregulation of the related transcription factor CREM, suggesting partial redundancy. Striatal deletion of CBP (CREB1 coactivator) produced even greater psychostimulant sensitivity.","method":"Cre/lox conditional KO of CREB1 or CBP in striatal medium spiny neurons, locomotor and sensitization behavioral assays, qRT-PCR and immunohistochemistry for CREM","journal":"Psychopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined behavioral phenotype, compensatory mechanism identified; single lab","pmids":["21766169"],"is_preprint":false},{"year":2019,"finding":"In C. elegans, a specific isoform of CREB1/CRH-1 (CRH-1e) is primarily responsible for long-term memory (LTM) formation. Expression of CRH-1e in RIM neurons is sufficient to rescue LTM defects in crh-1 null mutants. Two amino acids, K247 and K266, within CREB1/CRH-1 are required for LTM-related functions but dispensable for innate chemotaxis behavior.","method":"Isoform-specific null mutants, neuron-specific rescue expression, site-directed mutagenesis (K247, K266), LTM behavioral assays, neuron silencing during training","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-specific KO + neuron-specific rescue + mutagenesis establishing distinct residue requirements; C. elegans ortholog of mammalian CREB1","pmids":["31413073"],"is_preprint":false},{"year":2024,"finding":"Forskolin-driven neuronal reprogramming of human somatic cells operates via the cAMP-CREB1-JNK signaling axis: forskolin upregulates cAMP-CREB1 expression and downregulates JNK expression to convert somatic cells into induced neurons (FiNs).","method":"Small-molecule-driven reprogramming, western blot for cAMP/CREB1/JNK pathway components, immunofluorescence for neuronal markers, electrophysiological activity recordings in vitro and survival in vivo","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway identified with biochemical readouts and functional neuronal outcome; single lab","pmids":["38389831"],"is_preprint":false},{"year":2024,"finding":"CREB1 signaling promotes ADT-induced neuroendocrine differentiation (NED) in prostate cancer cells by enhancing EZH2-mediated epigenetic repression of REST. Genetic rescue experiments showed that ADT induces NED through EZH2's repression of REST, with ADT-activated CREB1 signaling enhancing EZH2 activity. CREB1 signaling also directly represses REST expression.","method":"REST overexpression/knockdown, CREB1 signaling inhibition, EZH2 inhibition, genetic rescue experiments, ADT treatment in PCa cell lines and mouse xenografts, patient sample analysis","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via rescue experiments, in vivo xenograft, multiple pathway perturbations; single lab","pmids":["38777812"],"is_preprint":false},{"year":2021,"finding":"CREB1 directly binds the promoter of miR-922 in liver cancer cells (confirmed by ChIP-PCR), activating its transcription. miR-922 then targets and suppresses ARID2 expression (confirmed by dual luciferase), enhancing malignant behavior.","method":"ChIP-PCR (CREB1 at miR-922 promoter), dual luciferase reporter assay, RIP assay, ARID2 overexpression rescue, xenograft tumor models","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-PCR and luciferase confirming direct transcriptional activation and downstream target; single lab","pmids":["33786634"],"is_preprint":false},{"year":2022,"finding":"Regorafenib inhibits p38 kinase phosphorylation and downstream Creb1/Klf4 activity in macrophages, reversing M2 polarization toward M1. ChIP confirmed p38/Creb1/Klf4 activity at relevant promoters. This mechanism is independent of anti-angiogenic effects.","method":"ChIP (Creb1/Klf4 at target genes), p38 kinase inhibitor, MAPK14 knockdown, macrophage polarization markers (flow cytometry, ELISA, qRT-PCR), in vivo syngeneic liver cancer models","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming Creb1/Klf4 pathway activity, multiple orthogonal methods; single lab","pmids":["33753566"],"is_preprint":false},{"year":2022,"finding":"CRTC2 and CREB1 act as transcriptional activators of miR-93-3p in renal tubular epithelial cells exposed to calcium oxalate crystals; CREB1/CRTC2 binding to the miR-93-3p promoter was confirmed by EMSA and ChIP-qPCR.","method":"EMSA, ChIP-qPCR (CREB1/CRTC2 at miR-93-3p promoter), dual-luciferase reporter assay, siRNA knockdown, in vivo mouse model","journal":"Journal of nanobiotechnology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA and ChIP-qPCR confirming direct binding, functional rescue; single lab","pmids":["40069788"],"is_preprint":false},{"year":1990,"finding":"The human CREB1 gene was assigned to chromosome 2q32.3-q34 using somatic cell hybrid Southern blot analysis and in situ hybridization. CREB1 was identified as a nuclear phosphoprotein involved in transcriptional regulation of cAMP-inducible genes.","method":"Southern blot analysis of mouse-human somatic cell hybrids, in situ hybridization, chromosome 2 translocation mapping","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 2 / Strong — chromosomal localization confirmed by two independent mapping methods (somatic cell hybrids + in situ hybridization); foundational genomic characterization","pmids":["2142119"],"is_preprint":false}],"current_model":"CREB1 is a nuclear phosphoprotein transcription factor that binds CRE (cAMP-response element) sites in target gene promoters upon phosphorylation (e.g., at Ser133 by PKA, CaMKIV, CDK5, RSK, or AKT-activated kinases); it recruits co-activators such as CBP/p300 and CRTC family coactivators (notably CRTC1/CRTC2) to drive transcription of diverse target genes (including TGFB2, CCAT1, HLA-E, SCD, LTBR, SRGN, miR-320a, miR-373, miR-922, Lin28, VASP, ZEB1, TH, and many others); its activity is repressed by CCDC6 (which recruits HDAC1 and PP1 to CRE sites), regulated post-translationally by Cullin-5-mediated ubiquitylation and degradation, and at the mRNA level by m6A modification via Mettl3, placing CREB1 as a central, signal-integrating transcriptional hub downstream of cAMP/PKA, PI3K/AKT/mTOR, MAPK/ERK, CaMKK/CaMKIV, and p38 signaling cascades with defined roles in energy homeostasis, neuronal function and memory, immune cell differentiation, cancer cell plasticity, viral replication, and organ development."},"narrative":{"mechanistic_narrative":"CREB1 is a nuclear phosphoprotein transcription factor that integrates multiple upstream signaling cascades to drive transcription of cAMP-responsive target genes, functioning as a central, signal-convergent regulator of cellular proliferation, differentiation, energy homeostasis, and stress responses [PMID:2142119, PMID:25084773]. Its activity is gated by phosphorylation: PKA downstream of cAMP/AKIP1 [PMID:35474062], CDK5 in a PKA-independent manner [PMID:29742423], CaMKIV downstream of DJ-1/CaMKKβ [PMID:31232473], PI3K/AKT and RSK pathways [PMID:25084773, PMID:26348925], S6K1 downstream of HTR2B/Akt/mTOR (which drives Ser133 phosphorylation and nuclear translocation) [PMID:38381131], and p38 MAPK [PMID:33753566]. Once activated, CREB1 binds CRE elements (including CREB half-sites such as GTCA) in target promoters and recruits co-activators — it cooperates with CRTC1/CRTC2 [PMID:18758446, PMID:40069788], with the CBP/p300 histone acetyltransferases via the Lyl1 interaction [PMID:18160048], and with sequence-specific partners including SMAD3, MeCP2, PGR, and FoxO1 to activate context-specific programs [PMID:25084773, PMID:23493374, PMID:37786383, PMID:35562411]. Through these mechanisms CREB1 directly transactivates a broad target repertoire including TGFB2, SCD, HLA-E, ZEB1, Lin28/VASP, SRGN, the lncRNAs CCAT1 and PVT1, and numerous miRNAs (miR-320a, miR-373, miR-922, miR-93-3p), thereby controlling tumor cell proliferation, migration, EMT, ferroptosis resistance, immune evasion, and viral replication [PMID:25084773, PMID:37957645, PMID:38902472, PMID:38381131, PMID:31754343, PMID:35696016, PMID:33786634]. CREB1 output is restrained by CCDC6, which recruits HDAC1 and PP1 to CRE sites [PMID:20498639], and CREB1 levels are set post-translationally by Cullin-5-mediated ubiquitylation and degradation [PMID:36662868] and post-transcriptionally by Mettl3-dependent m6A stabilization of its mRNA [PMID:37267102]. In the nervous system CREB1 governs long-term memory and neuronal reprogramming and modulates psychostimulant sensitivity, with CREM providing partial functional redundancy [PMID:31413073, PMID:38389831, PMID:21766169].","teleology":[{"year":1990,"claim":"Established CREB1 as a discrete genomic locus and identified it as a nuclear phosphoprotein regulating cAMP-inducible transcription, providing the foundational identity of the gene.","evidence":"Somatic cell hybrid Southern blot and in situ hybridization mapping to chromosome 2q32.3-q34","pmids":["2142119"],"confidence":"High","gaps":["No mechanistic detail of target genes or co-activator recruitment at this stage","Phosphorylation sites not yet mapped"]},{"year":2007,"claim":"Resolved how CREB1 can activate transcription independent of Ser133 phosphorylation, showing a partner protein bridges CREB1 to histone acetyltransferases.","evidence":"Co-IP with domain mapping, genome-wide ChIP-chip and reporter assays identifying Lyl1 recruitment of p300/CBP to CREB1 targets","pmids":["18160048"],"confidence":"High","gaps":["Generality of phosphorylation-independent activation across other partners unknown","Physiological contexts limited to mapped targets (Id1, Id3, cyclin D3, etc.)"]},{"year":2008,"claim":"Defined the CREB1-CRTC1 module as the effector of leptin signaling in the hypothalamus, linking CREB1 to whole-body energy balance and fertility.","evidence":"Dominant-negative CREB1, hypothalamic ChIP of CRTC1 at Cartpt/Kiss1 promoters, Crtc1 KO mouse","pmids":["18758446"],"confidence":"High","gaps":["Does not address CREB1 phosphorylation requirement in this context","CRTC1 dephosphorylation mechanism not fully resolved"]},{"year":2010,"claim":"Identified a direct repressor of CREB1, showing transcriptional output is actively restrained at CRE sites and that loss of this brake drives oncogenic CREB1 activity.","evidence":"Reciprocal Co-IP, ChIP and reporter assays showing CCDC6 recruits HDAC1/PP1 to CRE promoters; PTC tumor validation","pmids":["20498639"],"confidence":"High","gaps":["Whether CCDC6 acts on all CREB1 targets or a subset unknown","Dynamics of repression versus activation switching not defined"]},{"year":2011,"claim":"Established that CREB1 functions in feedback miRNA loops and that striatal CREB1 modulates behavior, with CREM compensation revealing functional redundancy.","evidence":"ChIP of CREB1 at miRNA regulatory regions in thyroid cells (TSH loop); conditional striatal CREB1/CBP KO with behavioral assays","pmids":["21816899","21766169"],"confidence":"Medium","gaps":["Extent of CREM redundancy across tissues unquantified","Direct versus indirect miRNA suppression mechanism incomplete"]},{"year":2013,"claim":"Placed CREB1 within the mTOR/autophagy axis and showed it cooperates with methyl-CpG-binding machinery, expanding its mechanistic repertoire to methylation-dependent transactivation and DNA-damage responses.","evidence":"siRNA epistasis in TSC2/PTEN-loss models with etoposide (mTOR axis); sequential ChIP and Co-IP with MeCP2 at the methylated Glut3 promoter","pmids":["24189100","23493374"],"confidence":"Medium","gaps":["How mTOR mechanistically activates CREB1 not defined","Generality of CREB1-MeCP2 cooperation beyond Glut3 unknown"]},{"year":2014,"claim":"Demonstrated CREB1 cooperates with SMAD3 to drive an autocrine TGFB2 loop, integrating PI3K/AKT and RSK inputs into a defined oncogenic transcriptional output.","evidence":"ChIP of CREB1 at the TGFB2 promoter, pathway inhibitor epistasis, patient-derived glioblastoma xenografts","pmids":["25084773"],"confidence":"High","gaps":["Structural basis of CREB1-SMAD3 cooperation not resolved","Relative contribution of AKT versus RSK phosphorylation unclear"]},{"year":2015,"claim":"Connected CREB1 to specific receptor-driven proliferation and to mitophagy, broadening its role across estrogen signaling and metabolic/organelle quality-control programs.","evidence":"ERα structure-function mutagenesis with PI3K/AKT inhibition and CREB1 reporters (E2 proliferation); promoter mapping and ChIP of CREB1 at miR-320a controlling VDAC1/mitophagy","pmids":["26348925","26472185"],"confidence":"Medium","gaps":["Single-lab evidence for each axis","Direct CREB1 kinase in the ERα context not pinned down"]},{"year":2018,"claim":"Identified phosphorylation-independent and epigenetic kinase inputs to CREB1, showing CDK5 and SETD2/H3K36me3-supported ERK signaling sustain CREB1 activity in cancer.","evidence":"Drosophila suppressor screen with CDK5 inhibition in glioma stem cells; SETD2 mutant expression and CREB1 siQ in NSCLC with H3K36me3/pCREB1 readouts","pmids":["29742423","30093630"],"confidence":"Medium","gaps":["Direct versus indirect CDK5 phosphorylation of CREB1 not shown biochemically","Mechanistic link from H3K36me3 to CREB1 phosphorylation incomplete"]},{"year":2019,"claim":"Linked CREB1 to CaMKIV-dependent neuronal gene control and defined isoform- and residue-specific requirements for its memory function, distinguishing roles from innate behavior.","evidence":"DJ-1/CaMKKβ Co-IP and Dj-1 KO mice (TH regulation); 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p38/Creb1/Klf4 ChIP in macrophages; ChIP of CREB1 at PVT1 in cardiac fibroblasts","pmids":["35474062","33753566","35063587"],"confidence":"High","gaps":["Function of CREB1 within viral ribonucleoprotein complexes mechanistically unresolved","Direct DNA-binding role versus signaling role in VIBs not separated"]},{"year":2023,"claim":"Defined the post-translational and post-transcriptional control layers governing CREB1 abundance and extended its target repertoire to lipid metabolism and immune modulation.","evidence":"In vivo ubiquitylation assay and genetic screens (Cullin-5 degrades CREB1, CREB1-CCL2 axis); conditional Mettl3/Creb1 KO with m6A mapping and rescue (iNKT); ChIP/luciferase of SCD with rescue (ferroptosis); PGR/CREB1 EMSA/ChIP at PTPN11 (decidualization)","pmids":["36662868","37267102","37957645","37786383"],"confidence":"High","gaps":["Stress signals triggering Cullin-5-mediated degradation incompletely defined","m6A reader linking Mettl3 to Creb1 mRNA stability not identified"]},{"year":2024,"claim":"Connected CREB1 to receptor-driven EMT/metastasis, neuroendocrine differentiation, and neuronal reprogramming, reinforcing its role as a convergent effector across signaling-to-fate programs.","evidence":"HTR2B/S6K1 axis with ChIP of pCREB1 at ZEB1 and metastasis models; 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Leptin promotes nuclear dephosphorylation of Crtc1, which then co-occupies Cartpt and Kiss1 promoters with Creb1; a dominant-negative Creb1 polypeptide disrupted these effects, establishing Creb1-Crtc1 as the pathway mediating leptin's central effects on energy balance and fertility.\",\n      \"method\": \"Dominant-negative CREB1 expression, ChIP (chromatin immunoprecipitation) of hypothalamic Crtc1 at target promoters, Crtc1 overexpression/depletion in hypothalamic cells, Crtc1−/− mouse model\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional experiments (dominant-negative, KO mouse, ChIP), multiple orthogonal methods in one study, clear phenotypic readout\",\n      \"pmids\": [\"18758446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CCDC6 physically interacts with CREB1 and represses its transcriptional activity by recruiting histone deacetylase 1 (HDAC1) and protein phosphatase 1 (PP1) to CRE-containing promoters of CREB1 target genes (including AREG and cyclin A). Loss of CCDC6 via RET/PTC1 fusion leads to increased CREB1 phosphorylation and target gene expression in papillary thyroid carcinoma.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), reporter assays, expression analysis in PTC tumor specimens\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP identifying complex components, ChIP confirming promoter recruitment, functional reporter assays, with disease-context validation\",\n      \"pmids\": [\"20498639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Creb1 forms a complex with Mecp2 at methylated CpG sites in the Glut3 gene promoter to transactivate neuronal Glut3 expression. Sequential ChIP showed Creb1 recruitment of Mecp2 to glut3-mCpGs; co-IP confirmed Creb1-Mecp2 association; siRNA depletion of Creb1 or Mecp2 reduced Glut3 expression, establishing a methylation-dependent transactivation mechanism.\",\n      \"method\": \"Sequential chromatin immunoprecipitation (ChIP), co-immunoprecipitation, siRNA knockdown, luciferase reporter assay, bisulfite sequencing\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (sequential ChIP, Co-IP, siRNA, reporter), single lab but comprehensive mechanistic dissection\",\n      \"pmids\": [\"23493374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MTOR positively regulates CREB1 activity; impaired autophagy (due to TSC2 or PTEN loss) leads to CREB1 hyperactivation; CREB1 in turn promotes DNA damage and apoptosis in response to etoposide. Silencing Creb1 with siRNA protected MTOR-hyperactive cells from DNA damage-induced apoptosis, placing CREB1 downstream of MTOR and upstream of DNA damage responses.\",\n      \"method\": \"siRNA knockdown of Creb1, TSC2/PTEN loss-of-function models (MEFs and cancer lines), etoposide treatment, autophagy manipulation, analysis in TSC patient kidney tumor tissue and hepatocyte-specific PTEN-KO mouse livers\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via KO/KD with defined phenotypic readout, multiple cell and in vivo models, single lab\",\n      \"pmids\": [\"24189100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CREB1 directly binds the TGFB2 gene promoter in cooperation with SMAD3 to mediate TGFβ-induced TGFβ2 transcription, creating an autocrine loop. The PI3K-AKT and RSK pathways regulate this loop through CREB1. Patient-derived glioblastoma in vivo models confirmed that CREB1 levels determine TGFβ2 expression.\",\n      \"method\": \"ChIP (CREB1 binding at TGFB2 promoter), dominant-negative and overexpression constructs, PI3K/AKT/RSK pathway inhibitors, patient-derived glioblastoma xenograft models\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP establishing direct promoter binding, pathway inhibitor epistasis, in vivo patient-derived models, multiple orthogonal methods in one study\",\n      \"pmids\": [\"25084773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CREB1 interacts with the transcription factor Lyl1 via the N-terminal domain of Lyl1 and the Q2 and KID domains of CREB1; this interaction recruits histone acetyltransferases p300 and CBP to CREB1-target promoters (including Id1, Id3, cyclin D3, Brca1, Btg2, Egr1) in the absence of CREB1 Ser133 phosphorylation, resulting in transcriptional activation.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, ChIP-chip (genome-wide promoter occupancy), reporter assays\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with domain mapping, genome-wide ChIP-chip, functional reporter assays; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"18160048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CREB1 binds the promoter of miR-320a and activates its transcription during serum starvation; this induces mitophagy by downregulating VDAC1 in cervical cancer cells. Serum starvation sequentially induced CREB1, then miR-320a, then reduced VDAC1 to facilitate mitophagy.\",\n      \"method\": \"Promoter cloning and deletion mapping, ChIP (CREB1 at miR-320a promoter), overexpression/knockdown experiments, immunoblot for VDAC1 and mitophagy markers\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming direct promoter binding, promoter core region mapped, functional rescue; single lab\",\n      \"pmids\": [\"26472185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A TSH-CREB1-miRNA loop controls thyroid cell proliferation: thyrotropin (TSH) activates CREB1, which binds the regulatory regions of five specific miRNAs (miR-1, miR-28-A, miR-290-5p, miR-296-3p, miR-297a) and suppresses their expression; three of these miRNAs target CREB1, forming a feedback loop required for TSH-driven thyroid cell growth.\",\n      \"method\": \"ChIP (CREB1 binding to miRNA regulatory regions), overexpression of miRNAs, reporter assays, TSH stimulation of thyroid cells\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishing direct binding, miRNA overexpression phenotype, feedback loop validated; single lab\",\n      \"pmids\": [\"21816899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"E2-induced PI3K/AKT pathway activation drives CREB1 phosphorylation and CREB1-mediated transcriptional activity that controls 17β-estradiol (E2)-induced cell proliferation. ERα residues L429 and A430 are required for E2-induced PI3K/AKT/CREB1 pathway activation; mutation of these residues abolishes E2-induced CREB1 phosphorylation and proliferation.\",\n      \"method\": \"Stable cell lines expressing L429A,A430G-ERα mutants, PI3K/AKT inhibition, CREB1 reporter assays, proliferation assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structure-function mutagenesis of ERα, pathway inhibitors, CREB1 reporter assays; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"26348925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CDK5 (PKA/cAMP-independent) maintains CREB1 activation in glioma stem cells (GSCs) to support self-renewal. Pharmacological CDK5 inhibition suppresses CREB1 activation in vitro and in GSC xenograft tumors. A Drosophila genetic suppressor screen identified dCdk5 as a critical regulator, with human CDK5 (79% identity) validated as the ortholog.\",\n      \"method\": \"Drosophila genetic suppressor screen, CDK5 pharmacological inhibition, GSC self-renewal assays in vitro and xenograft tumors, TCGA data analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic suppressor screen (ortholog validated), in vitro and in vivo pharmacological inhibition; single lab\",\n      \"pmids\": [\"29742423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SETD2-mediated H3K36 trimethylation (H3K36me3) is required for CREB1 phosphorylation and ERK pathway activation in NSCLC cells; a SETD2 missense mutation (p.T1171K) found in cisplatin-resistant metastatic NSCLC impairs H3K36me3 and CREB1 phosphorylation, conferring cisplatin resistance. Suppression of either SETD2 or CREB1 reduced cisplatin sensitivity.\",\n      \"method\": \"NGS identification of SETD2 mutation, ectopic expression of mutant SETD2, CREB1 siRNA knockdown, measurement of H3K36me3 and CREB1 phosphorylation, cisplatin cytotoxicity assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (mutant overexpression + siRNA KD), biochemical readouts of H3K36me3 and pCREB1; single lab\",\n      \"pmids\": [\"30093630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DJ-1 directly interacts with CaMKKβ and modulates CaMKIV/CREB1 (Ser133) phosphorylation to regulate tyrosine hydroxylase (TH) expression. In Dj-1 knockout mouse substantia nigra, CaMKIV phosphorylation, CREB1 Ser133 phosphorylation, and TH levels are all reduced. siRNA knockdown of Creb1 abolishes DJ-1's effect on TH.\",\n      \"method\": \"Co-immunoprecipitation (DJ-1 with CaMKKβ), Dj-1 knockout mice, siRNA knockdown of Creb1, immunoblot for phospho-CaMKIV and phospho-CREB1 Ser133\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying complex, KO mice, epistasis via Creb1 siRNA; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"31232473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CREB1 is constitutively active in prostate luminal (but not basal) cells and transcriptionally activates ING4 and its E3 ligase JFK. CREB1-dependent transient ING4 expression is required for luminal cell induction; failure to downregulate ING4 causes luminal cell death. Oncogenic PTEN loss causes constitutive CREB1 activation, which suppresses ING4, disrupting luminal differentiation.\",\n      \"method\": \"RNA-Seq, CREB1 blocking (pharmacological), overexpression/knockdown constructs, identification of ING4 and JFK as CREB1 transcriptional targets, PTEN-KO oncogenic transformation model, IHC of primary prostate tumors, xenograft tumor growth assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-Seq transcriptomics, pharmacological CREB1 inhibition, in vivo xenograft, IHC of patient tumors; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"33846571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EBOV VP35 binds human AKIP1, which activates PKA and its downstream transcription factor CREB1. During Ebola infection, CREB1 is recruited into viral ribonucleoprotein complexes in viral inclusion bodies (VIBs) and is required for viral replication. AKIP1 depletion or PKA-CREB1 inhibition dramatically impairs EBOV replication. VP35-dependent CREB1 activation also upregulates coagulation genes THBD and SERPINB2.\",\n      \"method\": \"Co-immunoprecipitation (VP35-AKIP1), confocal colocalization in VIBs, siRNA depletion of AKIP1, PKA-CREB1 pharmacological inhibition, EBOV replication assays, transcriptomic analysis of CREB1 target genes\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, imaging-based localization in functional viral structures, multiple genetic/pharmacological perturbations, replicated mechanistic chain; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"35474062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Mettl3 (m6A methyltransferase) modulates the stability of Creb1 mRNA in an m6A-dependent manner in iNKT cells; Mettl3 deficiency decreases Creb1 mRNA stability and reduces Creb1 protein and phosphorylation levels. Conditional ablation of Creb1 in DP thymocytes phenocopies Mettl3 loss; ectopic Creb1 expression rescues developmental defects in Mettl3-deficient iNKT cells.\",\n      \"method\": \"Conditional KO of Mettl3 and Creb1 in DP thymocytes, transcriptomic and epi-transcriptomic analyses (m6A mapping), ectopic Creb1 expression rescue, flow cytometry, cytokine secretion assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (double KO and rescue), epi-transcriptomic m6A mapping, multiple functional readouts; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"37267102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cullin-5 acts as an E3 ubiquitin ligase that ubiquitylates and degrades CREB1 protein, especially under proteotoxic stress. Cullin-5 deficiency leads to CREB1 accumulation and activation of CREB1-CCL2 signaling, promoting monocyte/MDSC accumulation and T-cell reduction in the tumor microenvironment.\",\n      \"method\": \"CRISPR-Cas9 genome-wide screen and Sleeping Beauty transposon mutagenesis in mice, ubiquitylation assay (Cullin-5 ubiquitylates CREB1), CREB1 inhibitor treatment, immune cell profiling by flow cytometry\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vivo ubiquitylation assay identifying CREB1 as Cullin-5 substrate, two independent genetic screens, pharmacological validation; single lab\",\n      \"pmids\": [\"36662868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CREB1 directly binds the promoter of CCAT1 lncRNA and activates its transcription to sustain MYC expression and cell proliferation. Additionally, in the absence of CREB1, competition between CREB1 and p65 for CBP/p300 is unbalanced, leading to NF-κB pathway activation and EMT in colorectal cancer cells.\",\n      \"method\": \"CREB1 CRISPR knockout in HCT116 cells, monitoring of 45 signaling pathways, ChIP (CREB1 at CCAT1 promoter), co-activator competition assay\",\n      \"journal\": \"Science China. Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming direct promoter binding, CRISPR KO with signaling pathway profiling; single lab, multiple methods\",\n      \"pmids\": [\"35696016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CREB1 acts as a transcription factor that binds the promoter of the Lin28 gene to activate Lin28 expression; CREB1 also directly binds the VASP promoter. Through this dual transcriptional control, CREB1 activates a CREB1/Lin28/miR-638/VASP interactive network promoting cell proliferation and migration in breast cancer.\",\n      \"method\": \"ChIP (CREB1 binding at Lin28 and VASP promoters), reporter assays, RNA-binding protein assays, overexpression/knockdown\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming direct promoter binding at two targets; single lab\",\n      \"pmids\": [\"31754343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Norepinephrine (NE) induces CREB1 phosphorylation, and phosphorylated CREB1 binds to the miR-373 promoter to transcriptionally activate miR-373 expression, which promotes colon cancer cell proliferation and invasion through TIMP2 and APC suppression.\",\n      \"method\": \"ChIP (pCREB1 at miR-373 promoter), reporter assays, siRNA/overexpression of CREB1 and miR-373, in vitro and in vivo tumor models\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming direct binding, in vivo tumor model; single lab\",\n      \"pmids\": [\"32118353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CREB1 transcriptionally activates SCD (stearoyl-CoA desaturase) via direct promoter binding; SCD increases monounsaturated fatty acid availability and thereby confers ferroptosis resistance. PKA inhibition reduces CREB1 activity and sensitizes NSCLC cells to ferroptosis inducers; SCD overexpression rescues the effect of CREB1 knockdown.\",\n      \"method\": \"High-throughput ChIP screening, dual-luciferase assay, CREB1 knockdown, SCD overexpression rescue, lipid peroxidation assays, xenograft tumor experiments\",\n      \"journal\": \"Respiratory research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase assay confirming direct activation, genetic rescue experiment, in vivo xenograft; single lab\",\n      \"pmids\": [\"37957645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CREB1 directly binds to the promoter of HLA-E and activates its transcription in multiple myeloma cells. Pharmacological or genomic inhibition of CREB1 reduces HLA-E levels even in the presence of IFN-γ, thereby restoring NK cell-mediated cytotoxicity against MM cells.\",\n      \"method\": \"ChIP (CREB1 at HLA-E promoter), CREB1 knockdown/knockout and pharmacological inhibition, NK cell cytotoxicity assays, IFN-γ stimulation\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming direct promoter binding, genetic and pharmacological perturbation, functional NK cell assay; single lab\",\n      \"pmids\": [\"38902472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HTR2B (serotonin receptor) signaling activates S6K1 via Akt/mTOR, which phosphorylates CREB1 at Ser133, promoting CREB1 nuclear translocation. Nuclear phospho-CREB1 then binds the CREB1 half-site (GTCA) in the ZEB1 promoter to transcriptionally activate ZEB1, driving EMT and colorectal cancer metastasis.\",\n      \"method\": \"Pharmacological blocking and genetic knockdown of HTR2B, ChIP (pCREB1 at ZEB1 promoter), reporter assay with CREB1 half-site, phospho-CREB1 nuclear translocation assay, in vivo metastasis mouse models\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with promoter half-site validation, in vivo metastasis models, pathway epistasis; single lab\",\n      \"pmids\": [\"38381131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CREB1 directly binds the promoter of SRGN to activate its transcription in nasopharyngeal carcinoma. CREB1 expression is controlled upstream by the FoxO1-miR-148a-5p axis (FoxO1 activates miR-148a-5p transcription; miR-148a-5p targets CREB1). STAT3 suppression upregulates FoxO1, leading to miR-148a-5p-mediated downregulation of CREB1 and SRGN.\",\n      \"method\": \"EMSA and ChIP (CREB1/FoxO1 binding at SRGN/miR-148a-5p promoters), dual-luciferase reporter assay, RIP assay, xenograft tumor model, siRNA knockdown\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA and ChIP confirming direct binding, dual-luciferase validation, in vivo xenograft; single lab\",\n      \"pmids\": [\"35562411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CREB1 binds to the promoter of the lncRNA PVT1 and activates its transcription in cardiac fibroblasts during TGF-β1-induced cardiac fibrosis, as confirmed by ChIP assay.\",\n      \"method\": \"ChIP assay (CREB1 at PVT1 promoter), luciferase reporter assay, siRNA knockdown, in vitro and in vivo cardiac fibrosis models\",\n      \"journal\": \"International journal of cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming direct binding, reporter assay validation; single lab\",\n      \"pmids\": [\"35063587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CREB1 and progesterone receptor (PGR) bind directly to the PTPN11 (SHP2) core promoter (-229 to +1 bp) in response to progesterone and cAMP during uterine stromal decidualization, as confirmed by EMSA and ChIP. Knockdown of either PGR or CREB1 significantly inhibits SHP2 expression induced by medroxyprogesterone acetate and cAMP.\",\n      \"method\": \"Luciferase reporter with promoter deletion mapping, EMSA, ChIP, siRNA knockdown of PGR and CREB1 in human endometrial stromal cells\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA and ChIP confirming direct binding, functional knockdown; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"37786383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Striatal CREB1 in medium spiny neurons negatively regulates sensitivity to psychostimulants (cocaine, amphetamine). Postnatal deletion of CREB1 in these neurons increased psychostimulant sensitivity; loss of CREB1 was accompanied by rapid upregulation of the related transcription factor CREM, suggesting partial redundancy. Striatal deletion of CBP (CREB1 coactivator) produced even greater psychostimulant sensitivity.\",\n      \"method\": \"Cre/lox conditional KO of CREB1 or CBP in striatal medium spiny neurons, locomotor and sensitization behavioral assays, qRT-PCR and immunohistochemistry for CREM\",\n      \"journal\": \"Psychopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined behavioral phenotype, compensatory mechanism identified; single lab\",\n      \"pmids\": [\"21766169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In C. elegans, a specific isoform of CREB1/CRH-1 (CRH-1e) is primarily responsible for long-term memory (LTM) formation. Expression of CRH-1e in RIM neurons is sufficient to rescue LTM defects in crh-1 null mutants. Two amino acids, K247 and K266, within CREB1/CRH-1 are required for LTM-related functions but dispensable for innate chemotaxis behavior.\",\n      \"method\": \"Isoform-specific null mutants, neuron-specific rescue expression, site-directed mutagenesis (K247, K266), LTM behavioral assays, neuron silencing during training\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific KO + neuron-specific rescue + mutagenesis establishing distinct residue requirements; C. elegans ortholog of mammalian CREB1\",\n      \"pmids\": [\"31413073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Forskolin-driven neuronal reprogramming of human somatic cells operates via the cAMP-CREB1-JNK signaling axis: forskolin upregulates cAMP-CREB1 expression and downregulates JNK expression to convert somatic cells into induced neurons (FiNs).\",\n      \"method\": \"Small-molecule-driven reprogramming, western blot for cAMP/CREB1/JNK pathway components, immunofluorescence for neuronal markers, electrophysiological activity recordings in vitro and survival in vivo\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway identified with biochemical readouts and functional neuronal outcome; single lab\",\n      \"pmids\": [\"38389831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CREB1 signaling promotes ADT-induced neuroendocrine differentiation (NED) in prostate cancer cells by enhancing EZH2-mediated epigenetic repression of REST. Genetic rescue experiments showed that ADT induces NED through EZH2's repression of REST, with ADT-activated CREB1 signaling enhancing EZH2 activity. CREB1 signaling also directly represses REST expression.\",\n      \"method\": \"REST overexpression/knockdown, CREB1 signaling inhibition, EZH2 inhibition, genetic rescue experiments, ADT treatment in PCa cell lines and mouse xenografts, patient sample analysis\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via rescue experiments, in vivo xenograft, multiple pathway perturbations; single lab\",\n      \"pmids\": [\"38777812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CREB1 directly binds the promoter of miR-922 in liver cancer cells (confirmed by ChIP-PCR), activating its transcription. miR-922 then targets and suppresses ARID2 expression (confirmed by dual luciferase), enhancing malignant behavior.\",\n      \"method\": \"ChIP-PCR (CREB1 at miR-922 promoter), dual luciferase reporter assay, RIP assay, ARID2 overexpression rescue, xenograft tumor models\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-PCR and luciferase confirming direct transcriptional activation and downstream target; single lab\",\n      \"pmids\": [\"33786634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Regorafenib inhibits p38 kinase phosphorylation and downstream Creb1/Klf4 activity in macrophages, reversing M2 polarization toward M1. ChIP confirmed p38/Creb1/Klf4 activity at relevant promoters. This mechanism is independent of anti-angiogenic effects.\",\n      \"method\": \"ChIP (Creb1/Klf4 at target genes), p38 kinase inhibitor, MAPK14 knockdown, macrophage polarization markers (flow cytometry, ELISA, qRT-PCR), in vivo syngeneic liver cancer models\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming Creb1/Klf4 pathway activity, multiple orthogonal methods; single lab\",\n      \"pmids\": [\"33753566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CRTC2 and CREB1 act as transcriptional activators of miR-93-3p in renal tubular epithelial cells exposed to calcium oxalate crystals; CREB1/CRTC2 binding to the miR-93-3p promoter was confirmed by EMSA and ChIP-qPCR.\",\n      \"method\": \"EMSA, ChIP-qPCR (CREB1/CRTC2 at miR-93-3p promoter), dual-luciferase reporter assay, siRNA knockdown, in vivo mouse model\",\n      \"journal\": \"Journal of nanobiotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA and ChIP-qPCR confirming direct binding, functional rescue; single lab\",\n      \"pmids\": [\"40069788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"The human CREB1 gene was assigned to chromosome 2q32.3-q34 using somatic cell hybrid Southern blot analysis and in situ hybridization. CREB1 was identified as a nuclear phosphoprotein involved in transcriptional regulation of cAMP-inducible genes.\",\n      \"method\": \"Southern blot analysis of mouse-human somatic cell hybrids, in situ hybridization, chromosome 2 translocation mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — chromosomal localization confirmed by two independent mapping methods (somatic cell hybrids + in situ hybridization); foundational genomic characterization\",\n      \"pmids\": [\"2142119\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CREB1 is a nuclear phosphoprotein transcription factor that binds CRE (cAMP-response element) sites in target gene promoters upon phosphorylation (e.g., at Ser133 by PKA, CaMKIV, CDK5, RSK, or AKT-activated kinases); it recruits co-activators such as CBP/p300 and CRTC family coactivators (notably CRTC1/CRTC2) to drive transcription of diverse target genes (including TGFB2, CCAT1, HLA-E, SCD, LTBR, SRGN, miR-320a, miR-373, miR-922, Lin28, VASP, ZEB1, TH, and many others); its activity is repressed by CCDC6 (which recruits HDAC1 and PP1 to CRE sites), regulated post-translationally by Cullin-5-mediated ubiquitylation and degradation, and at the mRNA level by m6A modification via Mettl3, placing CREB1 as a central, signal-integrating transcriptional hub downstream of cAMP/PKA, PI3K/AKT/mTOR, MAPK/ERK, CaMKK/CaMKIV, and p38 signaling cascades with defined roles in energy homeostasis, neuronal function and memory, immune cell differentiation, cancer cell plasticity, viral replication, and organ development.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CREB1 is a nuclear phosphoprotein transcription factor that integrates multiple upstream signaling cascades to drive transcription of cAMP-responsive target genes, functioning as a central, signal-convergent regulator of cellular proliferation, differentiation, energy homeostasis, and stress responses [#32, #4]. Its activity is gated by phosphorylation: PKA downstream of cAMP/AKIP1 [#13], CDK5 in a PKA-independent manner [#9], CaMKIV downstream of DJ-1/CaMKK\\u03b2 [#11], PI3K/AKT and RSK pathways [#4, #8], S6K1 downstream of HTR2B/Akt/mTOR (which drives Ser133 phosphorylation and nuclear translocation) [#21], and p38 MAPK [#30]. Once activated, CREB1 binds CRE elements (including CREB half-sites such as GTCA) in target promoters and recruits co-activators \\u2014 it cooperates with CRTC1/CRTC2 [#0, #31], with the CBP/p300 histone acetyltransferases via the Lyl1 interaction [#5], and with sequence-specific partners including SMAD3, MeCP2, PGR, and FoxO1 to activate context-specific programs [#4, #2, #24, #22]. Through these mechanisms CREB1 directly transactivates a broad target repertoire including TGFB2, SCD, HLA-E, ZEB1, Lin28/VASP, SRGN, the lncRNAs CCAT1 and PVT1, and numerous miRNAs (miR-320a, miR-373, miR-922, miR-93-3p), thereby controlling tumor cell proliferation, migration, EMT, ferroptosis resistance, immune evasion, and viral replication [#4, #19, #20, #21, #17, #16, #29]. CREB1 output is restrained by CCDC6, which recruits HDAC1 and PP1 to CRE sites [#1], and CREB1 levels are set post-translationally by Cullin-5-mediated ubiquitylation and degradation [#15] and post-transcriptionally by Mettl3-dependent m6A stabilization of its mRNA [#14]. In the nervous system CREB1 governs long-term memory and neuronal reprogramming and modulates psychostimulant sensitivity, with CREM providing partial functional redundancy [#26, #27, #25].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Established CREB1 as a discrete genomic locus and identified it as a nuclear phosphoprotein regulating cAMP-inducible transcription, providing the foundational identity of the gene.\",\n      \"evidence\": \"Somatic cell hybrid Southern blot and in situ hybridization mapping to chromosome 2q32.3-q34\",\n      \"pmids\": [\"2142119\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No mechanistic detail of target genes or co-activator recruitment at this stage\", \"Phosphorylation sites not yet mapped\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Resolved how CREB1 can activate transcription independent of Ser133 phosphorylation, showing a partner protein bridges CREB1 to histone acetyltransferases.\",\n      \"evidence\": \"Co-IP with domain mapping, genome-wide ChIP-chip and reporter assays identifying Lyl1 recruitment of p300/CBP to CREB1 targets\",\n      \"pmids\": [\"18160048\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of phosphorylation-independent activation across other partners unknown\", \"Physiological contexts limited to mapped targets (Id1, Id3, cyclin D3, etc.)\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the CREB1-CRTC1 module as the effector of leptin signaling in the hypothalamus, linking CREB1 to whole-body energy balance and fertility.\",\n      \"evidence\": \"Dominant-negative CREB1, hypothalamic ChIP of CRTC1 at Cartpt/Kiss1 promoters, Crtc1 KO mouse\",\n      \"pmids\": [\"18758446\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address CREB1 phosphorylation requirement in this context\", \"CRTC1 dephosphorylation mechanism not fully resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified a direct repressor of CREB1, showing transcriptional output is actively restrained at CRE sites and that loss of this brake drives oncogenic CREB1 activity.\",\n      \"evidence\": \"Reciprocal Co-IP, ChIP and reporter assays showing CCDC6 recruits HDAC1/PP1 to CRE promoters; PTC tumor validation\",\n      \"pmids\": [\"20498639\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CCDC6 acts on all CREB1 targets or a subset unknown\", \"Dynamics of repression versus activation switching not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established that CREB1 functions in feedback miRNA loops and that striatal CREB1 modulates behavior, with CREM compensation revealing functional redundancy.\",\n      \"evidence\": \"ChIP of CREB1 at miRNA regulatory regions in thyroid cells (TSH loop); conditional striatal CREB1/CBP KO with behavioral assays\",\n      \"pmids\": [\"21816899\", \"21766169\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Extent of CREM redundancy across tissues unquantified\", \"Direct versus indirect miRNA suppression mechanism incomplete\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed CREB1 within the mTOR/autophagy axis and showed it cooperates with methyl-CpG-binding machinery, expanding its mechanistic repertoire to methylation-dependent transactivation and DNA-damage responses.\",\n      \"evidence\": \"siRNA epistasis in TSC2/PTEN-loss models with etoposide (mTOR axis); sequential ChIP and Co-IP with MeCP2 at the methylated Glut3 promoter\",\n      \"pmids\": [\"24189100\", \"23493374\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How mTOR mechanistically activates CREB1 not defined\", \"Generality of CREB1-MeCP2 cooperation beyond Glut3 unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated CREB1 cooperates with SMAD3 to drive an autocrine TGFB2 loop, integrating PI3K/AKT and RSK inputs into a defined oncogenic transcriptional output.\",\n      \"evidence\": \"ChIP of CREB1 at the TGFB2 promoter, pathway inhibitor epistasis, patient-derived glioblastoma xenografts\",\n      \"pmids\": [\"25084773\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CREB1-SMAD3 cooperation not resolved\", \"Relative contribution of AKT versus RSK phosphorylation unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected CREB1 to specific receptor-driven proliferation and to mitophagy, broadening its role across estrogen signaling and metabolic/organelle quality-control programs.\",\n      \"evidence\": \"ERα structure-function mutagenesis with PI3K/AKT inhibition and CREB1 reporters (E2 proliferation); promoter mapping and ChIP of CREB1 at miR-320a controlling VDAC1/mitophagy\",\n      \"pmids\": [\"26348925\", \"26472185\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab evidence for each axis\", \"Direct CREB1 kinase in the ERα context not pinned down\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified phosphorylation-independent and epigenetic kinase inputs to CREB1, showing CDK5 and SETD2/H3K36me3-supported ERK signaling sustain CREB1 activity in cancer.\",\n      \"evidence\": \"Drosophila suppressor screen with CDK5 inhibition in glioma stem cells; SETD2 mutant expression and CREB1 siQ in NSCLC with H3K36me3/pCREB1 readouts\",\n      \"pmids\": [\"29742423\", \"30093630\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect CDK5 phosphorylation of CREB1 not shown biochemically\", \"Mechanistic link from H3K36me3 to CREB1 phosphorylation incomplete\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked CREB1 to CaMKIV-dependent neuronal gene control and defined isoform- and residue-specific requirements for its memory function, distinguishing roles from innate behavior.\",\n      \"evidence\": \"DJ-1/CaMKKβ Co-IP and Dj-1 KO mice (TH regulation); C. elegans CRH-1e isoform-specific KO, neuron-specific rescue and K247/K266 mutagenesis (LTM); ChIP of CREB1 at Lin28/VASP\",\n      \"pmids\": [\"31232473\", \"31413073\", \"31754343\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional roles of K247/K266 residues mechanistically undefined\", \"Conservation of isoform specialization in mammals untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established CREB1 as a constitutive driver of lineage differentiation and an immune-evasion factor, and showed coactivator competition (CREB1 vs p65 for CBP/p300) shapes pathway crosstalk.\",\n      \"evidence\": \"RNA-Seq and CREB1 inhibition in prostate luminal cells (ING4/JFK); CRISPR KO with pathway profiling and ChIP of CCAT1 (colorectal); ChIP at HLA-E with NK cytotoxicity assays (myeloma)\",\n      \"pmids\": [\"33846571\", \"35696016\", \"38902472\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism setting constitutive CREB1 activity in luminal cells beyond PTEN loss unclear\", \"Quantitative basis of coactivator competition not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapped CREB1 to additional disease programs \\u2014 viral replication, macrophage polarization, and fibrosis \\u2014 demonstrating its recruitment into viral structures and p38-driven activity.\",\n      \"evidence\": \"EBOV VP35-AKIP1 Co-IP, confocal colocalization in viral inclusion bodies, PKA-CREB1 inhibition; p38/Creb1/Klf4 ChIP in macrophages; ChIP of CREB1 at PVT1 in cardiac fibroblasts\",\n      \"pmids\": [\"35474062\", \"33753566\", \"35063587\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Function of CREB1 within viral ribonucleoprotein complexes mechanistically unresolved\", \"Direct DNA-binding role versus signaling role in VIBs not separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined the post-translational and post-transcriptional control layers governing CREB1 abundance and extended its target repertoire to lipid metabolism and immune modulation.\",\n      \"evidence\": \"In vivo ubiquitylation assay and genetic screens (Cullin-5 degrades CREB1, CREB1-CCL2 axis); conditional Mettl3/Creb1 KO with m6A mapping and rescue (iNKT); ChIP/luciferase of SCD with rescue (ferroptosis); PGR/CREB1 EMSA/ChIP at PTPN11 (decidualization)\",\n      \"pmids\": [\"36662868\", \"37267102\", \"37957645\", \"37786383\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stress signals triggering Cullin-5-mediated degradation incompletely defined\", \"m6A reader linking Mettl3 to Creb1 mRNA stability not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected CREB1 to receptor-driven EMT/metastasis, neuroendocrine differentiation, and neuronal reprogramming, reinforcing its role as a convergent effector across signaling-to-fate programs.\",\n      \"evidence\": \"HTR2B/S6K1 axis with ChIP of pCREB1 at ZEB1 and metastasis models; CREB1/EZH2/REST rescue experiments in prostate NED; forskolin cAMP-CREB1-JNK reprogramming with electrophysiology\",\n      \"pmids\": [\"38381131\", \"38777812\", \"38389831\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which CREB1 enhances EZH2 activity not biochemically resolved\", \"Direct versus indirect repression of REST by CREB1 not separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the many converging kinase inputs, coactivator/repressor competitions, and post-translational/RNA controls are integrated to specify which CREB1 target program is activated in a given cell type remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model for context-specific target selection\", \"Quantitative interplay of CRTC, CBP/p300, CCDC6, and partner TFs at single promoters undefined\", \"Genome-wide phospho-form-resolved occupancy maps lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 4, 5, 16, 17, 19, 20, 21, 32]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [4, 17, 19, 20, 21, 22, 24, 29]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [32]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [21, 32]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [4, 16, 20, 21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 4, 5, 16, 17, 19, 20]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 8, 9, 11, 13, 21, 30]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 4, 13, 15, 20, 28]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CRTC1\", \"CRTC2\", \"CCDC6\", \"CREBBP\", \"EP300\", \"SMAD3\", \"MECP2\", \"PGR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}