| 1993 |
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. |
CAT cotransfection assay in CV-1 cells, DNA-binding experiments, identification of splice variants |
Oncogene |
Medium |
8378084
|
| 2019 |
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. |
ORF expression screen, tumor xenografts, patient-derived organoid, ChIP-seq |
Cell reports |
High |
31747605
|
| 2020 |
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. |
ChIP assay (chromatin immunoprecipitation), gene set enrichment analysis, in vitro migration/invasion assays, orthotopic implantation in nude mice |
Journal of experimental & clinical cancer research : CR |
High |
32843066
|
| 2021 |
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. |
Chromatin-IP (ChIP), ATAC-Seq, forced expression experiments, loss-of-function mouse model |
Communications biology |
High |
33712729
|
| 2022 |
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. |
ChIP-seq, rapid immunoprecipitation and mass spectrometry of endogenous proteins (RIME), transcriptome analysis |
eLife |
High |
35550030
|
| 2022 |
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. |
Conditional knockout mouse model, postnatal Cre-mediated deletion, gene expression analysis |
Nature communications |
High |
36435829
|
| 2022 |
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. |
Single-cell RNAseq, mouse conditional knockout (Osr2-Cre), in vivo rescue with exogenous Fgf18 |
eLife |
Medium |
36542062
|
| 2022 |
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. |
ChIP assay, dual-luciferase reporter assay, immunoblotting, gain/loss-of-function experiments in vitro and in vivo |
BMC medicine |
Medium |
35773668
|
| 2022 |
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. |
shRNA silencing, matrigel-based VM assay under hypoxia, luciferase reporter assay for miR-204/CREB5 interaction |
Cancer biomarkers |
Medium |
35662106
|
| 2023 |
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. |
Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis (K432), in vitro and in vivo metastasis assays |
Biochimica et biophysica acta. Molecular cell research |
High |
37996058
|
| 2023 |
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. |
Luciferase reporter assay, ChIP assay, transfection experiments, co-immunoprecipitation |
Communications biology |
Medium |
37816820
|
| 2024 |
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. |
Mouse pressure-overload model, metabolomics, transcriptional analysis, NR4a1 knockdown experiments |
Nature communications |
Medium |
38834564
|
| 2024 |
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. |
shRNA knockdown, in vitro proliferation/self-renewal assays, in vivo tumor formation, RNA-seq, luciferase reporter assay, ChIP assay |
Cell death discovery |
Medium |
38418476
|
| 2024 |
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. |
RNA-seq of Z-fusion transfectants and clinical ALL samples, ChIP-qPCR |
Cancer medicine |
Medium |
39015025
|
| 2025 |
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. |
Integrative transcriptome, chromatin accessibility (ATAC-seq), Creb5 ChIP-seq, functional enhancer analysis with transgene expression |
Proceedings of the National Academy of Sciences of the United States of America |
High |
40472036
|
| 2025 |
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. |
In vivo CRISPR gain-of-function screen, transcriptional profiling, engineered tumor models, LAIR1 knockout mice, LAIR2 overexpression rescue experiments |
bioRxivpreprint |
High |
bio_10.1101_2025.04.22.649109
|
| 2025 |
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. |
Spatial transcriptomics, EGFR perturbation experiments, pharmacologic activation, proximity-sensing assays |
bioRxivpreprint |
Medium |
41427340
|
| 2025 |
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. |
ChIP-seq and RNA-seq for SE identification, CRISPR-Cas9 SE disruption, ChIP assay for CREB5-TNC promoter binding, functional assays |
Cell death & disease |
Medium |
39915455
|
| 2025 |
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. |
In vitro lymphangiogenesis screening model, chromatin immunoprecipitation (ChIP), functional inhibition assays, preclinical CCa models |
Cell death discovery |
Medium |
41145436
|
| 2025 |
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. |
RNA interference, CREB5 overexpression, in vitro and in vivo (SVZ) proliferation assays (BrdU, Ki-67), TUNEL staining, ChIP assay, luciferase reporter assay |
Cells |
Medium |
40862718
|
| 2025 |
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. |
H3K27me3 ChIP-seq, super-enhancer disruption with ABBV-075, BRG1 inhibitor combination, functional tumor growth assays |
Nature communications |
Medium |
40246858
|
| 2025 |
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. |
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 |
Oncotarget |
Medium |
41954995
|
| 2026 |
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. |
Immunoprecipitation, immunofluorescence, Western blot, qRT-PCR, CREB5 overexpression/knockdown in NP cells and rat IDD model |
Osteoarthritis and cartilage |
Medium |
41856459
|
| 2026 |
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. |
scRNA-seq, scATAC-seq, primary neuron experiments, CREB5 knockdown/overexpression, ApoL6 overexpression rescue, in vivo mouse SCI model |
CNS neuroscience & therapeutics |
Medium |
41700484
|
| 2016 |
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. |
Dual-luciferase assay, western blot, siRNA knockdown in primary human monocytes |
Translational psychiatry |
Medium |
26978739
|
| 2024 |
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. |
CLP mouse model, LPS-induced HK-2 cell model, FOXQ1 overexpression/knockdown, rescue experiments with CREB5 manipulation, NF-κB pathway readouts |
Biochimica et biophysica acta. Molecular basis of disease |
Low |
38960057
|
| 2027 |
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. |
RNA-seq identification of miR-32533, northern blot, APP/PS1 and 5xFAD mouse models, CREB5 overexpression/inhibition, bioinformatics and confirmatory promoter-binding experiments |
Advanced science |
Low |
39840513
|
| 2026 |
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. |
scRNA-seq, mRNA-seq, Western blot, overexpression experiments, in vivo TMJOA model with PLPP3 overexpression rescue |
Molecular biomedicine |
Low |
41870835
|