{"gene":"CREB5","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":1993,"finding":"CREB5 (CRE-BPa) binds to CRE (cAMP response element) as a homodimer or heterodimer with c-Jun or CRE-BP1, and functions as a CRE-dependent transcriptional activator. Its weak trans-activating capacity is enhanced 2.7- to 3.6-fold by TPA treatment, conferring TPA inducibility on CRE-dependent transcription. Three alternative splicing forms (alpha, beta, gamma, delta) were identified.","method":"CAT cotransfection assay in CV-1 cells, DNA-binding experiments, identification of splice variants","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro transcription assay with functional readout, single lab, single study","pmids":["8378084"],"is_preprint":false},{"year":2019,"finding":"CREB5 confers enzalutamide (androgen receptor antagonist) resistance in prostate cancer cells. In AR-expressing prostate cancer cells, CREB5 enhances AR transcriptional activity at a subset of promoters and enhancers upon enzalutamide treatment, including MYC and cell cycle genes.","method":"ORF expression screen, tumor xenografts, patient-derived organoid, ChIP-seq","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ORF screen, xenografts, organoids, ChIP-seq), validated in patient-derived models","pmids":["31747605"],"is_preprint":false},{"year":2020,"finding":"CREB5 directly interacts with the MET promoter and transcriptionally activates the HGF-MET signaling pathway, promoting invasiveness and metastasis of colorectal cancer cells. Inhibition of MET reduced invasion and metastasis of CREB5-overexpressing CRC cells.","method":"ChIP assay (chromatin immunoprecipitation), gene set enrichment analysis, in vitro migration/invasion assays, orthotopic implantation in nude mice","journal":"Journal of experimental & clinical cancer research : CR","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct ChIP evidence for promoter binding plus in vivo rescue experiments, single lab, multiple orthogonal methods","pmids":["32843066"],"is_preprint":false},{"year":2021,"finding":"Creb5 is specifically expressed in superficial zone articular chondrocytes and is required for TGF-β and EGFR signaling to induce Prg4 (lubricin) expression. Creb5 directly binds to two Prg4 promoter-proximal regulatory elements that display open chromatin conformation specifically in superficial zone chondrocytes. Forced expression of Creb5 in deep zone chondrocytes confers competence for TGF-β/EGFR-induced Prg4 expression.","method":"Chromatin-IP (ChIP), ATAC-Seq, forced expression experiments, loss-of-function mouse model","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — ChIP and ATAC-seq with functional rescue experiments, multiple orthogonal methods, replicated by same lab in subsequent work","pmids":["33712729"],"is_preprint":false},{"year":2022,"finding":"CREB5 physically interacts with AR (androgen receptor), the pioneer factor FOXA1, and other co-factors (GRHL2, HOXB13, TBX3, NFIC) at transcription regulatory elements active in mCRPC. CREB5 overexpression causes extensive reprogramming of nuclear protein-protein interactions in response to enzalutamide. CREB5/FOXA1 co-interaction is associated with Wnt signaling and EMT pathways.","method":"ChIP-seq, rapid immunoprecipitation and mass spectrometry of endogenous proteins (RIME), transcriptome analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — ChIP-seq plus RIME (endogenous protein MS), multiple orthogonal methods, rigorous mechanistic follow-up","pmids":["35550030"],"is_preprint":false},{"year":2022,"finding":"Creb5 is necessary to initiate expression of signaling molecules directing synovial joint formation and articular cartilage development from perichondrial precursors. Postnatal deletion of Creb5 in articular cartilage leads to loss of flat superficial zone articular chondrocytes, loss of Prg4 and Wif1 expression, and non-cell-autonomous upregulation of Ctgf. Creb5 promotes joint formation partly by inducing signaling molecules that block a Wnt5a autoregulatory loop.","method":"Conditional knockout mouse model, postnatal Cre-mediated deletion, gene expression analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean conditional knockout with multiple defined phenotypic readouts, pathway placement via genetic epistasis","pmids":["36435829"],"is_preprint":false},{"year":2022,"finding":"Creb5 cooperates with TGF-β signaling in perimysial fibroblasts to activate Fgf18 expression, which in turn supports pharyngeal (levator veli palatini) muscle development. Loss of TGF-β signaling leads to defects in perimysial fibroblasts and muscle malformation in the soft palate.","method":"Single-cell RNAseq, mouse conditional knockout (Osr2-Cre), in vivo rescue with exogenous Fgf18","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — scRNAseq and genetic mouse model with rescue, single lab","pmids":["36542062"],"is_preprint":false},{"year":2022,"finding":"CREB5 transcriptionally activates TOP1MT expression via a canonical CRE motif. AKT signaling induced by cisplatin promotes nuclear translocation of CREB5 in cisplatin-resistant HNSCC cells. CREB5 silencing triggers mitochondrial apoptosis, and TOP1MT overexpression reverses this effect.","method":"ChIP assay, dual-luciferase reporter assay, immunoblotting, gain/loss-of-function experiments in vitro and in vivo","journal":"BMC medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase reporter for direct transcriptional activation, single lab, multiple orthogonal methods","pmids":["35773668"],"is_preprint":false},{"year":2022,"finding":"Silencing CREB5 impaired hypoxia-induced vasculogenic mimicry (formation of 3D channel-like structures) in MDA-MB-231 breast cancer cells. miR-204 directly binds to the 3'-UTR of CREB5 and negatively regulates CREB5 expression in breast cancer cells.","method":"shRNA silencing, matrigel-based VM assay under hypoxia, luciferase reporter assay for miR-204/CREB5 interaction","journal":"Cancer biomarkers","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional knockdown with cellular phenotype plus direct 3'-UTR binding validation, single lab","pmids":["35662106"],"is_preprint":false},{"year":2023,"finding":"SPOP (speckle-type POZ protein) facilitates non-degradative K63-polyubiquitination of CREB5 at the K432 site, hindering CREB5's ability to activate the receptor tyrosine kinase MET. A liver cancer-associated SPOP mutant S119N disrupts SPOP-CREB5 interaction and impairs CREB5 ubiquitination, leading to MET pathway activation.","method":"Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis (K432), in vitro and in vivo metastasis assays","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — site-specific mutagenesis identifying ubiquitination site, co-IP, functional consequences in vitro and in vivo, single lab with multiple orthogonal methods","pmids":["37996058"],"is_preprint":false},{"year":2023,"finding":"CREB5 cooperates with ATF2 in colorectal cancer: ATF2 negatively regulates transcription of miR-3913-5p by binding to its promoter, and miR-3913-5p directly targets the 3'-UTR of CREB5. CREB5 is required for ATF2 to regulate miR-3913-5p levels, establishing a regulatory feedback axis.","method":"Luciferase reporter assay, ChIP assay, transfection experiments, co-immunoprecipitation","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, luciferase reporter, and co-IP demonstrating direct interactions, single lab","pmids":["37816820"],"is_preprint":false},{"year":2024,"finding":"Semaglutide regulates myocardial energy metabolism through the Creb5/NR4a1 axis in the PI3K/AKT pathway, reducing NR4a1 expression and its translocation to mitochondria. NR4a1 knockdown ameliorates mitochondrial dysfunction and abnormal glucose and lipid metabolism in the heart.","method":"Mouse pressure-overload model, metabolomics, transcriptional analysis, NR4a1 knockdown experiments","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptional analysis and in vivo NR4a1 knockdown with metabolic readouts, single lab","pmids":["38834564"],"is_preprint":false},{"year":2024,"finding":"CREB5 promotes proliferation and self-renewal of glioma stem cells (GSCs). CREB5 shRNA knockdown prevents GSC proliferation and self-renewal in vitro and decreases tumor-forming ability in vivo. CREB5 directly regulates OLIG2 expression, as demonstrated by luciferase reporter assay and ChIP assay.","method":"shRNA knockdown, in vitro proliferation/self-renewal assays, in vivo tumor formation, RNA-seq, luciferase reporter assay, ChIP assay","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase confirming direct target (OLIG2), functional KD in vitro and in vivo, single lab","pmids":["38418476"],"is_preprint":false},{"year":2024,"finding":"CREB5 expression is directly regulated by ZNF384-fusion (Z-fusion) proteins in B-ALL. Z-fusion proteins bind to regulatory regions of CREB5, as confirmed by ChIP-qPCR, establishing CREB5 as a direct transcriptional target.","method":"RNA-seq of Z-fusion transfectants and clinical ALL samples, ChIP-qPCR","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR for direct binding, validated in both cell lines and clinical samples, single lab","pmids":["39015025"],"is_preprint":false},{"year":2025,"finding":"Creb5 directly binds to its own two promoters (autoregulation) and to the regulatory regions of Gdf5 and Sfrp2 in joint progenitors. Creb5 binding sites in Creb5 promoters, Gdf5, and Sfrp2 regulatory elements are necessary for transgene expression in developing synovial joints. Creb5 activates Barx1 specifically in the outer joint interzone, while activating Gdf5 and Sfrp2 in the inner joint interzone.","method":"Integrative transcriptome, chromatin accessibility (ATAC-seq), Creb5 ChIP-seq, functional enhancer analysis with transgene expression","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — ChIP-seq, ATAC-seq, and functional enhancer validation with transgene assays, multiple orthogonal methods, replicated across related studies","pmids":["40472036"],"is_preprint":false},{"year":2025,"finding":"CREB5 drives immune checkpoint blockade resistance in melanoma by promoting a mesenchymal-like phenotype and upregulating extracellular matrix genes including collagens and collagen-stabilizing factors. Tumor-intrinsic collagen deposition mediates resistance through collagen-LAIR1 inhibitory signaling on immune cells. Deletion of LAIR1 or overexpression of decoy receptor LAIR2 in tumors abrogated CREB5-induced resistance.","method":"In vivo CRISPR gain-of-function screen, transcriptional profiling, engineered tumor models, LAIR1 knockout mice, LAIR2 overexpression rescue experiments","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-scale in vivo CRISPR screen plus genetic rescue experiments (LAIR1 KO, LAIR2 OE) with multiple orthogonal approaches","pmids":["bio_10.1101_2025.04.22.649109"],"is_preprint":true},{"year":2025,"finding":"CREB5 promotes synovial lining fibroblast quiescence through HB-EGF-EGFR signaling, which leads to phosphorylation of CREB5. Perturbation of the EGFR-CREB5 axis abolishes fibroblast proximity-sensing and blocks synovial lining fibroblast differentiation. Pharmacologic activation of CREB5 or EGFR ligand HB-EGF is sufficient to induce synovial lining fibroblast differentiation.","method":"Spatial transcriptomics, EGFR perturbation experiments, pharmacologic activation, proximity-sensing assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — spatial transcriptomics plus functional perturbation and rescue experiments, preprint, single lab","pmids":["41427340"],"is_preprint":true},{"year":2025,"finding":"CREB5 transcriptionally activates tenascin-C (TNC) by directly binding to its promoter region, promoting EMT in liver cancer cells. ERS (endoplasmic reticulum stress) activation enhances CREB5 expression via super-enhancer-mediated regulation.","method":"ChIP-seq and RNA-seq for SE identification, CRISPR-Cas9 SE disruption, ChIP assay for CREB5-TNC promoter binding, functional assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for direct promoter binding plus CRISPR SE disruption, single lab, multiple methods","pmids":["39915455"],"is_preprint":false},{"year":2025,"finding":"CREB5 transcriptionally activates APLN (apelin) by directly binding to its canonical TGACG motif in the promoter region, promoting APLN-mediated lymphangiogenesis and lymph node metastasis in cervical cancer.","method":"In vitro lymphangiogenesis screening model, chromatin immunoprecipitation (ChIP), functional inhibition assays, preclinical CCa models","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct promoter binding, functional in vitro and in vivo validation, single lab","pmids":["41145436"],"is_preprint":false},{"year":2025,"finding":"CREB5 promotes neural stem/progenitor cell (NSPC) proliferation by binding to the AP-1 site in the NFIX promoter, enhancing NFIX expression. CREB5 knockdown reduced cell viability, neurosphere formation, and BrdU/Ki-67-positive cells; overexpression had opposing effects. NFIX alteration reversed the proliferative effects of CREB5.","method":"RNA interference, CREB5 overexpression, in vitro and in vivo (SVZ) proliferation assays (BrdU, Ki-67), TUNEL staining, ChIP assay, luciferase reporter assay","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase reporter confirming direct NFIX regulation plus functional rescue, single lab","pmids":["40862718"],"is_preprint":false},{"year":2025,"finding":"H3.3K27M oncohistone directly enhances CREB5 expression by reshaping the H3K27me3 landscape at the CREB5 locus, particularly at super-enhancer regions. CREB5 mediates elevated ID1 levels in H3.3K27M/ACVR1WT DIPG, promoting tumor growth. CREB5 collaborates with BRG1, the SWI/SNF chromatin remodeling complex catalytic subunit, to drive oncogenic transcriptional changes.","method":"H3K27me3 ChIP-seq, super-enhancer disruption with ABBV-075, BRG1 inhibitor combination, functional tumor growth assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq for epigenetic regulation plus pharmacologic perturbation experiments, single lab","pmids":["40246858"],"is_preprint":false},{"year":2025,"finding":"CREB5 interacts with AP-1 proteins and binds to regulatory elements of AP-1 target genes in prostate cancer, regulating basal and stem cell-like transcriptional programs including FOSL1. CREB5 overexpression in AR-positive cells promoted colony growth with tumorigenic properties and increased tumor size in vivo.","method":"In silico transcriptome analysis, co-immunoprecipitation for AP-1 interaction, ChIP for AP-1 gene regulatory elements, in vitro colony assays, in vivo tumor assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ChIP for mechanistic interactions plus in vivo functional validation, single lab","pmids":["41954995"],"is_preprint":false},{"year":2026,"finding":"CREB5 directly activates NR4A1 transcription and thereby promotes NR4A1-dependent transcription of PGC-1α, inhibiting ferroptosis in nucleus pulposus cells by restoring anti-ferroptotic enzyme GPX4 and suppressing ACSL4. In vivo, CREB5 delivery preserved disc height and reduced lipid peroxidation in a rat IDD model.","method":"Immunoprecipitation, immunofluorescence, Western blot, qRT-PCR, CREB5 overexpression/knockdown in NP cells and rat IDD model","journal":"Osteoarthritis and cartilage","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway dissection with multiple biochemical assays and in vivo validation, single lab","pmids":["41856459"],"is_preprint":false},{"year":2026,"finding":"CREB5 inhibits neuronal ferroptosis after spinal cord injury by enhancing transcription of ApoL6 (a lipolysis-related protein), which inhibits decomposition of neuronal lipid droplets, reducing free fatty acid release and fatty acid oxidation, thereby decreasing ROS and lipid peroxidation.","method":"scRNA-seq, scATAC-seq, primary neuron experiments, CREB5 knockdown/overexpression, ApoL6 overexpression rescue, in vivo mouse SCI model","journal":"CNS neuroscience & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptomics-guided mechanistic study with in vitro and in vivo rescue validation, single lab","pmids":["41700484"],"is_preprint":false},{"year":2016,"finding":"CREB5 is a direct target gene of miR-590-5p, as confirmed by dual-luciferase assay and western blot. Knockdown of CREB5 in human monocytes increased TNF-α levels and enhanced expression of phospho-NF-κB p65 and NF-κB p65, placing CREB5 upstream of NF-κB signaling in opioid-induced immunosuppression.","method":"Dual-luciferase assay, western blot, siRNA knockdown in primary human monocytes","journal":"Translational psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'-UTR validation plus functional KD with pathway readout, single lab","pmids":["26978739"],"is_preprint":false},{"year":2024,"finding":"CREB5 is transcriptionally activated by FOXQ1, which binds to the CREB5 promoter. CREB5 mediates the protective role of FOXQ1 in sepsis-induced acute kidney injury by modulating the NF-κB signaling axis; CREB5 overexpression suppressed phosphorylation and nuclear transport of p65.","method":"CLP mouse model, LPS-induced HK-2 cell model, FOXQ1 overexpression/knockdown, rescue experiments with CREB5 manipulation, NF-κB pathway readouts","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional rescue experiments but promoter binding for FOXQ1→CREB5 not directly confirmed by ChIP in abstract; single lab","pmids":["38960057"],"is_preprint":false},{"year":2027,"finding":"miR-32533 targets CREB5, which interacts with the ADAM10, BACE1, and PS1 promoters, enhancing Aβ production through BACE1 and PS1 upregulation while suppressing non-amyloidogenic APP processing via ADAM10 downregulation in Alzheimer's disease models.","method":"RNA-seq identification of miR-32533, northern blot, APP/PS1 and 5xFAD mouse models, CREB5 overexpression/inhibition, bioinformatics and confirmatory promoter-binding experiments","journal":"Advanced science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — promoter interaction described but full mechanistic details of CREB5-promoter binding not rigorously validated in abstract; single lab","pmids":["39840513"],"is_preprint":false},{"year":2026,"finding":"Reduced ECM stiffness in TMJOA deactivates the PI3K-AKT pathway, reducing nuclear translocation of CREB5, which in turn limits PLPP3 expression. CREB5 transcriptionally regulates PLPP3 in superficial zone chondrocytes.","method":"scRNA-seq, mRNA-seq, Western blot, overexpression experiments, in vivo TMJOA model with PLPP3 overexpression rescue","journal":"Molecular biomedicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mechanistic link between CREB5 and PLPP3 described but direct ChIP evidence not explicitly confirmed in abstract; single lab","pmids":["41870835"],"is_preprint":false}],"current_model":"CREB5 is a bZIP/ATF family transcription factor that binds CRE elements as homodimers or heterodimers with c-Jun or CRE-BP1, acts as a transcriptional activator whose activity is enhanced by TPA/PKC signaling, and directly occupies promoters of target genes including MET, TOP1MT, TNC, APLN, NFIX, ApoL6, NR4A1, Prg4, Gdf5, Sfrp2, and its own promoters; it physically interacts with AR, FOXA1, and AP-1 proteins to reprogram oncogenic transcriptional programs in prostate cancer, and its activity and stability are regulated by AKT-driven nuclear translocation and SPOP-mediated K63-polyubiquitination at K432, placing CREB5 as a context-dependent transcriptional hub in development (synovial joint formation, articular cartilage, pharyngeal myogenesis), cancer resistance (AR-pathway, cisplatin, immunotherapy via collagen-LAIR1 axis), and metabolic/ferroptosis pathways."},"narrative":{"mechanistic_narrative":"CREB5 is a bZIP/ATF-family transcription factor that binds cAMP response elements (CRE) as a homodimer or as a heterodimer with c-Jun or CRE-BP1, and functions as a CRE-dependent transcriptional activator whose weak intrinsic activity is enhanced by TPA/PKC signaling [PMID:8378084]. It acts largely as a context-dependent transcriptional hub, directly occupying promoters and enhancers of diverse targets and reprogramming oncogenic and developmental gene programs. In prostate cancer, CREB5 physically interacts with the androgen receptor (AR) and the pioneer factor FOXA1 together with cofactors GRHL2, HOXB13, TBX3 and NFIC, redirecting AR transcriptional output at MYC and cell-cycle genes to drive enzalutamide resistance [PMID:31747605, PMID:35550030], and it cooperates with AP-1 proteins to control basal/stem-like programs including FOSL1 [PMID:41954995]. Across other malignancies it directly transactivates target genes by binding their promoters: MET in colorectal and liver cancer [PMID:32843066], TOP1MT in cisplatin-resistant HNSCC under AKT-driven nuclear translocation [PMID:35773668], OLIG2 in glioma stem cells [PMID:38418476], TNC in liver cancer EMT [PMID:39915455], APLN to drive lymphangiogenesis in cervical cancer [PMID:41145436], and ID1 in DIPG where it collaborates with the SWI/SNF subunit BRG1 [PMID:40246858]. In development, Creb5 marks superficial-zone articular chondrocytes and is required for TGF-β/EGFR-induced Prg4 (lubricin) expression and for synovial joint and articular cartilage formation, where it autoregulates its own promoters and binds Gdf5 and Sfrp2 regulatory elements [PMID:33712729, PMID:36435829, PMID:40472036]; it likewise cooperates with TGF-β in perimysial fibroblasts to activate Fgf18 during pharyngeal muscle development [PMID:36542062]. CREB5 activity and abundance are tightly regulated: AKT signaling promotes its nuclear translocation [PMID:35773668], SPOP catalyzes non-degradative K63-polyubiquitination at K432 to restrain its activation of MET [PMID:37996058], and its expression is governed by microRNAs and chromatin-level inputs including super-enhancers and oncohistone-remodeled H3K27me3 landscapes [PMID:35662106, PMID:39915455, PMID:40246858]. CREB5 also suppresses ferroptosis through NR4A1/PGC-1α/GPX4 and ApoL6 lipid-handling axes [PMID:41856459, PMID:41700484] and drives immune-checkpoint resistance by inducing extracellular-matrix collagen deposition that engages inhibitory collagen-LAIR1 signaling [PMID:bio_10.1101_2025.04.22.649109].","teleology":[{"year":1993,"claim":"Established CREB5's foundational biochemistry: that it is a CRE-binding transcriptional activator that dimerizes with AP-1/CRE-BP partners and is responsive to phorbol ester signaling.","evidence":"CAT cotransfection and DNA-binding assays in CV-1 cells with identification of splice variants","pmids":["8378084"],"confidence":"Medium","gaps":["No endogenous target genes identified","Trans-activation domain and dimerization surfaces not mapped structurally","Physiological context of TPA-induced activity unknown"]},{"year":2016,"claim":"Placed CREB5 upstream of NF-κB signaling and under microRNA control, linking it to immune regulation.","evidence":"Dual-luciferase 3'-UTR validation and siRNA knockdown in primary human monocytes","pmids":["26978739"],"confidence":"Medium","gaps":["Direct transcriptional targets mediating NF-κB suppression not defined","Mechanism of CREB5 control over p65 phosphorylation unresolved"]},{"year":2019,"claim":"Identified CREB5 as a driver of androgen-receptor pathway drug resistance, transforming it from a generic CRE factor into an oncogenic transcriptional cofactor.","evidence":"ORF expression screen, xenografts, patient-derived organoids, and ChIP-seq in prostate cancer","pmids":["31747605"],"confidence":"High","gaps":["How CREB5 is recruited to AR-bound enhancers not defined here","Direct CREB5 binding motifs at resistance loci not parsed"]},{"year":2020,"claim":"Demonstrated direct promoter occupancy and transactivation of MET, establishing CREB5 as a pro-metastatic activator of receptor-tyrosine-kinase signaling.","evidence":"ChIP assay, GSEA, invasion assays, and orthotopic xenografts in colorectal cancer","pmids":["32843066"],"confidence":"High","gaps":["Upstream signals activating CREB5 in CRC not defined","Whether MET activation requires cofactors unknown"]},{"year":2021,"claim":"Defined a developmental role: CREB5 confers superficial-zone chondrocyte competence for TGF-β/EGFR-induced lubricin (Prg4) expression via binding to open-chromatin promoter elements.","evidence":"ChIP, ATAC-seq, and forced-expression and loss-of-function mouse experiments","pmids":["33712729"],"confidence":"High","gaps":["How CREB5 reads zone-specific chromatin accessibility unclear","Direct partner factors at Prg4 elements not identified"]},{"year":2022,"claim":"Resolved CREB5's protein-interaction landscape in prostate cancer (AR, FOXA1, GRHL2, HOXB13, TBX3, NFIC) and showed it reprograms nuclear interactions and AP-1 programs upon enzalutamide.","evidence":"ChIP-seq, RIME endogenous-protein mass spectrometry, and transcriptome analysis in mCRPC models","pmids":["35550030","31747605"],"confidence":"High","gaps":["Direct vs. bridged interactions within the complex not distinguished","Stoichiometry and structural basis of CREB5/FOXA1 cooperation unknown"]},{"year":2022,"claim":"Extended CREB5's developmental scope and showed AKT-driven nuclear translocation activates target transcription (TOP1MT) to suppress mitochondrial apoptosis in drug-resistant cancer.","evidence":"Conditional knockout mice (joint, palate development), ChIP, luciferase reporters, and gain/loss-of-function in HNSCC","pmids":["36435829","36542062","35773668"],"confidence":"High","gaps":["Direct AKT phosphosites on CREB5 not mapped","Genetic epistasis distinguishing direct vs. indirect developmental targets incomplete"]},{"year":2022,"claim":"Linked CREB5 abundance to microRNA control (miR-204) in the context of hypoxia-driven vasculogenic mimicry.","evidence":"shRNA silencing, matrigel VM assays, and luciferase 3'-UTR validation in breast cancer cells","pmids":["35662106"],"confidence":"Medium","gaps":["Transcriptional targets driving VM not identified","Single-lab finding"]},{"year":2023,"claim":"Uncovered post-translational control of CREB5 by SPOP-mediated K63-polyubiquitination at K432, a non-degradative brake on its MET-activating function disrupted by cancer-associated SPOP mutation.","evidence":"Co-IP, ubiquitination assays, K432 site-directed mutagenesis, and in vivo metastasis assays","pmids":["37996058"],"confidence":"High","gaps":["Structural basis of K63 chain effect on CREB5 activity unknown","Whether other E3s regulate CREB5 unexplored"]},{"year":2023,"claim":"Identified a reciprocal CREB5–ATF2–miR-3913-5p regulatory axis in colorectal cancer.","evidence":"Luciferase reporter, ChIP, and co-IP assays","pmids":["37816820"],"confidence":"Medium","gaps":["Direct CREB5/ATF2 physical interaction at target loci not fully resolved","Functional output of the feedback loop incomplete"]},{"year":2024,"claim":"Broadened CREB5's direct target repertoire (OLIG2, NFIX, NR4A1) across glioma stem cells, neural progenitors, and cardiac metabolism, and established its position as a B-ALL fusion-protein target.","evidence":"shRNA/overexpression with ChIP and luciferase reporters; ZNF384-fusion ChIP-qPCR; in vivo pressure-overload metabolic model","pmids":["38418476","40862718","38834564","39015025"],"confidence":"Medium","gaps":["Whether these targets share a common CREB5 binding mode unclear","Cell-type determinants of target selection unknown"]},{"year":2025,"claim":"Defined chromatin-level and developmental regulation: CREB5 autoregulates its own promoters and binds Gdf5/Sfrp2/Barx1 elements in joint progenitors, while super-enhancers, ER stress, and oncohistone-reshaped H3K27me3 drive its expression in cancer where it partners with BRG1.","evidence":"ChIP-seq, ATAC-seq, transgene enhancer assays, CRISPR super-enhancer disruption, and H3K27me3 ChIP-seq","pmids":["40472036","39915455","40246858"],"confidence":"High","gaps":["How distinct enhancer inputs converge on CREB5 across tissues unclear","Direct BRG1–CREB5 contact not structurally defined"]},{"year":2025,"claim":"Established CREB5 as a driver of immune-checkpoint resistance via tumor collagen deposition engaging inhibitory collagen-LAIR1 signaling, and as a regulator of synovial fibroblast quiescence through HB-EGF-EGFR-driven phosphorylation.","evidence":"In vivo CRISPR gain-of-function screen with LAIR1 KO / LAIR2 OE rescue (preprint); spatial transcriptomics with EGFR perturbation (preprint)","pmids":["bio_10.1101_2025.04.22.649109","41427340"],"confidence":"High","gaps":["EGFR-induced CREB5 phosphosites not mapped","Direct collagen-gene promoter occupancy by CREB5 not fully resolved"]},{"year":2026,"claim":"Identified an anti-ferroptotic function for CREB5 through NR4A1/PGC-1α/GPX4 and ApoL6 lipid-handling axes in disc and neuronal degeneration models.","evidence":"IP, immunofluorescence, Western/qRT-PCR with overexpression/knockdown and in vivo rat IDD and mouse SCI rescue models","pmids":["41856459","41700484"],"confidence":"Medium","gaps":["Direct ChIP evidence for some axis members limited","Whether ferroptosis suppression generalizes beyond these tissues unknown"]},{"year":null,"claim":"How CREB5 selects among its many context-specific targets and partners, and the structural basis of its regulation by AKT phosphorylation and SPOP K63-ubiquitination, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of CREB5 DNA-binding or cofactor complexes","Determinants of tissue-specific target selection undefined","Direct AKT and EGFR phosphosites on CREB5 unmapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,2,3,4,7,12,14,17,18,19,21,22]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,2,3,14,18]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7,27]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,3,14,17]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,2,15,17,20]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,5,6,14]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,16,27]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[22,23]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[15,24]}],"complexes":[],"partners":["AR","FOXA1","JUN","ATF2","BRG1","SPOP","GRHL2","HOXB13"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q02930","full_name":"Cyclic AMP-responsive element-binding protein 5","aliases":["cAMP-response element-binding protein A","CRE-BPa"],"length_aa":508,"mass_kda":56.9,"function":"Binds to the cAMP response element and activates transcription","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q02930/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CREB5","classification":"Not 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(cAMP response element) as a homodimer or heterodimer with c-Jun or CRE-BP1, and functions as a CRE-dependent transcriptional activator. Its weak trans-activating capacity is enhanced 2.7- to 3.6-fold by TPA treatment, conferring TPA inducibility on CRE-dependent transcription. Three alternative splicing forms (alpha, beta, gamma, delta) were identified.\",\n      \"method\": \"CAT cotransfection assay in CV-1 cells, DNA-binding experiments, identification of splice variants\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro transcription assay with functional readout, single lab, single study\",\n      \"pmids\": [\"8378084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CREB5 confers enzalutamide (androgen receptor antagonist) resistance in prostate cancer cells. In AR-expressing prostate cancer cells, CREB5 enhances AR transcriptional activity at a subset of promoters and enhancers upon enzalutamide treatment, including MYC and cell cycle genes.\",\n      \"method\": \"ORF expression screen, tumor xenografts, patient-derived organoid, ChIP-seq\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ORF screen, xenografts, organoids, ChIP-seq), validated in patient-derived models\",\n      \"pmids\": [\"31747605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CREB5 directly interacts with the MET promoter and transcriptionally activates the HGF-MET signaling pathway, promoting invasiveness and metastasis of colorectal cancer cells. Inhibition of MET reduced invasion and metastasis of CREB5-overexpressing CRC cells.\",\n      \"method\": \"ChIP assay (chromatin immunoprecipitation), gene set enrichment analysis, in vitro migration/invasion assays, orthotopic implantation in nude mice\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ChIP evidence for promoter binding plus in vivo rescue experiments, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"32843066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Creb5 is specifically expressed in superficial zone articular chondrocytes and is required for TGF-β and EGFR signaling to induce Prg4 (lubricin) expression. Creb5 directly binds to two Prg4 promoter-proximal regulatory elements that display open chromatin conformation specifically in superficial zone chondrocytes. Forced expression of Creb5 in deep zone chondrocytes confers competence for TGF-β/EGFR-induced Prg4 expression.\",\n      \"method\": \"Chromatin-IP (ChIP), ATAC-Seq, forced expression experiments, loss-of-function mouse model\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ChIP and ATAC-seq with functional rescue experiments, multiple orthogonal methods, replicated by same lab in subsequent work\",\n      \"pmids\": [\"33712729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CREB5 physically interacts with AR (androgen receptor), the pioneer factor FOXA1, and other co-factors (GRHL2, HOXB13, TBX3, NFIC) at transcription regulatory elements active in mCRPC. CREB5 overexpression causes extensive reprogramming of nuclear protein-protein interactions in response to enzalutamide. CREB5/FOXA1 co-interaction is associated with Wnt signaling and EMT pathways.\",\n      \"method\": \"ChIP-seq, rapid immunoprecipitation and mass spectrometry of endogenous proteins (RIME), transcriptome analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ChIP-seq plus RIME (endogenous protein MS), multiple orthogonal methods, rigorous mechanistic follow-up\",\n      \"pmids\": [\"35550030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Creb5 is necessary to initiate expression of signaling molecules directing synovial joint formation and articular cartilage development from perichondrial precursors. Postnatal deletion of Creb5 in articular cartilage leads to loss of flat superficial zone articular chondrocytes, loss of Prg4 and Wif1 expression, and non-cell-autonomous upregulation of Ctgf. Creb5 promotes joint formation partly by inducing signaling molecules that block a Wnt5a autoregulatory loop.\",\n      \"method\": \"Conditional knockout mouse model, postnatal Cre-mediated deletion, gene expression analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean conditional knockout with multiple defined phenotypic readouts, pathway placement via genetic epistasis\",\n      \"pmids\": [\"36435829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Creb5 cooperates with TGF-β signaling in perimysial fibroblasts to activate Fgf18 expression, which in turn supports pharyngeal (levator veli palatini) muscle development. Loss of TGF-β signaling leads to defects in perimysial fibroblasts and muscle malformation in the soft palate.\",\n      \"method\": \"Single-cell RNAseq, mouse conditional knockout (Osr2-Cre), in vivo rescue with exogenous Fgf18\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — scRNAseq and genetic mouse model with rescue, single lab\",\n      \"pmids\": [\"36542062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CREB5 transcriptionally activates TOP1MT expression via a canonical CRE motif. AKT signaling induced by cisplatin promotes nuclear translocation of CREB5 in cisplatin-resistant HNSCC cells. CREB5 silencing triggers mitochondrial apoptosis, and TOP1MT overexpression reverses this effect.\",\n      \"method\": \"ChIP assay, dual-luciferase reporter assay, immunoblotting, gain/loss-of-function experiments in vitro and in vivo\",\n      \"journal\": \"BMC medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase reporter for direct transcriptional activation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"35773668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Silencing CREB5 impaired hypoxia-induced vasculogenic mimicry (formation of 3D channel-like structures) in MDA-MB-231 breast cancer cells. miR-204 directly binds to the 3'-UTR of CREB5 and negatively regulates CREB5 expression in breast cancer cells.\",\n      \"method\": \"shRNA silencing, matrigel-based VM assay under hypoxia, luciferase reporter assay for miR-204/CREB5 interaction\",\n      \"journal\": \"Cancer biomarkers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional knockdown with cellular phenotype plus direct 3'-UTR binding validation, single lab\",\n      \"pmids\": [\"35662106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SPOP (speckle-type POZ protein) facilitates non-degradative K63-polyubiquitination of CREB5 at the K432 site, hindering CREB5's ability to activate the receptor tyrosine kinase MET. A liver cancer-associated SPOP mutant S119N disrupts SPOP-CREB5 interaction and impairs CREB5 ubiquitination, leading to MET pathway activation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis (K432), in vitro and in vivo metastasis assays\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-specific mutagenesis identifying ubiquitination site, co-IP, functional consequences in vitro and in vivo, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37996058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CREB5 cooperates with ATF2 in colorectal cancer: ATF2 negatively regulates transcription of miR-3913-5p by binding to its promoter, and miR-3913-5p directly targets the 3'-UTR of CREB5. CREB5 is required for ATF2 to regulate miR-3913-5p levels, establishing a regulatory feedback axis.\",\n      \"method\": \"Luciferase reporter assay, ChIP assay, transfection experiments, co-immunoprecipitation\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, luciferase reporter, and co-IP demonstrating direct interactions, single lab\",\n      \"pmids\": [\"37816820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Semaglutide regulates myocardial energy metabolism through the Creb5/NR4a1 axis in the PI3K/AKT pathway, reducing NR4a1 expression and its translocation to mitochondria. NR4a1 knockdown ameliorates mitochondrial dysfunction and abnormal glucose and lipid metabolism in the heart.\",\n      \"method\": \"Mouse pressure-overload model, metabolomics, transcriptional analysis, NR4a1 knockdown experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptional analysis and in vivo NR4a1 knockdown with metabolic readouts, single lab\",\n      \"pmids\": [\"38834564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CREB5 promotes proliferation and self-renewal of glioma stem cells (GSCs). CREB5 shRNA knockdown prevents GSC proliferation and self-renewal in vitro and decreases tumor-forming ability in vivo. CREB5 directly regulates OLIG2 expression, as demonstrated by luciferase reporter assay and ChIP assay.\",\n      \"method\": \"shRNA knockdown, in vitro proliferation/self-renewal assays, in vivo tumor formation, RNA-seq, luciferase reporter assay, ChIP assay\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase confirming direct target (OLIG2), functional KD in vitro and in vivo, single lab\",\n      \"pmids\": [\"38418476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CREB5 expression is directly regulated by ZNF384-fusion (Z-fusion) proteins in B-ALL. Z-fusion proteins bind to regulatory regions of CREB5, as confirmed by ChIP-qPCR, establishing CREB5 as a direct transcriptional target.\",\n      \"method\": \"RNA-seq of Z-fusion transfectants and clinical ALL samples, ChIP-qPCR\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR for direct binding, validated in both cell lines and clinical samples, single lab\",\n      \"pmids\": [\"39015025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Creb5 directly binds to its own two promoters (autoregulation) and to the regulatory regions of Gdf5 and Sfrp2 in joint progenitors. Creb5 binding sites in Creb5 promoters, Gdf5, and Sfrp2 regulatory elements are necessary for transgene expression in developing synovial joints. Creb5 activates Barx1 specifically in the outer joint interzone, while activating Gdf5 and Sfrp2 in the inner joint interzone.\",\n      \"method\": \"Integrative transcriptome, chromatin accessibility (ATAC-seq), Creb5 ChIP-seq, functional enhancer analysis with transgene expression\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ChIP-seq, ATAC-seq, and functional enhancer validation with transgene assays, multiple orthogonal methods, replicated across related studies\",\n      \"pmids\": [\"40472036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CREB5 drives immune checkpoint blockade resistance in melanoma by promoting a mesenchymal-like phenotype and upregulating extracellular matrix genes including collagens and collagen-stabilizing factors. Tumor-intrinsic collagen deposition mediates resistance through collagen-LAIR1 inhibitory signaling on immune cells. Deletion of LAIR1 or overexpression of decoy receptor LAIR2 in tumors abrogated CREB5-induced resistance.\",\n      \"method\": \"In vivo CRISPR gain-of-function screen, transcriptional profiling, engineered tumor models, LAIR1 knockout mice, LAIR2 overexpression rescue experiments\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-scale in vivo CRISPR screen plus genetic rescue experiments (LAIR1 KO, LAIR2 OE) with multiple orthogonal approaches\",\n      \"pmids\": [\"bio_10.1101_2025.04.22.649109\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CREB5 promotes synovial lining fibroblast quiescence through HB-EGF-EGFR signaling, which leads to phosphorylation of CREB5. Perturbation of the EGFR-CREB5 axis abolishes fibroblast proximity-sensing and blocks synovial lining fibroblast differentiation. Pharmacologic activation of CREB5 or EGFR ligand HB-EGF is sufficient to induce synovial lining fibroblast differentiation.\",\n      \"method\": \"Spatial transcriptomics, EGFR perturbation experiments, pharmacologic activation, proximity-sensing assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — spatial transcriptomics plus functional perturbation and rescue experiments, preprint, single lab\",\n      \"pmids\": [\"41427340\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CREB5 transcriptionally activates tenascin-C (TNC) by directly binding to its promoter region, promoting EMT in liver cancer cells. ERS (endoplasmic reticulum stress) activation enhances CREB5 expression via super-enhancer-mediated regulation.\",\n      \"method\": \"ChIP-seq and RNA-seq for SE identification, CRISPR-Cas9 SE disruption, ChIP assay for CREB5-TNC promoter binding, functional assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for direct promoter binding plus CRISPR SE disruption, single lab, multiple methods\",\n      \"pmids\": [\"39915455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CREB5 transcriptionally activates APLN (apelin) by directly binding to its canonical TGACG motif in the promoter region, promoting APLN-mediated lymphangiogenesis and lymph node metastasis in cervical cancer.\",\n      \"method\": \"In vitro lymphangiogenesis screening model, chromatin immunoprecipitation (ChIP), functional inhibition assays, preclinical CCa models\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct promoter binding, functional in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"41145436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CREB5 promotes neural stem/progenitor cell (NSPC) proliferation by binding to the AP-1 site in the NFIX promoter, enhancing NFIX expression. CREB5 knockdown reduced cell viability, neurosphere formation, and BrdU/Ki-67-positive cells; overexpression had opposing effects. NFIX alteration reversed the proliferative effects of CREB5.\",\n      \"method\": \"RNA interference, CREB5 overexpression, in vitro and in vivo (SVZ) proliferation assays (BrdU, Ki-67), TUNEL staining, ChIP assay, luciferase reporter assay\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase reporter confirming direct NFIX regulation plus functional rescue, single lab\",\n      \"pmids\": [\"40862718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"H3.3K27M oncohistone directly enhances CREB5 expression by reshaping the H3K27me3 landscape at the CREB5 locus, particularly at super-enhancer regions. CREB5 mediates elevated ID1 levels in H3.3K27M/ACVR1WT DIPG, promoting tumor growth. CREB5 collaborates with BRG1, the SWI/SNF chromatin remodeling complex catalytic subunit, to drive oncogenic transcriptional changes.\",\n      \"method\": \"H3K27me3 ChIP-seq, super-enhancer disruption with ABBV-075, BRG1 inhibitor combination, functional tumor growth assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq for epigenetic regulation plus pharmacologic perturbation experiments, single lab\",\n      \"pmids\": [\"40246858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CREB5 interacts with AP-1 proteins and binds to regulatory elements of AP-1 target genes in prostate cancer, regulating basal and stem cell-like transcriptional programs including FOSL1. CREB5 overexpression in AR-positive cells promoted colony growth with tumorigenic properties and increased tumor size in vivo.\",\n      \"method\": \"In silico transcriptome analysis, co-immunoprecipitation for AP-1 interaction, ChIP for AP-1 gene regulatory elements, in vitro colony assays, in vivo tumor assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ChIP for mechanistic interactions plus in vivo functional validation, single lab\",\n      \"pmids\": [\"41954995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CREB5 directly activates NR4A1 transcription and thereby promotes NR4A1-dependent transcription of PGC-1α, inhibiting ferroptosis in nucleus pulposus cells by restoring anti-ferroptotic enzyme GPX4 and suppressing ACSL4. In vivo, CREB5 delivery preserved disc height and reduced lipid peroxidation in a rat IDD model.\",\n      \"method\": \"Immunoprecipitation, immunofluorescence, Western blot, qRT-PCR, CREB5 overexpression/knockdown in NP cells and rat IDD model\",\n      \"journal\": \"Osteoarthritis and cartilage\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway dissection with multiple biochemical assays and in vivo validation, single lab\",\n      \"pmids\": [\"41856459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CREB5 inhibits neuronal ferroptosis after spinal cord injury by enhancing transcription of ApoL6 (a lipolysis-related protein), which inhibits decomposition of neuronal lipid droplets, reducing free fatty acid release and fatty acid oxidation, thereby decreasing ROS and lipid peroxidation.\",\n      \"method\": \"scRNA-seq, scATAC-seq, primary neuron experiments, CREB5 knockdown/overexpression, ApoL6 overexpression rescue, in vivo mouse SCI model\",\n      \"journal\": \"CNS neuroscience & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptomics-guided mechanistic study with in vitro and in vivo rescue validation, single lab\",\n      \"pmids\": [\"41700484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CREB5 is a direct target gene of miR-590-5p, as confirmed by dual-luciferase assay and western blot. Knockdown of CREB5 in human monocytes increased TNF-α levels and enhanced expression of phospho-NF-κB p65 and NF-κB p65, placing CREB5 upstream of NF-κB signaling in opioid-induced immunosuppression.\",\n      \"method\": \"Dual-luciferase assay, western blot, siRNA knockdown in primary human monocytes\",\n      \"journal\": \"Translational psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'-UTR validation plus functional KD with pathway readout, single lab\",\n      \"pmids\": [\"26978739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CREB5 is transcriptionally activated by FOXQ1, which binds to the CREB5 promoter. CREB5 mediates the protective role of FOXQ1 in sepsis-induced acute kidney injury by modulating the NF-κB signaling axis; CREB5 overexpression suppressed phosphorylation and nuclear transport of p65.\",\n      \"method\": \"CLP mouse model, LPS-induced HK-2 cell model, FOXQ1 overexpression/knockdown, rescue experiments with CREB5 manipulation, NF-κB pathway readouts\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional rescue experiments but promoter binding for FOXQ1→CREB5 not directly confirmed by ChIP in abstract; single lab\",\n      \"pmids\": [\"38960057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2027,\n      \"finding\": \"miR-32533 targets CREB5, which interacts with the ADAM10, BACE1, and PS1 promoters, enhancing Aβ production through BACE1 and PS1 upregulation while suppressing non-amyloidogenic APP processing via ADAM10 downregulation in Alzheimer's disease models.\",\n      \"method\": \"RNA-seq identification of miR-32533, northern blot, APP/PS1 and 5xFAD mouse models, CREB5 overexpression/inhibition, bioinformatics and confirmatory promoter-binding experiments\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — promoter interaction described but full mechanistic details of CREB5-promoter binding not rigorously validated in abstract; single lab\",\n      \"pmids\": [\"39840513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Reduced ECM stiffness in TMJOA deactivates the PI3K-AKT pathway, reducing nuclear translocation of CREB5, which in turn limits PLPP3 expression. CREB5 transcriptionally regulates PLPP3 in superficial zone chondrocytes.\",\n      \"method\": \"scRNA-seq, mRNA-seq, Western blot, overexpression experiments, in vivo TMJOA model with PLPP3 overexpression rescue\",\n      \"journal\": \"Molecular biomedicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mechanistic link between CREB5 and PLPP3 described but direct ChIP evidence not explicitly confirmed in abstract; single lab\",\n      \"pmids\": [\"41870835\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CREB5 is a bZIP/ATF family transcription factor that binds CRE elements as homodimers or heterodimers with c-Jun or CRE-BP1, acts as a transcriptional activator whose activity is enhanced by TPA/PKC signaling, and directly occupies promoters of target genes including MET, TOP1MT, TNC, APLN, NFIX, ApoL6, NR4A1, Prg4, Gdf5, Sfrp2, and its own promoters; it physically interacts with AR, FOXA1, and AP-1 proteins to reprogram oncogenic transcriptional programs in prostate cancer, and its activity and stability are regulated by AKT-driven nuclear translocation and SPOP-mediated K63-polyubiquitination at K432, placing CREB5 as a context-dependent transcriptional hub in development (synovial joint formation, articular cartilage, pharyngeal myogenesis), cancer resistance (AR-pathway, cisplatin, immunotherapy via collagen-LAIR1 axis), and metabolic/ferroptosis pathways.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CREB5 is a bZIP/ATF-family transcription factor that binds cAMP response elements (CRE) as a homodimer or as a heterodimer with c-Jun or CRE-BP1, and functions as a CRE-dependent transcriptional activator whose weak intrinsic activity is enhanced by TPA/PKC signaling [#0]. It acts largely as a context-dependent transcriptional hub, directly occupying promoters and enhancers of diverse targets and reprogramming oncogenic and developmental gene programs. In prostate cancer, CREB5 physically interacts with the androgen receptor (AR) and the pioneer factor FOXA1 together with cofactors GRHL2, HOXB13, TBX3 and NFIC, redirecting AR transcriptional output at MYC and cell-cycle genes to drive enzalutamide resistance [#1, #4], and it cooperates with AP-1 proteins to control basal/stem-like programs including FOSL1 [#21]. Across other malignancies it directly transactivates target genes by binding their promoters: MET in colorectal and liver cancer [#2], TOP1MT in cisplatin-resistant HNSCC under AKT-driven nuclear translocation [#7], OLIG2 in glioma stem cells [#12], TNC in liver cancer EMT [#17], APLN to drive lymphangiogenesis in cervical cancer [#18], and ID1 in DIPG where it collaborates with the SWI/SNF subunit BRG1 [#20]. In development, Creb5 marks superficial-zone articular chondrocytes and is required for TGF-\\u03b2/EGFR-induced Prg4 (lubricin) expression and for synovial joint and articular cartilage formation, where it autoregulates its own promoters and binds Gdf5 and Sfrp2 regulatory elements [#3, #5, #14]; it likewise cooperates with TGF-\\u03b2 in perimysial fibroblasts to activate Fgf18 during pharyngeal muscle development [#6]. CREB5 activity and abundance are tightly regulated: AKT signaling promotes its nuclear translocation [#7], SPOP catalyzes non-degradative K63-polyubiquitination at K432 to restrain its activation of MET [#9], and its expression is governed by microRNAs and chromatin-level inputs including super-enhancers and oncohistone-remodeled H3K27me3 landscapes [#8, #17, #20]. CREB5 also suppresses ferroptosis through NR4A1/PGC-1\\u03b1/GPX4 and ApoL6 lipid-handling axes [#22, #23] and drives immune-checkpoint resistance by inducing extracellular-matrix collagen deposition that engages inhibitory collagen-LAIR1 signaling [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established CREB5's foundational biochemistry: that it is a CRE-binding transcriptional activator that dimerizes with AP-1/CRE-BP partners and is responsive to phorbol ester signaling.\",\n      \"evidence\": \"CAT cotransfection and DNA-binding assays in CV-1 cells with identification of splice variants\",\n      \"pmids\": [\"8378084\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No endogenous target genes identified\", \"Trans-activation domain and dimerization surfaces not mapped structurally\", \"Physiological context of TPA-induced activity unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed CREB5 upstream of NF-\\u03baB signaling and under microRNA control, linking it to immune regulation.\",\n      \"evidence\": \"Dual-luciferase 3'-UTR validation and siRNA knockdown in primary human monocytes\",\n      \"pmids\": [\"26978739\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional targets mediating NF-\\u03baB suppression not defined\", \"Mechanism of CREB5 control over p65 phosphorylation unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified CREB5 as a driver of androgen-receptor pathway drug resistance, transforming it from a generic CRE factor into an oncogenic transcriptional cofactor.\",\n      \"evidence\": \"ORF expression screen, xenografts, patient-derived organoids, and ChIP-seq in prostate cancer\",\n      \"pmids\": [\"31747605\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CREB5 is recruited to AR-bound enhancers not defined here\", \"Direct CREB5 binding motifs at resistance loci not parsed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated direct promoter occupancy and transactivation of MET, establishing CREB5 as a pro-metastatic activator of receptor-tyrosine-kinase signaling.\",\n      \"evidence\": \"ChIP assay, GSEA, invasion assays, and orthotopic xenografts in colorectal cancer\",\n      \"pmids\": [\"32843066\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals activating CREB5 in CRC not defined\", \"Whether MET activation requires cofactors unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a developmental role: CREB5 confers superficial-zone chondrocyte competence for TGF-\\u03b2/EGFR-induced lubricin (Prg4) expression via binding to open-chromatin promoter elements.\",\n      \"evidence\": \"ChIP, ATAC-seq, and forced-expression and loss-of-function mouse experiments\",\n      \"pmids\": [\"33712729\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CREB5 reads zone-specific chromatin accessibility unclear\", \"Direct partner factors at Prg4 elements not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved CREB5's protein-interaction landscape in prostate cancer (AR, FOXA1, GRHL2, HOXB13, TBX3, NFIC) and showed it reprograms nuclear interactions and AP-1 programs upon enzalutamide.\",\n      \"evidence\": \"ChIP-seq, RIME endogenous-protein mass spectrometry, and transcriptome analysis in mCRPC models\",\n      \"pmids\": [\"35550030\", \"31747605\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs. bridged interactions within the complex not distinguished\", \"Stoichiometry and structural basis of CREB5/FOXA1 cooperation unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended CREB5's developmental scope and showed AKT-driven nuclear translocation activates target transcription (TOP1MT) to suppress mitochondrial apoptosis in drug-resistant cancer.\",\n      \"evidence\": \"Conditional knockout mice (joint, palate development), ChIP, luciferase reporters, and gain/loss-of-function in HNSCC\",\n      \"pmids\": [\"36435829\", \"36542062\", \"35773668\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct AKT phosphosites on CREB5 not mapped\", \"Genetic epistasis distinguishing direct vs. indirect developmental targets incomplete\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked CREB5 abundance to microRNA control (miR-204) in the context of hypoxia-driven vasculogenic mimicry.\",\n      \"evidence\": \"shRNA silencing, matrigel VM assays, and luciferase 3'-UTR validation in breast cancer cells\",\n      \"pmids\": [\"35662106\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional targets driving VM not identified\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Uncovered post-translational control of CREB5 by SPOP-mediated K63-polyubiquitination at K432, a non-degradative brake on its MET-activating function disrupted by cancer-associated SPOP mutation.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, K432 site-directed mutagenesis, and in vivo metastasis assays\",\n      \"pmids\": [\"37996058\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of K63 chain effect on CREB5 activity unknown\", \"Whether other E3s regulate CREB5 unexplored\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a reciprocal CREB5\\u2013ATF2\\u2013miR-3913-5p regulatory axis in colorectal cancer.\",\n      \"evidence\": \"Luciferase reporter, ChIP, and co-IP assays\",\n      \"pmids\": [\"37816820\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CREB5/ATF2 physical interaction at target loci not fully resolved\", \"Functional output of the feedback loop incomplete\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Broadened CREB5's direct target repertoire (OLIG2, NFIX, NR4A1) across glioma stem cells, neural progenitors, and cardiac metabolism, and established its position as a B-ALL fusion-protein target.\",\n      \"evidence\": \"shRNA/overexpression with ChIP and luciferase reporters; ZNF384-fusion ChIP-qPCR; in vivo pressure-overload metabolic model\",\n      \"pmids\": [\"38418476\", \"40862718\", \"38834564\", \"39015025\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these targets share a common CREB5 binding mode unclear\", \"Cell-type determinants of target selection unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined chromatin-level and developmental regulation: CREB5 autoregulates its own promoters and binds Gdf5/Sfrp2/Barx1 elements in joint progenitors, while super-enhancers, ER stress, and oncohistone-reshaped H3K27me3 drive its expression in cancer where it partners with BRG1.\",\n      \"evidence\": \"ChIP-seq, ATAC-seq, transgene enhancer assays, CRISPR super-enhancer disruption, and H3K27me3 ChIP-seq\",\n      \"pmids\": [\"40472036\", \"39915455\", \"40246858\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How distinct enhancer inputs converge on CREB5 across tissues unclear\", \"Direct BRG1\\u2013CREB5 contact not structurally defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established CREB5 as a driver of immune-checkpoint resistance via tumor collagen deposition engaging inhibitory collagen-LAIR1 signaling, and as a regulator of synovial fibroblast quiescence through HB-EGF-EGFR-driven phosphorylation.\",\n      \"evidence\": \"In vivo CRISPR gain-of-function screen with LAIR1 KO / LAIR2 OE rescue (preprint); spatial transcriptomics with EGFR perturbation (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.04.22.649109\", \"41427340\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"EGFR-induced CREB5 phosphosites not mapped\", \"Direct collagen-gene promoter occupancy by CREB5 not fully resolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified an anti-ferroptotic function for CREB5 through NR4A1/PGC-1\\u03b1/GPX4 and ApoL6 lipid-handling axes in disc and neuronal degeneration models.\",\n      \"evidence\": \"IP, immunofluorescence, Western/qRT-PCR with overexpression/knockdown and in vivo rat IDD and mouse SCI rescue models\",\n      \"pmids\": [\"41856459\", \"41700484\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ChIP evidence for some axis members limited\", \"Whether ferroptosis suppression generalizes beyond these tissues unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CREB5 selects among its many context-specific targets and partners, and the structural basis of its regulation by AKT phosphorylation and SPOP K63-ubiquitination, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of CREB5 DNA-binding or cofactor complexes\", \"Determinants of tissue-specific target selection undefined\", \"Direct AKT and EGFR phosphosites on CREB5 unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 7, 12, 14, 17, 18, 19, 21, 22]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 2, 3, 14, 18]},\n      {\"term_id\": \"GO:0003700\", \"supporting_discovery_ids\": [0, 2, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7, 27]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 3, 14, 17]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 2, 15, 17, 20]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 5, 6, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 16, 27]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [22, 23]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [15, 24]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"AR\", \"FOXA1\", \"JUN\", \"ATF2\", \"BRG1\", \"SPOP\", \"GRHL2\", \"HOXB13\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}