{"gene":"CEBPD","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":1992,"finding":"CEBPD (NF-IL6-beta) forms a heterodimer with NF-IL6 (C/EBPbeta) in vitro; the heterodimeric complex binds to the same DNA sequences as respective homodimers, and CEBPD shows stronger transactivation than NF-IL6 and synergistic transcriptional activation when co-expressed with NF-IL6.","method":"In vitro heterodimerization assay, DNA binding (EMSA), transient luciferase reporter assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of heterodimer, DNA binding assay, and reporter transactivation in a single focused study","pmids":["1741402"],"is_preprint":false},{"year":1993,"finding":"CEBPD (C/EBP-delta/NF-IL6-beta) is transcriptionally induced by IL-6 in Hep3B hepatoma cells and becomes the major IL-6-induced protein binding to IL-6 responsive elements (IL-6REs) in nuclei, contrasting with C/EBPbeta (IL-6DBP/NF-IL6) whose activity is modulated post-translationally by IL-6.","method":"Nuclear protein binding assays, transient transfection reporter assays, cDNA transfection","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — protein binding assays, reporter assays, and mechanistic contrast with NF-IL6 in a single focused study","pmids":["7680115"],"is_preprint":false},{"year":1993,"finding":"CEBPD protein is induced in nuclei of Hep3B cells after IL-1 treatment and binds the proximal C/EBP site (bZIP1) in the complement C3 promoter; CEBPD trans-activates the C3 promoter in an IL-1-responsive manner, and site-directed mutagenesis of the bZIP1 site significantly reduces basal expression and IL-1 responsiveness.","method":"EMSA with antibody supershift, Western immunoblot, co-transfection reporter assay, site-directed mutagenesis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis, EMSA/supershift, Western blot, and functional reporter assays in a single study; replicated across multiple methods","pmids":["8385337"],"is_preprint":false},{"year":1993,"finding":"The human CEBPD (C/EBP delta, CRP3, CELF) gene is intronless and maps to the pericentromeric region of human chromosome 8 (8q11), as determined by fluorescence in situ hybridization (FISH) and somatic cell hybrid analysis.","method":"FISH, restriction mapping, somatic cell hybrid DNA analysis, sequence analysis","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct chromosomal localization by FISH confirmed with STS/hybrid panel, single study","pmids":["8314590"],"is_preprint":false},{"year":1995,"finding":"CEBPD (NF-IL6-beta/CRP3) physically interacts with the transcription factor PU.1; deletion of the C-terminal 28 amino acids of PU.1 (Ets domain) or deletion of the CEBPD leucine zipper domain disrupts this interaction. PU.1 and CEBPD simultaneously bind adjacent DNA sites and synergistically activate transcription.","method":"Far Western blot, cDNA library screen, deletion mutagenesis, EMSA, transient expression transcription assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct physical interaction shown by Far Western, domain mapping by mutagenesis, and functional synergy by reporter assay in a single study","pmids":["7594592"],"is_preprint":false},{"year":1995,"finding":"Growth hormone (GH) induces CEBPD transcription (not translation) in 3T3-F442A preadipocytes, increasing CEBPD mRNA (superinducible by cycloheximide), in contrast to C/EBPbeta which is regulated at the translational level by GH; this induction is involved in initiating adipocyte differentiation.","method":"EMSA with specific antibodies, Western blot, Northern blot, Janus kinase 2 inhibitor treatment","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA, Western, Northern, and inhibitor experiments in same study distinguishing transcriptional vs translational regulation","pmids":["7760844"],"is_preprint":false},{"year":1996,"finding":"VIP, PACAP, and noradrenaline induce CEBPD (and C/EBPbeta) mRNA expression in mouse cortical astrocytes via the cAMP second-messenger pathway; CEBPD behaves as a cAMP-inducible immediate-early gene (induced in the presence of protein synthesis inhibitor). Transfection of CEBPD (or active C/EBPbeta) expression vectors enhances glycogen resynthesis elicited by noradrenaline.","method":"Northern blot, protein synthesis inhibitor treatment, transfection with expression vectors, glycogen resynthesis assay","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cAMP pathway defined by inhibitor experiments, and functional rescue by CEBPD overexpression in astrocytes","pmids":["8558260"],"is_preprint":false},{"year":1997,"finding":"CEBPD expression is induced in G0-arrested mouse mammary epithelial cells (COMMA D) by serum/growth factor withdrawal or contact inhibition; antisense CEBPD expression markedly delays growth arrest, establishing CEBPD as required for initiation of G0 arrest in mammary epithelial cells.","method":"Northern blot, Western blot, EMSA, antisense construct expression, cell cycle analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function via antisense with defined growth arrest phenotype, replicated across multiple measurement methods in single lab","pmids":["9045647"],"is_preprint":false},{"year":2001,"finding":"LPS-induced COX-2 mRNA induction in macrophages is biphasic: the first phase requires C/EBPbeta (but not de novo protein synthesis), while the second, sustained phase requires both C/EBPbeta and CEBPD. CEBPD synthesis is dramatically increased by LPS and repressed by combined inhibition of MAPK and SAPK2/p38 cascades.","method":"C/EBPbeta knockout macrophages, protein synthesis inhibitors, MAPK inhibitors, Northern blot, functional COX-2 induction assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout combined with pharmacological inhibitors and multiple readouts, orthogonal methods, single lab but robust mechanistic definition","pmids":["11668179"],"is_preprint":false},{"year":2003,"finding":"CEBPD protein is ubiquitinated and degraded in a ubiquitin-dependent manner primarily in the nucleus during G0 growth arrest in mouse mammary epithelial cells; the CEBPD mRNA has a short half-life (~35 min) and a short poly(A) tail (~100 nt) with degradation via a deadenylation-independent pathway.","method":"Transcriptional inhibitor pulse-chase, oligo/RNase H cleavage, RACE-PAT, proteasome inhibitor experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical measurement of mRNA and protein stability with pathway inhibitors, single lab","pmids":["12554732"],"is_preprint":false},{"year":2005,"finding":"CEBPD transcriptional activity is regulated by the p38 MAP kinase pathway downstream of IL-1beta; a domain between amino acids 70–108 of CEBPD contains both a transactivation region and a docking site for p38 MAP kinase (residues 75–85) required for CEBPD phosphorylation and IL-1-dependent haptoglobin induction.","method":"p38 inhibitor (SB203580), mutagenesis of CEBPD domains, transient transfection reporter assays, Northern blot","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mutagenesis plus pharmacological inhibition with functional reporter readout, single lab","pmids":["15694370"],"is_preprint":false},{"year":2008,"finding":"CEBPD is sumoylated at lysine 120 by SUMO1 in HepG2 cells; sumoylated CEBPD recruits HDAC1 and HDAC3 to the PPARG2 promoter, inactivating PPARG2 transcription. Non-sumoylated CEBPD activates PPARG2 transcription via two C/EBP binding motifs (-324/-311 and -158/-145), and excess CEBPD reverses suCEBPD/HDAC1/HDAC3-mediated PPARG2 inactivation to promote hepatic lipogenesis.","method":"5'-serial deletion reporter analysis, ChIP assay, site-directed mutagenesis of CEBPD (K120), co-immunoprecipitation, sumoylation assays","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct SUMO modification at specific residue, ChIP, mutagenesis, and functional reporter assays in single study","pmids":["18619497"],"is_preprint":false},{"year":2010,"finding":"CEBPD induces expression of the CDC27 (APC3) subunit of the anaphase-promoting complex/cyclosome (APC/C), leading to polyubiquitination and proteasomal degradation of cyclin D1, and also downregulates cyclin B1, Skp2, and Plk-1. Loss of CEBPD in knockout MEFs reduces Cdc27 and increases cyclin D1 even with activated GSK-3beta.","method":"Knockout MEFs, siRNA silencing, ChIP, luciferase reporter, overexpression studies, Western blot","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout, siRNA knockdown, ChIP, and reporter assays across multiple cell types; mechanistic chain from CEBPD to APC/C to cyclin D1 degradation established","pmids":["20439707"],"is_preprint":false},{"year":2010,"finding":"CEBPD mediates nuclear import of FANCD2 by interacting with both FANCD2 and importin 4 (IPO4) via separate domains, forming a FANCD2-IPO4 complex that augments nuclear import of FANCD2—a prerequisite for its monoubiquitination required for DNA repair. This represents a transcription-independent activity of CEBPD in the DNA damage response.","method":"Co-immunoprecipitation, gene knockout (CEBPD KO MEFs), siRNA depletion, overexpression, Western blot, nuclear fractionation, mitomycin C survival assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP identifying separate interacting domains, genetic KO, siRNA, and functional rescue across multiple cell types in a single rigorous study","pmids":["20805509"],"is_preprint":false},{"year":2010,"finding":"CEBPD drives expression of pentraxin-3 (PTX3) in astrocytes; PTX3 secreted by CEBPD-activated astrocytes attenuates macrophage-mediated phagocytosis of damaged neuron cells, revealing a role for astrocytic CEBPD in accumulation of damaged neurons.","method":"Global gene expression profiling, reporter assay, ChIP, loss-of-function (siRNA), phagocytosis functional assay","journal":"Neurobiology of aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional phagocytosis assay, single lab with two orthogonal methods","pmids":["21112127"],"is_preprint":false},{"year":2010,"finding":"CEBPD trans-activates the SOD1 promoter, reducing cisplatin-induced reactive oxygen species and apoptosis in bladder urothelial carcinoma cells; this represents a novel pro-survival (drug resistance) role for CEBPD through direct transcriptional regulation of SOD1.","method":"Reporter assay (promoter transactivation), ChIP, ROS measurement, apoptosis assays, siRNA knockdown","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay plus ChIP supporting direct promoter binding, functional ROS/apoptosis readout, single lab","pmids":["20385105"],"is_preprint":false},{"year":2010,"finding":"CEBPD and STAT-1 are required for TLR8 basal and R848-stimulated transcriptional activity; ChIP assays showed CEBPD and C/EBPbeta bind C/EBP cis-elements in the TLR8 promoter, and R848 stimulation enhances binding of CEBPD (but not C/EBPbeta) to these sites.","method":"Reporter gene analysis, ChIP assay, cytokine stimulation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assays with stimulation-specific binding distinction, single lab","pmids":["20829351"],"is_preprint":false},{"year":2010,"finding":"LPS-induced CEBPD expression is inhibited by the HDAC inhibitor trichostatin A (TSA) through reduction of c-Jun recruitment (via Sp1) to the CEBPD promoter. A DAPA and ChIP assay showed that c-Jun is recruited via Sp1 to the CEBPD promoter upon LPS treatment, and TSA represses this recruitment; loss of CEBPD results in increased binding of C/EBPalpha and C/EBPbeta to the COX-2 promoter.","method":"Reporter assay (Sp1 site mutagenesis), DAPA, ChIP, Western blot, HDAC inhibitor treatment","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and DAPA with promoter mutagenesis, single lab","pmids":["20506344"],"is_preprint":false},{"year":2011,"finding":"Miz1 is phosphorylated at Ser178 after LPS stimulation, which is required for recruitment of HDAC1 to repress transcription of the CEBPD gene, thereby terminating LPS-induced inflammation. Genetic disruption of the Miz1 POZ domain results in prolonged CEBPD expression and hyperinflammation.","method":"Genetic mouse model (Miz1 POZ domain disruption), phosphorylation mapping, HDAC1 recruitment assay, in vivo LPS challenge","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic model, phosphorylation site identification, HDAC1 recruitment, and functional inflammatory phenotype across multiple experiments","pmids":["23525087"],"is_preprint":false},{"year":2011,"finding":"CEBPD regulates VEGF-C and VEGFR3 expression in lymphatic endothelial cells (LECs) to promote lymphangiogenesis; hypoxia induces CEBPD expression via HIF-1alpha, and CEBPD in turn regulates HIF-1alpha expression. Blocking HIF-1alpha activity abolishes CEBPD-induced VEGF-C and VEGFR3 expression in LECs.","method":"Genetic deletion in mice, forced expression/knockdown in LECs, in vitro tube formation, in vivo lymphangiogenesis assay, reporter assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mouse KO plus cell-based gain/loss-of-function with functional angiogenesis readout, single lab","pmids":["21666710"],"is_preprint":false},{"year":2012,"finding":"CEBPD silencing in pancreatic beta-cells exacerbates cytokine-induced apoptosis by increasing CHOP expression and its downstream target BIM; CEBPD overexpression inhibits BIM expression and partially protects beta-cells. CEBPD also hampers IRF-1 upregulation and increases STAT1 activation, boosting production of CXCL1, 9, 10, and CCL20 chemokines when silenced.","method":"siRNA knockdown (single and double), overexpression, caspase assays, apoptosis quantification in rat INS-1E, primary rat beta-cells, and human islets","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown plus overexpression with mechanistic dissection across multiple cell types, single lab","pmids":["22347430"],"is_preprint":false},{"year":2007,"finding":"CEBPD represses ΔNp63alpha expression in keratinocytes (identified as a primary p63 target by RNAi screening and ChIP); reciprocally, CEBPD binds to and activates the ΔNp63 promoter. CEBPD overexpression alters the normal p63 isoform profile and is found on p63 target gene promoters by ChIP, indicating direct co-regulation.","method":"RNAi screening, RT-PCR, ChIP, overexpression in HaCaT and primary keratinocytes","journal":"BMC molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and functional RNAi with isoform-level analysis, single lab","pmids":["17903252"],"is_preprint":false},{"year":2010,"finding":"CEBPD reverses RB/E2F1-mediated repression of PPARG2 and GADD153 promoters; increased CEBPD attenuates E2F1-induced cancer cell proliferation. HMDB-induced CEBPD expression is activated through the p38/CREB pathway. ChIP assays demonstrate direct CEBPD binding at PPARG2 and GADD153 promoters.","method":"Methylation-specific PCR, reporter assay, ChIP, p38/CREB pathway inhibitors, xenograft mouse model","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus pathway inhibitors and reporter assays with in vivo xenograft validation, single lab","pmids":["20971808"],"is_preprint":false},{"year":2016,"finding":"The EGFR/STAT3 signaling pathway drives cisplatin-induced CEBPD expression in bladder urothelial carcinoma cells; CEBPD in turn directly activates ABCB1 and ABCC2 drug transporter genes (shown by reporter and in vivo DNA-binding assays), conferring cross-resistance to paclitaxel. Loss-of-function of EGFR or STAT3 reduces CEBPD expression.","method":"Loss-of-function assays (siRNA/shRNA), reporter assays, in vivo DNA-binding (ChIP), xenograft animal assay, pharmacological inhibitors (gefitinib, S3I-201)","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, reporter assays, loss-of-function with in vivo xenograft, single lab","pmids":["27435393"],"is_preprint":false},{"year":2017,"finding":"Metformin reduces Src-mediated CEBPD protein degradation and activates AMPK, leading to increased CEBPD expression in hepatocellular carcinoma cells; CEBPD then transcriptionally activates LC3B and ATG3 to induce autophagy and apoptosis.","method":"Reporter assay, ChIP, siRNA knockdown, AMPK inhibitor/activator, Western blot, apoptosis assays in Huh7 cells","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter and ChIP assays with pharmacological and genetic perturbations, single lab","pmids":["28099155"],"is_preprint":false},{"year":2019,"finding":"DN-ATF5, a dominant-negative leucine zipper peptide, physically associates with CEBPD (and CEBPB) in cells, as revealed by unbiased pulldown assays coupled with mass spectrometry and immunoblotting; DN-ATF5 suppresses CEBPD transcriptional activity and CEBPD knockdown promotes apoptosis in cancer cells but not normal astrocytes.","method":"Pull-down assay with mass spectrometry, immunoblotting, knockdown (siRNA), transcriptional reporter assay","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — unbiased MS-based pulldown plus functional knockdown assays, single lab","pmids":["31676720"],"is_preprint":false},{"year":2020,"finding":"Importin 4 (IPO4) augments nuclear translocation of CEBPD via nuclear localization signals (NLS), enabling CEBPD to transcriptionally upregulate PRKDC (DNA-PKcs), which mediates cisplatin-induced DNA damage repair. Knockdown of IPO4 or CEBPD reduces PRKDC expression and enhances cisplatin sensitivity in vitro and in vivo.","method":"shRNA knockdown, reporter assay, ChIP, xenograft assay, functional DNA repair assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assays and functional in vivo xenograft, mechanistically extending prior IPO4/CEBPD work, single lab","pmids":["32661323"],"is_preprint":false},{"year":2021,"finding":"BRD4 bromodomain-1 (not bromodomain-2) controls CEBPD expression through a BRD4/CEBPD/promoter/enhancer complex in vascular smooth muscle cells; endogenous BRD4 co-immunoprecipitates with CEBPD, and both co-immunoprecipitate Cebpd promoter and enhancer DNA fragments. BRD4 and CEBPD cooperate to upregulate PDGFRα expression in SMC inflammation.","method":"ChIP-seq (H3K27ac/BRD4), genomic deletion, gene silencing (BRD4), Co-IP, loss- and gain-of-function experiments, JQ1 pharmacological inhibition","journal":"Molecular therapy. Methods & clinical development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq plus reciprocal Co-IP with JQ1 validation and functional gain/loss assays, single lab","pmids":["33768129"],"is_preprint":false},{"year":2021,"finding":"Synthetic CEBPD leucine zipper decoy peptides (Dpep/Bpep) interfere with formation of active CEBPD homodimers and heterodimers, suppressing expression of CEBPD direct targets IL6, IL8, and asparagine synthetase (ASNS), depleting survivin, and elevating BMF to trigger cancer cell apoptosis without affecting non-transformed cells.","method":"Cell-penetrating peptide treatment, reporter assay for transcriptional activity, Western blot for target proteins, apoptosis assays, xenograft mouse models","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic validation via transcriptional target suppression and target protein changes, with in vivo xenograft, single lab","pmids":["34065488"],"is_preprint":false},{"year":2023,"finding":"In glioblastoma under hypoxia, HIF1α and HIF2α activate the CEBPD promoter; CEBPD then activates the FN1 (fibronectin) promoter (shown by ChIP-seq and luciferase reporter assay), and FN1-integrin receptor interactions promote EGFR phosphorylation activating the EGFR/PI3K pathway, driving invasion.","method":"Proteomic analysis, ChIP-seq and ChIP-qPCR, luciferase reporter assay, CEBPD knockdown, Western blot, in vitro and in vivo invasion/growth assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq/qPCR plus luciferase reporter with functional in vitro and in vivo knockdown validation, single lab","pmids":["37059730"],"is_preprint":false},{"year":2024,"finding":"CEBPD acts as a key transcription factor regulating the enhanced function of IL-21-engineered NK cells; CEBPD deletion results in loss of IL-21 NK cell anti-tumor potency, while CEBPD overexpression increases long-term cytotoxicity and metabolic fitness of NK cells.","method":"CRISPR-mediated CEBPD deletion, overexpression, chromatin accessibility (ATAC-seq), multiple in vivo GBM models, cytotoxicity assays","journal":"Cancer cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic deletion and overexpression with functional in vivo models and chromatin accessibility data, single lab","pmids":["39137729"],"is_preprint":false},{"year":2011,"finding":"CEBPD suppresses prolactin (PRL) promoter activity by 96% and inhibits cell proliferation in PRL-secreting pituitary tumor cells; CEBPD interacts with the transcription factor Pit1, and they attenuate each other's binding to the PRL promoter. CEBPD also suppresses c-Myc, survivin, and cyclins B1, B2, and D1.","method":"siRNA knockdown, forced expression, ChIP for PRL promoter binding, reporter assay, microarray expression profiling","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assay plus protein interaction data, with functional proliferation readout, single lab","pmids":["21980073"],"is_preprint":false},{"year":2014,"finding":"Androgen receptor (AR) directly binds to the CEBPD promoter region upon androgen stimulation and activates CEBPD transcription in prostate cancer cells; SUZ12 and EZH2 attenuate androgen-induced CEBPD transcription. CEBPD in turn directly binds and activates the CASP8 (caspase 8) promoter.","method":"Reporter assay, ChIP (in vivo DNA-binding assay), overexpression/knockdown studies, functional apoptosis assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assays demonstrating AR→CEBPD→CASP8 transcriptional chain, single lab","pmids":["24810056"],"is_preprint":false},{"year":2021,"finding":"In glioma, SUMOylation of PUM2 (by UBE2I/SUMO2/3) reduces PUM2's inhibitory effect on CEBPD mRNA, increasing CEBPD expression; CEBPD then binds the upstream promoter region of DSG2 and upregulates its expression to promote vasculogenic mimicry. Interactions were confirmed by Co-IP (PUM2 sumoylation), RIP assay (PUM2-CEBPD mRNA), and ChIP/luciferase (CEBPD-DSG2 promoter).","method":"Co-IP, immunofluorescence, RIP assay, ChIP assay, luciferase reporter assay, siRNA knockdown, 3D cell culture (vasculogenic mimicry assay)","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, RIP, ChIP, reporter), single lab","pmids":["32997416"],"is_preprint":false},{"year":2021,"finding":"In cancer-associated fibroblasts, cisplatin and 5-fluorouracil induce CEBPD expression; CEBPD transcriptionally activates SDF4 (stromal-cell-derived factor 4), which interacts with CXCR4 to trigger VEGFD expression via ERK1/2 and p38 pathways in endothelial cells, promoting tumor angiogenesis.","method":"ChIP assay, reporter assay, Co-IP (SDF4-CXCR4 interaction), siRNA knockdown, in vitro tube formation, in vivo angiogenesis assay","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP/reporter for CEBPD→SDF4, Co-IP for SDF4-CXCR4, with functional in vivo validation, single lab","pmids":["33953165"],"is_preprint":false}],"current_model":"CEBPD is a stimulus-inducible bZIP transcription factor that forms homodimers and heterodimers (with NF-IL6/C/EBPbeta and PU.1) to bind C/EBP DNA elements; its activity is regulated by transcriptional induction (via IL-6, IL-1, cAMP, p38 MAPK/CREB, EGFR/STAT3, and AR pathways), post-translational modification (SUMO1 at K120, which recruits HDAC1/3 to repress target genes; ubiquitin-dependent proteasomal degradation), and nuclear import (facilitated by IPO4); CEBPD drives acute-phase gene transcription (C3, haptoglobin, CRP), promotes G0 growth arrest and tumor suppression (via APC/C-Cdc27-mediated cyclin D1 degradation), exerts a transcription-independent role in DNA repair (by chaperoning FANCD2 nuclear import for monoubiquitination), and context-dependently regulates inflammation, lymphangiogenesis (through VEGF-C/VEGFR3), NK cell metabolic fitness, and drug resistance (via SOD1, ABCB1/ABCC2, and PRKDC transcriptional activation)."},"narrative":{"mechanistic_narrative":"CEBPD (C/EBPδ, NF-IL6-β) is a stimulus-inducible bZIP transcription factor that translates inflammatory, metabolic, and stress signals into changes in target-gene transcription [PMID:7680115, PMID:8385337]. It functions through leucine-zipper-mediated dimerization, forming homodimers and heterodimers with C/EBPβ (NF-IL6) that bind C/EBP DNA elements and synergistically transactivate target promoters [PMID:1741402]; it likewise pairs with PU.1 via its leucine zipper to co-occupy adjacent DNA sites [PMID:7594592], and synthetic leucine-zipper decoy peptides that block CEBPD dimer formation suppress its transcriptional output [PMID:34065488]. CEBPD is transcriptionally induced by IL-6 and IL-1 to drive acute-phase and inflammatory gene expression including complement C3, haptoglobin, and COX-2 [PMID:7680115, PMID:8385337, PMID:11668179], with its induction gated by p38 MAPK signaling — which both controls CEBPD synthesis and docks on a CEBPD transactivation domain (residues ~70–108) to phosphorylate it [PMID:11668179, PMID:15694370] — and terminated by Miz1-directed HDAC1 recruitment to the CEBPD gene [PMID:23525087]. Its own activity is further tuned by post-translational control: SUMO1 modification at lysine 120 converts CEBPD into a repressor that recruits HDAC1 and HDAC3 to silence target promoters such as PPARG2 [PMID:18619497], while ubiquitin-dependent proteasomal turnover limits its abundance [PMID:12554732]. CEBPD enforces G0 growth arrest and acts as a tumor suppressor by inducing the APC/C subunit CDC27 to drive cyclin D1 polyubiquitination and degradation [PMID:9045647, PMID:20439707]. Beyond transcription, CEBPD has a transcription-independent role in DNA repair, bridging FANCD2 to importin-4 (IPO4) to promote FANCD2 nuclear import required for its monoubiquitination [PMID:20805509]. In cancer contexts CEBPD is context-dependent, conferring chemoresistance through transcriptional activation of SOD1, the drug transporters ABCB1/ABCC2, and PRKDC [PMID:20385105, PMID:27435393, PMID:32661323], promoting hypoxia-driven invasion and angiogenesis via HIF/VEGF-C and FN1 axes [PMID:21666710, PMID:37059730], and shaping NK-cell anti-tumor function and metabolic fitness [PMID:39137729].","teleology":[{"year":1992,"claim":"Established the biochemical basis of CEBPD action by showing it is a bZIP factor that dimerizes and binds C/EBP DNA elements, defining how it engages the genome.","evidence":"In vitro heterodimerization, EMSA, and luciferase reporter assays with C/EBPβ","pmids":["1741402"],"confidence":"High","gaps":["Did not define physiological stimuli or endogenous target genes","Relative roles of homo- vs heterodimers in vivo unresolved"]},{"year":1993,"claim":"Showed CEBPD is itself transcriptionally induced by inflammatory cytokines and directs acute-phase gene transcription, placing it downstream of IL-6/IL-1 signaling.","evidence":"Nuclear binding assays, EMSA/supershift, and reporter/mutagenesis at IL-6RE and complement C3 promoter in Hep3B cells","pmids":["7680115","8385337"],"confidence":"High","gaps":["Upstream signal-transduction steps not yet mapped","Did not address post-translational regulation of CEBPD"]},{"year":1995,"claim":"Identified PU.1 as a direct CEBPD partner and mapped the interacting domains, extending the dimerization logic to cross-family transcriptional synergy.","evidence":"Far Western, deletion mutagenesis, EMSA, and reporter assays","pmids":["7594592"],"confidence":"High","gaps":["Target genes of the CEBPD/PU.1 pair not defined","Cell-type specificity of the interaction unaddressed"]},{"year":1997,"claim":"Defined a cell-cycle function by showing CEBPD induction is required to initiate G0 growth arrest, linking it to growth suppression.","evidence":"Antisense CEBPD with cell-cycle analysis in growth-arrested mammary epithelial cells","pmids":["9045647"],"confidence":"Medium","gaps":["Molecular effectors of arrest not yet identified","Antisense approach lacks single-gene specificity controls"]},{"year":2001,"claim":"Distinguished CEBPD from C/EBPβ functionally by showing it is specifically required for the sustained phase of inflammatory COX-2 induction downstream of MAPK/p38.","evidence":"C/EBPβ knockout macrophages, MAPK/p38 inhibitors, and COX-2 induction assays","pmids":["11668179"],"confidence":"High","gaps":["Direct phosphorylation events not yet mapped","Did not address transcriptional vs post-translational contributions"]},{"year":2003,"claim":"Revealed that CEBPD abundance is constrained by ubiquitin-dependent nuclear degradation and short mRNA half-life, explaining its transient, immediate-early behavior.","evidence":"Pulse-chase, RACE-PAT, and proteasome inhibitor experiments in mammary epithelial cells","pmids":["12554732"],"confidence":"Medium","gaps":["E3 ligase responsible not identified","Degron sequences not mapped"]},{"year":2005,"claim":"Mapped a bifunctional CEBPD domain that both transactivates and docks p38 MAPK, providing a structural basis for signal-dependent activation.","evidence":"Domain mutagenesis, p38 inhibitor, and reporter assays for haptoglobin induction","pmids":["15694370"],"confidence":"Medium","gaps":["Phosphoacceptor residues not pinpointed","Single-lab biochemistry without structural confirmation"]},{"year":2008,"claim":"Showed SUMO1 modification at K120 acts as a molecular switch converting CEBPD from activator to HDAC-recruiting repressor, explaining bidirectional control of target genes.","evidence":"Sumoylation assays, K120 mutagenesis, Co-IP with HDAC1/3, and ChIP/reporter at PPARG2 in HepG2 cells","pmids":["18619497"],"confidence":"High","gaps":["SUMO ligase/desumoylase enzymes not identified","Genome-wide scope of suCEBPD repression unknown"]},{"year":2010,"claim":"Connected CEBPD to the cell-cycle machinery mechanistically by showing it induces APC/C subunit CDC27 to drive cyclin D1 degradation, establishing a tumor-suppressive pathway.","evidence":"Knockout MEFs, siRNA, ChIP, reporter, and Western blot","pmids":["20439707"],"confidence":"High","gaps":["In vivo tumor-suppressor role not tested here","Crosstalk with GSK-3β pathway only partially defined"]},{"year":2010,"claim":"Uncovered a transcription-independent role: CEBPD chaperones FANCD2 into the nucleus via IPO4, a prerequisite for FANCD2 monoubiquitination in DNA repair.","evidence":"Reciprocal Co-IP mapping separate domains, KO MEFs, siRNA, nuclear fractionation, and mitomycin C survival assays","pmids":["20805509"],"confidence":"High","gaps":["Structural basis of the FANCD2–CEBPD–IPO4 ternary complex unknown","Whether this activity is regulated by the same signals as transcription unclear"]},{"year":2010,"claim":"Demonstrated context-dependent pro-survival and pro-resistance activity by showing CEBPD transactivates SOD1 to reduce chemotherapy-induced ROS and apoptosis.","evidence":"Reporter, ChIP, ROS/apoptosis assays, and siRNA in bladder urothelial carcinoma cells","pmids":["20385105"],"confidence":"Medium","gaps":["Reconciliation with tumor-suppressor role not addressed","Single tumor-cell context"]},{"year":2010,"claim":"Extended CEBPD into innate-immune and tissue functions through direct regulation of TLR8 and astrocytic PTX3.","evidence":"ChIP and reporter assays (TLR8); gene profiling, ChIP, siRNA, and phagocytosis assay (PTX3)","pmids":["20829351","21112127"],"confidence":"Medium","gaps":["In vivo immune phenotypes not established","Stimulus-specific binding mechanism at TLR8 unclear"]},{"year":2010,"claim":"Showed CEBPD opposes RB/E2F1 repression of growth-arrest gene promoters and is itself induced via the p38/CREB pathway, reinforcing its anti-proliferative axis.","evidence":"ChIP, reporter assays, p38/CREB inhibitors, and xenograft model","pmids":["20971808"],"confidence":"Medium","gaps":["Direct CEBPD–RB/E2F1 biochemical relationship not defined","Single-lab data"]},{"year":2011,"claim":"Identified Miz1/HDAC1 as the off-switch that terminates LPS-induced CEBPD transcription, defining how inflammatory CEBPD output is temporally bounded in vivo.","evidence":"Miz1 POZ-domain mutant mice, phosphorylation mapping, HDAC1 recruitment, and in vivo LPS challenge","pmids":["23525087"],"confidence":"High","gaps":["Kinase phosphorylating Miz1 Ser178 not identified","Generality beyond LPS inflammation untested"]},{"year":2011,"claim":"Linked CEBPD to hypoxia-driven lymphangiogenesis through a reciprocal HIF-1α loop controlling VEGF-C/VEGFR3.","evidence":"Mouse genetic deletion, LEC gain/loss-of-function, tube formation, and in vivo lymphangiogenesis assays","pmids":["21666710"],"confidence":"Medium","gaps":["Mechanism of CEBPD regulation of HIF-1α not resolved","Single-lab functional data"]},{"year":2011,"claim":"Showed CEBPD can act as a tissue-specific repressor by interacting with Pit1 to suppress prolactin and downregulating proliferation drivers in pituitary tumor cells.","evidence":"siRNA, forced expression, ChIP, reporter, and microarray profiling","pmids":["21980073"],"confidence":"Medium","gaps":["CEBPD–Pit1 interaction interface not mapped","In vivo tumor relevance untested"]},{"year":2012,"claim":"Defined a cytoprotective role in pancreatic beta-cells where CEBPD restrains CHOP/BIM-mediated apoptosis and dampens chemokine output, refining its context-dependence.","evidence":"siRNA, overexpression, and caspase/apoptosis assays in rat and human islet cells","pmids":["22347430"],"confidence":"Medium","gaps":["Direct CEBPD targets in this circuit not all identified","Single-lab data"]},{"year":2016,"claim":"Established a chemoresistance pathway in which EGFR/STAT3 drive CEBPD to activate ABCB1/ABCC2 drug transporters, conferring cross-resistance.","evidence":"siRNA/shRNA, reporter, ChIP, xenograft, and pharmacological inhibitors in bladder carcinoma","pmids":["27435393"],"confidence":"Medium","gaps":["Whether STAT3 directly co-regulates the transporter promoters with CEBPD unclear","Single tumor type"]},{"year":2017,"claim":"Showed metformin stabilizes CEBPD (via reduced Src degradation and AMPK activation), which then induces autophagy genes LC3B and ATG3, linking CEBPD to autophagy-coupled apoptosis.","evidence":"Reporter, ChIP, siRNA, AMPK modulators, and apoptosis assays in hepatocellular carcinoma cells","pmids":["28099155"],"confidence":"Medium","gaps":["Src-mediated degradation mechanism not detailed","Single-lab data"]},{"year":2019,"claim":"Confirmed CEBPD as a druggable dimerization target by showing a dominant-negative leucine-zipper peptide binds CEBPD and suppresses its activity selectively in cancer cells.","evidence":"MS-based pulldown, immunoblotting, knockdown, and reporter assays","pmids":["31676720"],"confidence":"Medium","gaps":["Endogenous binding partners displaced by DN-ATF5 not fully mapped","Selectivity mechanism for cancer cells unclear"]},{"year":2020,"claim":"Extended the IPO4–CEBPD axis to chemoresistance by showing IPO4-driven nuclear import of CEBPD enables transcriptional upregulation of PRKDC for cisplatin-induced DNA repair.","evidence":"shRNA, reporter, ChIP, DNA-repair assays, and xenograft","pmids":["32661323"],"confidence":"Medium","gaps":["NLS residues of CEBPD recognized by IPO4 not fully defined","Single-lab data"]},{"year":2021,"claim":"Identified BRD4 (bromodomain-1) as a chromatin reader required for CEBPD expression and a direct CEBPD co-factor in vascular smooth muscle inflammation.","evidence":"ChIP-seq, genomic deletion, BRD4 silencing, reciprocal Co-IP, and JQ1 inhibition","pmids":["33768129"],"confidence":"Medium","gaps":["Structural basis of BRD4 bromodomain-1 specificity not resolved","Single-lab data"]},{"year":2021,"claim":"Showed multiple cancer/stromal circuits route through CEBPD: post-transcriptional control via PUM2 SUMOylation driving DSG2/vasculogenic mimicry, and CAF-derived SDF4 driving CXCR4/VEGFD angiogenesis, plus AR-driven CEBPD→CASP8 control of apoptosis.","evidence":"Co-IP, RIP, ChIP, reporter assays, and in vivo angiogenesis/vasculogenic mimicry models","pmids":["32997416","33953165","24810056"],"confidence":"Medium","gaps":["Integration of these parallel circuits in a single tumor unclear","Each from a single lab/context"]},{"year":2021,"claim":"Validated leucine-zipper decoy peptides (Dpep/Bpep) as CEBPD-disrupting agents that suppress direct targets (IL6, IL8, ASNS) and trigger cancer-selective apoptosis.","evidence":"Cell-penetrating peptides, reporter, Western blot, apoptosis assays, and xenografts","pmids":["34065488"],"confidence":"Medium","gaps":["Off-target effects on other bZIP factors not fully excluded","Pharmacokinetics/in vivo delivery not optimized"]},{"year":2023,"claim":"Defined a hypoxia-to-invasion cascade where HIF1α/HIF2α induce CEBPD, which activates FN1 to drive EGFR/PI3K-dependent glioblastoma invasion.","evidence":"ChIP-seq/qPCR, luciferase reporter, knockdown, and in vitro/in vivo invasion assays","pmids":["37059730"],"confidence":"Medium","gaps":["Relative contribution of HIF1α vs HIF2α not resolved","Single tumor model"]},{"year":2024,"claim":"Established CEBPD as a master regulator of engineered NK-cell anti-tumor function and metabolic fitness, expanding its role into immune-effector programming.","evidence":"CRISPR deletion, overexpression, ATAC-seq, and in vivo GBM models with cytotoxicity assays","pmids":["39137729"],"confidence":"Medium","gaps":["Direct CEBPD target genes underpinning NK metabolic fitness not enumerated","Single-lab data"]},{"year":null,"claim":"How CEBPD's opposing roles — tumor-suppressive G0 arrest versus pro-survival chemoresistance, invasion, and angiogenesis — are selected within a given cell state remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model integrating SUMO/phosphorylation/degradation switches with context-specific output","Structural basis of dimer-partner choice and its functional consequences undefined","In vivo dose-dependence of CEBPD tumor-suppressor vs oncogenic behavior unmapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,2,12]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,2,11]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[13]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,2,9,13]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,11,12]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,8,16]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[7,12]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[13,26]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[15,23,29]}],"complexes":[],"partners":["CEBPB","PU.1","HDAC1","HDAC3","FANCD2","IPO4","BRD4","PIT1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P49716","full_name":"CCAAT/enhancer-binding protein delta","aliases":["Nuclear factor NF-IL6-beta","NF-IL6-beta"],"length_aa":269,"mass_kda":28.5,"function":"Transcription activator that recognizes two different DNA motifs: the CCAAT homology common to many promoters and the enhanced core homology common to many enhancers (PubMed:16397300). Important transcription factor regulating the expression of genes involved in immune and inflammatory responses (PubMed:16397300, PubMed:1741402). Transcriptional activator that enhances IL6 transcription alone and as heterodimer with CEBPB (PubMed:1741402)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P49716/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CEBPD","classification":"Not Classified","n_dependent_lines":30,"n_total_lines":1208,"dependency_fraction":0.024834437086092714},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CEBPD","total_profiled":1310},"omim":[{"mim_id":"612455","title":"SOLUTE CARRIER FAMILY 5 (SODIUM/GLUCOSE COTRANSPORTER), MEMBER 12; SLC5A12","url":"https://www.omim.org/entry/612455"},{"mim_id":"608044","title":"SOLUTE CARRIER FAMILY 5 (IODIDE TRANSPORTER), MEMBER 8; SLC5A8","url":"https://www.omim.org/entry/608044"},{"mim_id":"608004","title":"NUCLEAR FACTOR KAPPA-B INHIBITOR, ZETA; NFKBIZ","url":"https://www.omim.org/entry/608004"},{"mim_id":"607096","title":"SOLUTE CARRIER FAMILY 22 (URATE TRANSPORTER), MEMBER 12; SLC22A12","url":"https://www.omim.org/entry/607096"},{"mim_id":"607043","title":"TRAF3-INTERACTING PROTEIN 2; TRAF3IP2","url":"https://www.omim.org/entry/607043"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CEBPD"},"hgnc":{"alias_symbol":["CRP3","CELF","C/EBP-delta","NF-IL6-beta"],"prev_symbol":[]},"alphafold":{"accession":"P49716","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P49716","model_url":"https://alphafold.ebi.ac.uk/files/AF-P49716-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P49716-F1-predicted_aligned_error_v6.png","plddt_mean":65.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CEBPD","jax_strain_url":"https://www.jax.org/strain/search?query=CEBPD"},"sequence":{"accession":"P49716","fasta_url":"https://rest.uniprot.org/uniprotkb/P49716.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P49716/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P49716"}},"corpus_meta":[{"pmid":"19075228","id":"PMC_19075228","title":"A postnatal switch of CELF and MBNL proteins reprograms alternative splicing in the developing heart.","date":"2008","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19075228","citation_count":427,"is_preprint":false},{"pmid":"11158314","id":"PMC_11158314","title":"The CELF family of RNA binding proteins is implicated in cell-specific and developmentally regulated alternative splicing.","date":"2001","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11158314","citation_count":370,"is_preprint":false},{"pmid":"1741402","id":"PMC_1741402","title":"A member of the C/EBP family, NF-IL6 beta, forms a heterodimer and transcriptionally synergizes with NF-IL6.","date":"1992","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/1741402","citation_count":313,"is_preprint":false},{"pmid":"22180311","id":"PMC_22180311","title":"The importance of CELF control: molecular and biological roles of the CUG-BP, Elav-like family of RNA-binding proteins.","date":"2011","source":"Wiley interdisciplinary reviews. RNA","url":"https://pubmed.ncbi.nlm.nih.gov/22180311","citation_count":195,"is_preprint":false},{"pmid":"25883322","id":"PMC_25883322","title":"Antagonistic regulation of mRNA expression and splicing by CELF and MBNL proteins.","date":"2015","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/25883322","citation_count":162,"is_preprint":false},{"pmid":"7680115","id":"PMC_7680115","title":"The two C/EBP isoforms, IL-6DBP/NF-IL6 and C/EBP delta/NF-IL6 beta, are induced by IL-6 to promote acute phase gene transcription via different mechanisms.","date":"1993","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/7680115","citation_count":161,"is_preprint":false},{"pmid":"20220144","id":"PMC_20220144","title":"Induction of neutrophil gelatinase-associated lipocalin expression by co-stimulation with interleukin-17 and tumor necrosis factor-alpha is controlled by IkappaB-zeta but neither by C/EBP-beta nor C/EBP-delta.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20220144","citation_count":134,"is_preprint":false},{"pmid":"8385337","id":"PMC_8385337","title":"Participation of the transcription factor C/EBP delta in the acute-phase regulation of the human gene for complement component C3.","date":"1993","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/8385337","citation_count":133,"is_preprint":false},{"pmid":"16480813","id":"PMC_16480813","title":"Mammalian CELF/Bruno-like RNA-binding proteins: molecular characteristics and biological functions.","date":"2005","source":"Biochimie","url":"https://pubmed.ncbi.nlm.nih.gov/16480813","citation_count":127,"is_preprint":false},{"pmid":"11668179","id":"PMC_11668179","title":"The induction of cyclooxygenase-2 mRNA in macrophages is biphasic and requires both CCAAT enhancer-binding protein beta (C/EBP beta ) and C/EBP delta transcription factors.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11668179","citation_count":124,"is_preprint":false},{"pmid":"8981979","id":"PMC_8981979","title":"The processive endocellulase CelF, a major component of the Clostridium cellulolyticum cellulosome: purification and characterization of the recombinant form.","date":"1997","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/8981979","citation_count":113,"is_preprint":false},{"pmid":"7594592","id":"PMC_7594592","title":"Multiple proteins physically interact with PU.1. Transcriptional synergy with NF-IL6 beta (C/EBP delta, CRP3).","date":"1995","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/7594592","citation_count":95,"is_preprint":false},{"pmid":"12649496","id":"PMC_12649496","title":"Antagonistic regulation of alpha-actinin alternative splicing by CELF proteins and polypyrimidine tract binding protein.","date":"2003","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/12649496","citation_count":92,"is_preprint":false},{"pmid":"8558260","id":"PMC_8558260","title":"Vasoactive intestinal peptide, pituitary adenylate cyclase-activating peptide, and noradrenaline induce the transcription factors CCAAT/enhancer binding protein (C/EBP)-beta and C/EBP delta in mouse cortical astrocytes: involvement in cAMP-regulated glycogen metabolism.","date":"1996","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/8558260","citation_count":90,"is_preprint":false},{"pmid":"7760844","id":"PMC_7760844","title":"Early responses of trans-activating factors to growth hormone in preadipocytes: differential regulation of CCAAT enhancer-binding protein-beta (C/EBP beta) and C/EBP delta.","date":"1995","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/7760844","citation_count":81,"is_preprint":false},{"pmid":"19720736","id":"PMC_19720736","title":"MBNL and CELF proteins regulate alternative splicing of the skeletal muscle chloride channel CLCN1.","date":"2009","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/19720736","citation_count":80,"is_preprint":false},{"pmid":"14761971","id":"PMC_14761971","title":"CELF6, a member of the CELF family of RNA-binding proteins, regulates muscle-specific splicing enhancer-dependent alternative splicing.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14761971","citation_count":77,"is_preprint":false},{"pmid":"9045647","id":"PMC_9045647","title":"CCAAT/enhancer-binding protein-delta (C/EBP-delta) is induced in growth-arrested mouse mammary epithelial cells.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9045647","citation_count":76,"is_preprint":false},{"pmid":"21112127","id":"PMC_21112127","title":"CCAAT/enhancer binding protein delta (CEBPD) elevating PTX3 expression inhibits macrophage-mediated phagocytosis of dying neuron cells.","date":"2010","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/21112127","citation_count":73,"is_preprint":false},{"pmid":"39137729","id":"PMC_39137729","title":"Interleukin-21 engineering enhances NK cell activity against glioblastoma via CEBPD.","date":"2024","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/39137729","citation_count":71,"is_preprint":false},{"pmid":"23525087","id":"PMC_23525087","title":"Suppression of inflammation and acute lung injury by Miz1 via repression of C/EBP-δ.","date":"2013","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23525087","citation_count":71,"is_preprint":false},{"pmid":"18971639","id":"PMC_18971639","title":"Posttranscriptional regulation of gene networks by GU-rich elements and CELF proteins.","date":"2008","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/18971639","citation_count":70,"is_preprint":false},{"pmid":"15988035","id":"PMC_15988035","title":"Cardiac tissue-specific repression of CELF activity disrupts alternative splicing and causes cardiomyopathy.","date":"2005","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15988035","citation_count":69,"is_preprint":false},{"pmid":"21666710","id":"PMC_21666710","title":"C/EBP-δ regulates VEGF-C autocrine signaling in lymphangiogenesis and metastasis of lung cancer through HIF-1α.","date":"2011","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/21666710","citation_count":67,"is_preprint":false},{"pmid":"20439707","id":"PMC_20439707","title":"C/EBP{delta} targets cyclin D1 for proteasome-mediated degradation via induction of CDC27/APC3 expression.","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/20439707","citation_count":65,"is_preprint":false},{"pmid":"23247071","id":"PMC_23247071","title":"CUG-BP, Elav-like family (CELF)-mediated alternative splicing regulation in the brain during health and disease.","date":"2012","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/23247071","citation_count":61,"is_preprint":false},{"pmid":"12865412","id":"PMC_12865412","title":"Keratinocyte growth factor and the transcription factors C/EBP alpha, C/EBP delta, and SREBP-1c regulate fatty acid synthesis in alveolar type II cells.","date":"2003","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/12865412","citation_count":58,"is_preprint":false},{"pmid":"28099155","id":"PMC_28099155","title":"Metformin promotes apoptosis in hepatocellular carcinoma through the CEBPD-induced autophagy pathway.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28099155","citation_count":57,"is_preprint":false},{"pmid":"20385105","id":"PMC_20385105","title":"Transcriptional up-regulation of SOD1 by CEBPD: a potential target for cisplatin resistant human urothelial carcinoma cells.","date":"2010","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/20385105","citation_count":57,"is_preprint":false},{"pmid":"27435393","id":"PMC_27435393","title":"Inhibition of the EGFR/STAT3/CEBPD Axis Reverses Cisplatin Cross-resistance with Paclitaxel in the Urothelial Carcinoma of the Urinary Bladder.","date":"2016","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/27435393","citation_count":56,"is_preprint":false},{"pmid":"37059730","id":"PMC_37059730","title":"CEBPD is a master transcriptional factor for hypoxia regulated proteins in glioblastoma and augments hypoxia induced invasion through extracellular matrix-integrin mediated EGFR/PI3K pathway.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/37059730","citation_count":54,"is_preprint":false},{"pmid":"22347430","id":"PMC_22347430","title":"The transcription factor C/EBP delta has anti-apoptotic and anti-inflammatory roles in pancreatic beta cells.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22347430","citation_count":54,"is_preprint":false},{"pmid":"11916518","id":"PMC_11916518","title":"C/EBP-beta, C/EBP-delta, PU.1, AML1 genes: mutational analysis in 381 samples of hematopoietic and solid malignancies.","date":"2002","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/11916518","citation_count":50,"is_preprint":false},{"pmid":"28512194","id":"PMC_28512194","title":"Ancient antagonism between CELF and RBFOX families tunes mRNA splicing outcomes.","date":"2017","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/28512194","citation_count":49,"is_preprint":false},{"pmid":"23416545","id":"PMC_23416545","title":"Position-dependent and neuron-specific splicing regulation by the CELF family RNA-binding protein UNC-75 in Caenorhabditis elegans.","date":"2013","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/23416545","citation_count":47,"is_preprint":false},{"pmid":"27502555","id":"PMC_27502555","title":"Conserved functional antagonism of CELF and MBNL proteins controls stem cell-specific alternative splicing in planarians.","date":"2016","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/27502555","citation_count":47,"is_preprint":false},{"pmid":"18619497","id":"PMC_18619497","title":"HDAC1/HDAC3 modulates PPARG2 transcription through the sumoylated CEBPD in hepatic lipogenesis.","date":"2008","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/18619497","citation_count":46,"is_preprint":false},{"pmid":"10572139","id":"PMC_10572139","title":"Cellobiose-6-phosphate hydrolase (CelF) of Escherichia coli: characterization and assignment to the unusual family 4 of glycosylhydrolases.","date":"1999","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/10572139","citation_count":46,"is_preprint":false},{"pmid":"20971808","id":"PMC_20971808","title":"CEBPD reverses RB/E2F1-mediated gene repression and participates in HMDB-induced apoptosis of cancer cells.","date":"2010","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/20971808","citation_count":44,"is_preprint":false},{"pmid":"15894795","id":"PMC_15894795","title":"Identification of CELF splicing activation and repression domains in vivo.","date":"2005","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/15894795","citation_count":41,"is_preprint":false},{"pmid":"8936327","id":"PMC_8936327","title":"Molecular study and overexpression of the Clostridium cellulolyticum celF cellulase gene in Escherichia coli.","date":"1996","source":"Microbiology (Reading, England)","url":"https://pubmed.ncbi.nlm.nih.gov/8936327","citation_count":40,"is_preprint":false},{"pmid":"23468662","id":"PMC_23468662","title":"CELF family RNA-binding protein UNC-75 regulates two sets of mutually exclusive exons of the unc-32 gene in neuron-specific manners in Caenorhabditis elegans.","date":"2013","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23468662","citation_count":39,"is_preprint":false},{"pmid":"31676720","id":"PMC_31676720","title":"Dominant-Negative ATF5 Compromises Cancer Cell Survival by Targeting CEBPB and CEBPD.","date":"2019","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/31676720","citation_count":38,"is_preprint":false},{"pmid":"8650608","id":"PMC_8650608","title":"Effect of thermal injury on the expression of transcription factors that regulate acute phase response genes: the response of C/EBP alpha, C/EBP beta, and C/EBP delta to thermal injury.","date":"1996","source":"Surgery","url":"https://pubmed.ncbi.nlm.nih.gov/8650608","citation_count":38,"is_preprint":false},{"pmid":"20622515","id":"PMC_20622515","title":"The role of CELF proteins in neurological disorders.","date":"2010","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/20622515","citation_count":36,"is_preprint":false},{"pmid":"20805509","id":"PMC_20805509","title":"CCAAT/enhancer binding protein delta (C/EBPdelta, CEBPD)-mediated nuclear import of FANCD2 by IPO4 augments cellular response to DNA damage.","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/20805509","citation_count":35,"is_preprint":false},{"pmid":"32997416","id":"PMC_32997416","title":"SUMOylation of PUM2 promotes the vasculogenic mimicry of glioma cells via regulating CEBPD.","date":"2020","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32997416","citation_count":34,"is_preprint":false},{"pmid":"1805307","id":"PMC_1805307","title":"Nucleotide sequence of the cellulase gene celF of Clostridium thermocellum.","date":"1991","source":"Research in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/1805307","citation_count":33,"is_preprint":false},{"pmid":"8314590","id":"PMC_8314590","title":"The human C/EBP delta (CRP3/CELF) gene: structure and chromosomal localization.","date":"1993","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8314590","citation_count":32,"is_preprint":false},{"pmid":"25771860","id":"PMC_25771860","title":"ROCK2 promotes HCC proliferation by CEBPD inhibition through phospho-GSK3β/β-catenin signaling.","date":"2015","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/25771860","citation_count":32,"is_preprint":false},{"pmid":"19854948","id":"PMC_19854948","title":"The neurofibromatosis type I pre-mRNA is a novel target of CELF protein-mediated splicing regulation.","date":"2009","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/19854948","citation_count":32,"is_preprint":false},{"pmid":"34065488","id":"PMC_34065488","title":"Cell-Penetrating CEBPB and CEBPD Leucine Zipper Decoys as Broadly Acting Anti-Cancer Agents.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/34065488","citation_count":31,"is_preprint":false},{"pmid":"27253061","id":"PMC_27253061","title":"CELF RNA binding proteins promote axon regeneration in C. elegans and mammals through alternative splicing of Syntaxins.","date":"2016","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/27253061","citation_count":31,"is_preprint":false},{"pmid":"20829351","id":"PMC_20829351","title":"C/EBP{delta} and STAT-1 are required for TLR8 transcriptional activity.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20829351","citation_count":31,"is_preprint":false},{"pmid":"27918099","id":"PMC_27918099","title":"MiR-193b Mediates CEBPD-Induced Cisplatin Sensitization Through Targeting ETS1 and Cyclin D1 in Human Urothelial Carcinoma Cells.","date":"2016","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27918099","citation_count":31,"is_preprint":false},{"pmid":"21492414","id":"PMC_21492414","title":"The CCAAT/enhancer binding protein (C/EBP) δ is differently regulated by fibrillar and oligomeric forms of the Alzheimer amyloid-β peptide.","date":"2011","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/21492414","citation_count":31,"is_preprint":false},{"pmid":"34681716","id":"PMC_34681716","title":"CELF Family Proteins in Cancer: Highlights on the RNA-Binding Protein/Noncoding RNA Regulatory Axis.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34681716","citation_count":30,"is_preprint":false},{"pmid":"29482641","id":"PMC_29482641","title":"Transcription factors Tp73, Cebpd, Pax6, and Spi1 rather than DNA methylation regulate chronic transcriptomics changes after experimental traumatic brain injury.","date":"2018","source":"Acta neuropathologica communications","url":"https://pubmed.ncbi.nlm.nih.gov/29482641","citation_count":30,"is_preprint":false},{"pmid":"32661323","id":"PMC_32661323","title":"Inhibiting Importin 4-mediated nuclear import of CEBPD enhances chemosensitivity by repression of PRKDC-driven DNA damage repair in cervical cancer.","date":"2020","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/32661323","citation_count":30,"is_preprint":false},{"pmid":"33953165","id":"PMC_33953165","title":"Fibroblast CEBPD/SDF4 axis in response to chemotherapy-induced angiogenesis through CXCR4.","date":"2021","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/33953165","citation_count":29,"is_preprint":false},{"pmid":"22396222","id":"PMC_22396222","title":"Artemisinic acid is a regulator of adipocyte differentiation and C/EBP δ expression.","date":"2012","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22396222","citation_count":29,"is_preprint":false},{"pmid":"26270987","id":"PMC_26270987","title":"Multiple Protein Kinases via Activation of Transcription Factors NF-κB, AP-1 and C/EBP-δ Regulate the IL-6/IL-8 Production by HIV-1 Vpr in Astrocytes.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26270987","citation_count":29,"is_preprint":false},{"pmid":"17584860","id":"PMC_17584860","title":"Cloning and embryonic expression patterns of the chicken CELF family.","date":"2007","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/17584860","citation_count":27,"is_preprint":false},{"pmid":"8530045","id":"PMC_8530045","title":"Mouse chromosomal location of the CCAAT/enhancer binding proteins C/EBP beta (Cebpb), C/EBP delta (Cebpd), and CRP1 (Cebpe).","date":"1995","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8530045","citation_count":27,"is_preprint":false},{"pmid":"20631008","id":"PMC_20631008","title":"CELF proteins regulate CFTR pre-mRNA splicing: essential role of the divergent domain of ETR-3.","date":"2010","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/20631008","citation_count":27,"is_preprint":false},{"pmid":"8774705","id":"PMC_8774705","title":"Nuclear factor kappa B (NF-kappa B), nuclear factor interleukin-6 (NFIL-6 or C/EBP beta) and nuclear factor interleukin-6 beta (NFIL6-beta or C/EBP delta) are not sufficient to activate the endogenous interleukin-6 gene in the human breast carcinoma cell line MCF-7. Comparative analysis with MDA-MB-231 cells, an interleukin-6-expressing human breast carcinoma cell line.","date":"1996","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8774705","citation_count":27,"is_preprint":false},{"pmid":"17903252","id":"PMC_17903252","title":"Reciprocal regulation of p63 by C/EBP delta in human keratinocytes.","date":"2007","source":"BMC molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17903252","citation_count":26,"is_preprint":false},{"pmid":"12554732","id":"PMC_12554732","title":"Posttranscriptional and posttranslational regulation of C/EBP delta in G0 growth-arrested mammary epithelial cells.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12554732","citation_count":26,"is_preprint":false},{"pmid":"25403273","id":"PMC_25403273","title":"ABLIM1 splicing is abnormal in skeletal muscle of patients with DM1 and regulated by MBNL, CELF and PTBP1.","date":"2014","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/25403273","citation_count":26,"is_preprint":false},{"pmid":"24810056","id":"PMC_24810056","title":"The combination of the prodrugs perforin-CEBPD and perforin-granzyme B efficiently enhances the activation of caspase signaling and kills prostate cancer.","date":"2014","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/24810056","citation_count":25,"is_preprint":false},{"pmid":"36831248","id":"PMC_36831248","title":"Targeting Transcription Factors ATF5, CEBPB and CEBPD with Cell-Penetrating Peptides to Treat Brain and Other Cancers.","date":"2023","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/36831248","citation_count":23,"is_preprint":false},{"pmid":"34571881","id":"PMC_34571881","title":"CEBPD Potentiates the Macrophage Inflammatory Response but CEBPD Knock-Out Macrophages Fail to Identify CEBPD-Dependent Pro-Inflammatory Transcriptional Programs.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/34571881","citation_count":23,"is_preprint":false},{"pmid":"33768129","id":"PMC_33768129","title":"A hierarchical and collaborative BRD4/CEBPD partnership governs vascular smooth muscle cell inflammation.","date":"2021","source":"Molecular therapy. Methods & clinical development","url":"https://pubmed.ncbi.nlm.nih.gov/33768129","citation_count":23,"is_preprint":false},{"pmid":"32705251","id":"PMC_32705251","title":"Shikonin inhibits CEBPD downregulation in IL‑17‑treated HaCaT cells and in an imiquimod‑induced psoriasis model.","date":"2020","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/32705251","citation_count":23,"is_preprint":false},{"pmid":"15694370","id":"PMC_15694370","title":"IL-1 beta-dependent regulation of C/EBP delta transcriptional activity.","date":"2005","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/15694370","citation_count":23,"is_preprint":false},{"pmid":"19617893","id":"PMC_19617893","title":"C/EBP beta and C/EBP delta expression is elevated in the early phase of ethanol-induced hepatosteatosis in mice.","date":"2009","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/19617893","citation_count":22,"is_preprint":false},{"pmid":"18092000","id":"PMC_18092000","title":"The Cebpd (C/EBPdelta) gene is induced by luteinizing hormones in ovarian theca and interstitial cells but is not essential for mouse ovary function.","date":"2007","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/18092000","citation_count":21,"is_preprint":false},{"pmid":"19757395","id":"PMC_19757395","title":"Differential expression of the Brunol/CELF family genes during Xenopus laevis early development.","date":"2010","source":"The International journal of developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/19757395","citation_count":21,"is_preprint":false},{"pmid":"14691721","id":"PMC_14691721","title":"Expression pattern of the CCAAT/enhancer-binding proteins C/EBP-alpha, C/EBP-beta and C/EBP-delta in the human placenta.","date":"2003","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/14691721","citation_count":21,"is_preprint":false},{"pmid":"34209741","id":"PMC_34209741","title":"Exosomal microRNA let-7-5p from Taenia pisiformis Cysticercus Prompted Macrophage to M2 Polarization through Inhibiting the Expression of C/EBP δ.","date":"2021","source":"Microorganisms","url":"https://pubmed.ncbi.nlm.nih.gov/34209741","citation_count":21,"is_preprint":false},{"pmid":"17331722","id":"PMC_17331722","title":"Expression of MBNL and CELF mRNA transcripts in muscles with myotonic dystrophy.","date":"2007","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/17331722","citation_count":20,"is_preprint":false},{"pmid":"21980073","id":"PMC_21980073","title":"CEBPD suppresses prolactin expression and prolactinoma cell proliferation.","date":"2011","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/21980073","citation_count":20,"is_preprint":false},{"pmid":"22453899","id":"PMC_22453899","title":"Repression of nuclear CELF activity can rescue CELF-regulated alternative splicing defects in skeletal muscle models of myotonic dystrophy.","date":"2012","source":"PLoS currents","url":"https://pubmed.ncbi.nlm.nih.gov/22453899","citation_count":20,"is_preprint":false},{"pmid":"19351738","id":"PMC_19351738","title":"Induction of CRP3/MLP expression during vein arterialization is dependent on stretch rather than shear stress.","date":"2009","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/19351738","citation_count":18,"is_preprint":false},{"pmid":"32151175","id":"PMC_32151175","title":"MiR-324-5p/PTPRD/CEBPD axis promotes papillary thyroid carcinoma progression via microenvironment alteration.","date":"2020","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32151175","citation_count":18,"is_preprint":false},{"pmid":"19073192","id":"PMC_19073192","title":"CELF-mediated alternative splicing is required for cardiac function during early, but not later, postnatal life.","date":"2008","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/19073192","citation_count":18,"is_preprint":false},{"pmid":"21143913","id":"PMC_21143913","title":"CCAAT/Enhancer Binding Protein-delta (C/EBP-delta) regulates cell growth, migration and differentiation.","date":"2010","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/21143913","citation_count":18,"is_preprint":false},{"pmid":"10683316","id":"PMC_10683316","title":"CYP2B1 is regulated by C/EBP alpha and C/EBP delta inlung epithelial cells.","date":"2000","source":"Molecular cell biology research communications : MCBRC","url":"https://pubmed.ncbi.nlm.nih.gov/10683316","citation_count":18,"is_preprint":false},{"pmid":"29644527","id":"PMC_29644527","title":"Gemcabene, a first-in-class lipid-lowering agent in late-stage development, down-regulates acute-phase C-reactive protein via C/EBP-δ-mediated transcriptional mechanism.","date":"2018","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29644527","citation_count":18,"is_preprint":false},{"pmid":"9761829","id":"PMC_9761829","title":"Crystallization of the catalytic domain of Clostridium cellulolyticum CeLF cellulase in the presence of a newly synthesized cellulase inhibitor.","date":"1998","source":"Acta crystallographica. Section D, Biological crystallography","url":"https://pubmed.ncbi.nlm.nih.gov/9761829","citation_count":18,"is_preprint":false},{"pmid":"29642403","id":"PMC_29642403","title":"Cebpd Is Essential for Gamma-Tocotrienol Mediated Protection against Radiation-Induced Hematopoietic and Intestinal Injury.","date":"2018","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/29642403","citation_count":17,"is_preprint":false},{"pmid":"10634518","id":"PMC_10634518","title":"Local signals induce CCAAT/enhancer binding protein-delta (C/EBP-delta) and C/EBP-beta mRNA expression in the involuting mouse mammary gland.","date":"1999","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/10634518","citation_count":17,"is_preprint":false},{"pmid":"38729272","id":"PMC_38729272","title":"The role of CELF family in neurodevelopment and neurodevelopmental disorders.","date":"2024","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/38729272","citation_count":16,"is_preprint":false},{"pmid":"28881585","id":"PMC_28881585","title":"C/EBP-δ positively regulates MDSC expansion and endothelial VEGFR2 expression in tumor development.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28881585","citation_count":16,"is_preprint":false},{"pmid":"12721415","id":"PMC_12721415","title":"CelF of Orpinomyces PC-2 has an intron and encodes a cellulase (CelF) containing a carbohydrate-binding module.","date":"2003","source":"Applied biochemistry and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/12721415","citation_count":16,"is_preprint":false},{"pmid":"21541285","id":"PMC_21541285","title":"Expression of a dominant negative CELF protein in vivo leads to altered muscle organization, fiber size, and subtype.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21541285","citation_count":15,"is_preprint":false},{"pmid":"35203290","id":"PMC_35203290","title":"Angiogenesis Driven by the CEBPD-hsa-miR-429-VEGFA Signaling Axis Promotes Urothelial Carcinoma Progression.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/35203290","citation_count":14,"is_preprint":false},{"pmid":"34954904","id":"PMC_34954904","title":"Biological significance of MYC and CEBPD coamplification in urothelial carcinoma: Multilayered genomic, transcriptional and posttranscriptional positive feedback loops enhance oncogenic glycolysis.","date":"2021","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34954904","citation_count":14,"is_preprint":false},{"pmid":"33809617","id":"PMC_33809617","title":"High-Throughput Screening for CEBPD-Modulating Compounds in THP-1-Derived Reporter Macrophages Identifies Anti-Inflammatory HDAC and BET Inhibitors.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33809617","citation_count":14,"is_preprint":false},{"pmid":"20506344","id":"PMC_20506344","title":"Inhibition of LPS-induced C/EBP delta by trichostatin A has a positive effect on LPS-induced cyclooxygenase 2 expression in RAW264.7 cells.","date":"2010","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20506344","citation_count":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50449,"output_tokens":8955,"usd":0.142836,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18684,"output_tokens":7033,"usd":0.134623,"stage2_stop_reason":"end_turn"},"total_usd":0.277459,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1992,\n      \"finding\": \"CEBPD (NF-IL6-beta) forms a heterodimer with NF-IL6 (C/EBPbeta) in vitro; the heterodimeric complex binds to the same DNA sequences as respective homodimers, and CEBPD shows stronger transactivation than NF-IL6 and synergistic transcriptional activation when co-expressed with NF-IL6.\",\n      \"method\": \"In vitro heterodimerization assay, DNA binding (EMSA), transient luciferase reporter assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of heterodimer, DNA binding assay, and reporter transactivation in a single focused study\",\n      \"pmids\": [\"1741402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"CEBPD (C/EBP-delta/NF-IL6-beta) is transcriptionally induced by IL-6 in Hep3B hepatoma cells and becomes the major IL-6-induced protein binding to IL-6 responsive elements (IL-6REs) in nuclei, contrasting with C/EBPbeta (IL-6DBP/NF-IL6) whose activity is modulated post-translationally by IL-6.\",\n      \"method\": \"Nuclear protein binding assays, transient transfection reporter assays, cDNA transfection\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — protein binding assays, reporter assays, and mechanistic contrast with NF-IL6 in a single focused study\",\n      \"pmids\": [\"7680115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"CEBPD protein is induced in nuclei of Hep3B cells after IL-1 treatment and binds the proximal C/EBP site (bZIP1) in the complement C3 promoter; CEBPD trans-activates the C3 promoter in an IL-1-responsive manner, and site-directed mutagenesis of the bZIP1 site significantly reduces basal expression and IL-1 responsiveness.\",\n      \"method\": \"EMSA with antibody supershift, Western immunoblot, co-transfection reporter assay, site-directed mutagenesis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis, EMSA/supershift, Western blot, and functional reporter assays in a single study; replicated across multiple methods\",\n      \"pmids\": [\"8385337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"The human CEBPD (C/EBP delta, CRP3, CELF) gene is intronless and maps to the pericentromeric region of human chromosome 8 (8q11), as determined by fluorescence in situ hybridization (FISH) and somatic cell hybrid analysis.\",\n      \"method\": \"FISH, restriction mapping, somatic cell hybrid DNA analysis, sequence analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct chromosomal localization by FISH confirmed with STS/hybrid panel, single study\",\n      \"pmids\": [\"8314590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"CEBPD (NF-IL6-beta/CRP3) physically interacts with the transcription factor PU.1; deletion of the C-terminal 28 amino acids of PU.1 (Ets domain) or deletion of the CEBPD leucine zipper domain disrupts this interaction. PU.1 and CEBPD simultaneously bind adjacent DNA sites and synergistically activate transcription.\",\n      \"method\": \"Far Western blot, cDNA library screen, deletion mutagenesis, EMSA, transient expression transcription assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct physical interaction shown by Far Western, domain mapping by mutagenesis, and functional synergy by reporter assay in a single study\",\n      \"pmids\": [\"7594592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Growth hormone (GH) induces CEBPD transcription (not translation) in 3T3-F442A preadipocytes, increasing CEBPD mRNA (superinducible by cycloheximide), in contrast to C/EBPbeta which is regulated at the translational level by GH; this induction is involved in initiating adipocyte differentiation.\",\n      \"method\": \"EMSA with specific antibodies, Western blot, Northern blot, Janus kinase 2 inhibitor treatment\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA, Western, Northern, and inhibitor experiments in same study distinguishing transcriptional vs translational regulation\",\n      \"pmids\": [\"7760844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"VIP, PACAP, and noradrenaline induce CEBPD (and C/EBPbeta) mRNA expression in mouse cortical astrocytes via the cAMP second-messenger pathway; CEBPD behaves as a cAMP-inducible immediate-early gene (induced in the presence of protein synthesis inhibitor). Transfection of CEBPD (or active C/EBPbeta) expression vectors enhances glycogen resynthesis elicited by noradrenaline.\",\n      \"method\": \"Northern blot, protein synthesis inhibitor treatment, transfection with expression vectors, glycogen resynthesis assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cAMP pathway defined by inhibitor experiments, and functional rescue by CEBPD overexpression in astrocytes\",\n      \"pmids\": [\"8558260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"CEBPD expression is induced in G0-arrested mouse mammary epithelial cells (COMMA D) by serum/growth factor withdrawal or contact inhibition; antisense CEBPD expression markedly delays growth arrest, establishing CEBPD as required for initiation of G0 arrest in mammary epithelial cells.\",\n      \"method\": \"Northern blot, Western blot, EMSA, antisense construct expression, cell cycle analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function via antisense with defined growth arrest phenotype, replicated across multiple measurement methods in single lab\",\n      \"pmids\": [\"9045647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"LPS-induced COX-2 mRNA induction in macrophages is biphasic: the first phase requires C/EBPbeta (but not de novo protein synthesis), while the second, sustained phase requires both C/EBPbeta and CEBPD. CEBPD synthesis is dramatically increased by LPS and repressed by combined inhibition of MAPK and SAPK2/p38 cascades.\",\n      \"method\": \"C/EBPbeta knockout macrophages, protein synthesis inhibitors, MAPK inhibitors, Northern blot, functional COX-2 induction assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout combined with pharmacological inhibitors and multiple readouts, orthogonal methods, single lab but robust mechanistic definition\",\n      \"pmids\": [\"11668179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CEBPD protein is ubiquitinated and degraded in a ubiquitin-dependent manner primarily in the nucleus during G0 growth arrest in mouse mammary epithelial cells; the CEBPD mRNA has a short half-life (~35 min) and a short poly(A) tail (~100 nt) with degradation via a deadenylation-independent pathway.\",\n      \"method\": \"Transcriptional inhibitor pulse-chase, oligo/RNase H cleavage, RACE-PAT, proteasome inhibitor experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical measurement of mRNA and protein stability with pathway inhibitors, single lab\",\n      \"pmids\": [\"12554732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CEBPD transcriptional activity is regulated by the p38 MAP kinase pathway downstream of IL-1beta; a domain between amino acids 70–108 of CEBPD contains both a transactivation region and a docking site for p38 MAP kinase (residues 75–85) required for CEBPD phosphorylation and IL-1-dependent haptoglobin induction.\",\n      \"method\": \"p38 inhibitor (SB203580), mutagenesis of CEBPD domains, transient transfection reporter assays, Northern blot\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutagenesis plus pharmacological inhibition with functional reporter readout, single lab\",\n      \"pmids\": [\"15694370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CEBPD is sumoylated at lysine 120 by SUMO1 in HepG2 cells; sumoylated CEBPD recruits HDAC1 and HDAC3 to the PPARG2 promoter, inactivating PPARG2 transcription. Non-sumoylated CEBPD activates PPARG2 transcription via two C/EBP binding motifs (-324/-311 and -158/-145), and excess CEBPD reverses suCEBPD/HDAC1/HDAC3-mediated PPARG2 inactivation to promote hepatic lipogenesis.\",\n      \"method\": \"5'-serial deletion reporter analysis, ChIP assay, site-directed mutagenesis of CEBPD (K120), co-immunoprecipitation, sumoylation assays\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct SUMO modification at specific residue, ChIP, mutagenesis, and functional reporter assays in single study\",\n      \"pmids\": [\"18619497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CEBPD induces expression of the CDC27 (APC3) subunit of the anaphase-promoting complex/cyclosome (APC/C), leading to polyubiquitination and proteasomal degradation of cyclin D1, and also downregulates cyclin B1, Skp2, and Plk-1. Loss of CEBPD in knockout MEFs reduces Cdc27 and increases cyclin D1 even with activated GSK-3beta.\",\n      \"method\": \"Knockout MEFs, siRNA silencing, ChIP, luciferase reporter, overexpression studies, Western blot\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout, siRNA knockdown, ChIP, and reporter assays across multiple cell types; mechanistic chain from CEBPD to APC/C to cyclin D1 degradation established\",\n      \"pmids\": [\"20439707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CEBPD mediates nuclear import of FANCD2 by interacting with both FANCD2 and importin 4 (IPO4) via separate domains, forming a FANCD2-IPO4 complex that augments nuclear import of FANCD2—a prerequisite for its monoubiquitination required for DNA repair. This represents a transcription-independent activity of CEBPD in the DNA damage response.\",\n      \"method\": \"Co-immunoprecipitation, gene knockout (CEBPD KO MEFs), siRNA depletion, overexpression, Western blot, nuclear fractionation, mitomycin C survival assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP identifying separate interacting domains, genetic KO, siRNA, and functional rescue across multiple cell types in a single rigorous study\",\n      \"pmids\": [\"20805509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CEBPD drives expression of pentraxin-3 (PTX3) in astrocytes; PTX3 secreted by CEBPD-activated astrocytes attenuates macrophage-mediated phagocytosis of damaged neuron cells, revealing a role for astrocytic CEBPD in accumulation of damaged neurons.\",\n      \"method\": \"Global gene expression profiling, reporter assay, ChIP, loss-of-function (siRNA), phagocytosis functional assay\",\n      \"journal\": \"Neurobiology of aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional phagocytosis assay, single lab with two orthogonal methods\",\n      \"pmids\": [\"21112127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CEBPD trans-activates the SOD1 promoter, reducing cisplatin-induced reactive oxygen species and apoptosis in bladder urothelial carcinoma cells; this represents a novel pro-survival (drug resistance) role for CEBPD through direct transcriptional regulation of SOD1.\",\n      \"method\": \"Reporter assay (promoter transactivation), ChIP, ROS measurement, apoptosis assays, siRNA knockdown\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay plus ChIP supporting direct promoter binding, functional ROS/apoptosis readout, single lab\",\n      \"pmids\": [\"20385105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CEBPD and STAT-1 are required for TLR8 basal and R848-stimulated transcriptional activity; ChIP assays showed CEBPD and C/EBPbeta bind C/EBP cis-elements in the TLR8 promoter, and R848 stimulation enhances binding of CEBPD (but not C/EBPbeta) to these sites.\",\n      \"method\": \"Reporter gene analysis, ChIP assay, cytokine stimulation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assays with stimulation-specific binding distinction, single lab\",\n      \"pmids\": [\"20829351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LPS-induced CEBPD expression is inhibited by the HDAC inhibitor trichostatin A (TSA) through reduction of c-Jun recruitment (via Sp1) to the CEBPD promoter. A DAPA and ChIP assay showed that c-Jun is recruited via Sp1 to the CEBPD promoter upon LPS treatment, and TSA represses this recruitment; loss of CEBPD results in increased binding of C/EBPalpha and C/EBPbeta to the COX-2 promoter.\",\n      \"method\": \"Reporter assay (Sp1 site mutagenesis), DAPA, ChIP, Western blot, HDAC inhibitor treatment\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and DAPA with promoter mutagenesis, single lab\",\n      \"pmids\": [\"20506344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Miz1 is phosphorylated at Ser178 after LPS stimulation, which is required for recruitment of HDAC1 to repress transcription of the CEBPD gene, thereby terminating LPS-induced inflammation. Genetic disruption of the Miz1 POZ domain results in prolonged CEBPD expression and hyperinflammation.\",\n      \"method\": \"Genetic mouse model (Miz1 POZ domain disruption), phosphorylation mapping, HDAC1 recruitment assay, in vivo LPS challenge\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic model, phosphorylation site identification, HDAC1 recruitment, and functional inflammatory phenotype across multiple experiments\",\n      \"pmids\": [\"23525087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CEBPD regulates VEGF-C and VEGFR3 expression in lymphatic endothelial cells (LECs) to promote lymphangiogenesis; hypoxia induces CEBPD expression via HIF-1alpha, and CEBPD in turn regulates HIF-1alpha expression. Blocking HIF-1alpha activity abolishes CEBPD-induced VEGF-C and VEGFR3 expression in LECs.\",\n      \"method\": \"Genetic deletion in mice, forced expression/knockdown in LECs, in vitro tube formation, in vivo lymphangiogenesis assay, reporter assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mouse KO plus cell-based gain/loss-of-function with functional angiogenesis readout, single lab\",\n      \"pmids\": [\"21666710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CEBPD silencing in pancreatic beta-cells exacerbates cytokine-induced apoptosis by increasing CHOP expression and its downstream target BIM; CEBPD overexpression inhibits BIM expression and partially protects beta-cells. CEBPD also hampers IRF-1 upregulation and increases STAT1 activation, boosting production of CXCL1, 9, 10, and CCL20 chemokines when silenced.\",\n      \"method\": \"siRNA knockdown (single and double), overexpression, caspase assays, apoptosis quantification in rat INS-1E, primary rat beta-cells, and human islets\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown plus overexpression with mechanistic dissection across multiple cell types, single lab\",\n      \"pmids\": [\"22347430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CEBPD represses ΔNp63alpha expression in keratinocytes (identified as a primary p63 target by RNAi screening and ChIP); reciprocally, CEBPD binds to and activates the ΔNp63 promoter. CEBPD overexpression alters the normal p63 isoform profile and is found on p63 target gene promoters by ChIP, indicating direct co-regulation.\",\n      \"method\": \"RNAi screening, RT-PCR, ChIP, overexpression in HaCaT and primary keratinocytes\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and functional RNAi with isoform-level analysis, single lab\",\n      \"pmids\": [\"17903252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CEBPD reverses RB/E2F1-mediated repression of PPARG2 and GADD153 promoters; increased CEBPD attenuates E2F1-induced cancer cell proliferation. HMDB-induced CEBPD expression is activated through the p38/CREB pathway. ChIP assays demonstrate direct CEBPD binding at PPARG2 and GADD153 promoters.\",\n      \"method\": \"Methylation-specific PCR, reporter assay, ChIP, p38/CREB pathway inhibitors, xenograft mouse model\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus pathway inhibitors and reporter assays with in vivo xenograft validation, single lab\",\n      \"pmids\": [\"20971808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The EGFR/STAT3 signaling pathway drives cisplatin-induced CEBPD expression in bladder urothelial carcinoma cells; CEBPD in turn directly activates ABCB1 and ABCC2 drug transporter genes (shown by reporter and in vivo DNA-binding assays), conferring cross-resistance to paclitaxel. Loss-of-function of EGFR or STAT3 reduces CEBPD expression.\",\n      \"method\": \"Loss-of-function assays (siRNA/shRNA), reporter assays, in vivo DNA-binding (ChIP), xenograft animal assay, pharmacological inhibitors (gefitinib, S3I-201)\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, reporter assays, loss-of-function with in vivo xenograft, single lab\",\n      \"pmids\": [\"27435393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Metformin reduces Src-mediated CEBPD protein degradation and activates AMPK, leading to increased CEBPD expression in hepatocellular carcinoma cells; CEBPD then transcriptionally activates LC3B and ATG3 to induce autophagy and apoptosis.\",\n      \"method\": \"Reporter assay, ChIP, siRNA knockdown, AMPK inhibitor/activator, Western blot, apoptosis assays in Huh7 cells\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter and ChIP assays with pharmacological and genetic perturbations, single lab\",\n      \"pmids\": [\"28099155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DN-ATF5, a dominant-negative leucine zipper peptide, physically associates with CEBPD (and CEBPB) in cells, as revealed by unbiased pulldown assays coupled with mass spectrometry and immunoblotting; DN-ATF5 suppresses CEBPD transcriptional activity and CEBPD knockdown promotes apoptosis in cancer cells but not normal astrocytes.\",\n      \"method\": \"Pull-down assay with mass spectrometry, immunoblotting, knockdown (siRNA), transcriptional reporter assay\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — unbiased MS-based pulldown plus functional knockdown assays, single lab\",\n      \"pmids\": [\"31676720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Importin 4 (IPO4) augments nuclear translocation of CEBPD via nuclear localization signals (NLS), enabling CEBPD to transcriptionally upregulate PRKDC (DNA-PKcs), which mediates cisplatin-induced DNA damage repair. Knockdown of IPO4 or CEBPD reduces PRKDC expression and enhances cisplatin sensitivity in vitro and in vivo.\",\n      \"method\": \"shRNA knockdown, reporter assay, ChIP, xenograft assay, functional DNA repair assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assays and functional in vivo xenograft, mechanistically extending prior IPO4/CEBPD work, single lab\",\n      \"pmids\": [\"32661323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BRD4 bromodomain-1 (not bromodomain-2) controls CEBPD expression through a BRD4/CEBPD/promoter/enhancer complex in vascular smooth muscle cells; endogenous BRD4 co-immunoprecipitates with CEBPD, and both co-immunoprecipitate Cebpd promoter and enhancer DNA fragments. BRD4 and CEBPD cooperate to upregulate PDGFRα expression in SMC inflammation.\",\n      \"method\": \"ChIP-seq (H3K27ac/BRD4), genomic deletion, gene silencing (BRD4), Co-IP, loss- and gain-of-function experiments, JQ1 pharmacological inhibition\",\n      \"journal\": \"Molecular therapy. Methods & clinical development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq plus reciprocal Co-IP with JQ1 validation and functional gain/loss assays, single lab\",\n      \"pmids\": [\"33768129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Synthetic CEBPD leucine zipper decoy peptides (Dpep/Bpep) interfere with formation of active CEBPD homodimers and heterodimers, suppressing expression of CEBPD direct targets IL6, IL8, and asparagine synthetase (ASNS), depleting survivin, and elevating BMF to trigger cancer cell apoptosis without affecting non-transformed cells.\",\n      \"method\": \"Cell-penetrating peptide treatment, reporter assay for transcriptional activity, Western blot for target proteins, apoptosis assays, xenograft mouse models\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic validation via transcriptional target suppression and target protein changes, with in vivo xenograft, single lab\",\n      \"pmids\": [\"34065488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In glioblastoma under hypoxia, HIF1α and HIF2α activate the CEBPD promoter; CEBPD then activates the FN1 (fibronectin) promoter (shown by ChIP-seq and luciferase reporter assay), and FN1-integrin receptor interactions promote EGFR phosphorylation activating the EGFR/PI3K pathway, driving invasion.\",\n      \"method\": \"Proteomic analysis, ChIP-seq and ChIP-qPCR, luciferase reporter assay, CEBPD knockdown, Western blot, in vitro and in vivo invasion/growth assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq/qPCR plus luciferase reporter with functional in vitro and in vivo knockdown validation, single lab\",\n      \"pmids\": [\"37059730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CEBPD acts as a key transcription factor regulating the enhanced function of IL-21-engineered NK cells; CEBPD deletion results in loss of IL-21 NK cell anti-tumor potency, while CEBPD overexpression increases long-term cytotoxicity and metabolic fitness of NK cells.\",\n      \"method\": \"CRISPR-mediated CEBPD deletion, overexpression, chromatin accessibility (ATAC-seq), multiple in vivo GBM models, cytotoxicity assays\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic deletion and overexpression with functional in vivo models and chromatin accessibility data, single lab\",\n      \"pmids\": [\"39137729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CEBPD suppresses prolactin (PRL) promoter activity by 96% and inhibits cell proliferation in PRL-secreting pituitary tumor cells; CEBPD interacts with the transcription factor Pit1, and they attenuate each other's binding to the PRL promoter. CEBPD also suppresses c-Myc, survivin, and cyclins B1, B2, and D1.\",\n      \"method\": \"siRNA knockdown, forced expression, ChIP for PRL promoter binding, reporter assay, microarray expression profiling\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assay plus protein interaction data, with functional proliferation readout, single lab\",\n      \"pmids\": [\"21980073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Androgen receptor (AR) directly binds to the CEBPD promoter region upon androgen stimulation and activates CEBPD transcription in prostate cancer cells; SUZ12 and EZH2 attenuate androgen-induced CEBPD transcription. CEBPD in turn directly binds and activates the CASP8 (caspase 8) promoter.\",\n      \"method\": \"Reporter assay, ChIP (in vivo DNA-binding assay), overexpression/knockdown studies, functional apoptosis assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assays demonstrating AR→CEBPD→CASP8 transcriptional chain, single lab\",\n      \"pmids\": [\"24810056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In glioma, SUMOylation of PUM2 (by UBE2I/SUMO2/3) reduces PUM2's inhibitory effect on CEBPD mRNA, increasing CEBPD expression; CEBPD then binds the upstream promoter region of DSG2 and upregulates its expression to promote vasculogenic mimicry. Interactions were confirmed by Co-IP (PUM2 sumoylation), RIP assay (PUM2-CEBPD mRNA), and ChIP/luciferase (CEBPD-DSG2 promoter).\",\n      \"method\": \"Co-IP, immunofluorescence, RIP assay, ChIP assay, luciferase reporter assay, siRNA knockdown, 3D cell culture (vasculogenic mimicry assay)\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, RIP, ChIP, reporter), single lab\",\n      \"pmids\": [\"32997416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In cancer-associated fibroblasts, cisplatin and 5-fluorouracil induce CEBPD expression; CEBPD transcriptionally activates SDF4 (stromal-cell-derived factor 4), which interacts with CXCR4 to trigger VEGFD expression via ERK1/2 and p38 pathways in endothelial cells, promoting tumor angiogenesis.\",\n      \"method\": \"ChIP assay, reporter assay, Co-IP (SDF4-CXCR4 interaction), siRNA knockdown, in vitro tube formation, in vivo angiogenesis assay\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP/reporter for CEBPD→SDF4, Co-IP for SDF4-CXCR4, with functional in vivo validation, single lab\",\n      \"pmids\": [\"33953165\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CEBPD is a stimulus-inducible bZIP transcription factor that forms homodimers and heterodimers (with NF-IL6/C/EBPbeta and PU.1) to bind C/EBP DNA elements; its activity is regulated by transcriptional induction (via IL-6, IL-1, cAMP, p38 MAPK/CREB, EGFR/STAT3, and AR pathways), post-translational modification (SUMO1 at K120, which recruits HDAC1/3 to repress target genes; ubiquitin-dependent proteasomal degradation), and nuclear import (facilitated by IPO4); CEBPD drives acute-phase gene transcription (C3, haptoglobin, CRP), promotes G0 growth arrest and tumor suppression (via APC/C-Cdc27-mediated cyclin D1 degradation), exerts a transcription-independent role in DNA repair (by chaperoning FANCD2 nuclear import for monoubiquitination), and context-dependently regulates inflammation, lymphangiogenesis (through VEGF-C/VEGFR3), NK cell metabolic fitness, and drug resistance (via SOD1, ABCB1/ABCC2, and PRKDC transcriptional activation).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CEBPD (C/EBPδ, NF-IL6-β) is a stimulus-inducible bZIP transcription factor that translates inflammatory, metabolic, and stress signals into changes in target-gene transcription [#1, #2]. It functions through leucine-zipper-mediated dimerization, forming homodimers and heterodimers with C/EBPβ (NF-IL6) that bind C/EBP DNA elements and synergistically transactivate target promoters [#0]; it likewise pairs with PU.1 via its leucine zipper to co-occupy adjacent DNA sites [#4], and synthetic leucine-zipper decoy peptides that block CEBPD dimer formation suppress its transcriptional output [#28]. CEBPD is transcriptionally induced by IL-6 and IL-1 to drive acute-phase and inflammatory gene expression including complement C3, haptoglobin, and COX-2 [#1, #2, #8], with its induction gated by p38 MAPK signaling — which both controls CEBPD synthesis and docks on a CEBPD transactivation domain (residues ~70–108) to phosphorylate it [#8, #10] — and terminated by Miz1-directed HDAC1 recruitment to the CEBPD gene [#18]. Its own activity is further tuned by post-translational control: SUMO1 modification at lysine 120 converts CEBPD into a repressor that recruits HDAC1 and HDAC3 to silence target promoters such as PPARG2 [#11], while ubiquitin-dependent proteasomal turnover limits its abundance [#9]. CEBPD enforces G0 growth arrest and acts as a tumor suppressor by inducing the APC/C subunit CDC27 to drive cyclin D1 polyubiquitination and degradation [#7, #12]. Beyond transcription, CEBPD has a transcription-independent role in DNA repair, bridging FANCD2 to importin-4 (IPO4) to promote FANCD2 nuclear import required for its monoubiquitination [#13]. In cancer contexts CEBPD is context-dependent, conferring chemoresistance through transcriptional activation of SOD1, the drug transporters ABCB1/ABCC2, and PRKDC [#15, #23, #26], promoting hypoxia-driven invasion and angiogenesis via HIF/VEGF-C and FN1 axes [#19, #29], and shaping NK-cell anti-tumor function and metabolic fitness [#30].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Established the biochemical basis of CEBPD action by showing it is a bZIP factor that dimerizes and binds C/EBP DNA elements, defining how it engages the genome.\",\n      \"evidence\": \"In vitro heterodimerization, EMSA, and luciferase reporter assays with C/EBPβ\",\n      \"pmids\": [\"1741402\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define physiological stimuli or endogenous target genes\", \"Relative roles of homo- vs heterodimers in vivo unresolved\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Showed CEBPD is itself transcriptionally induced by inflammatory cytokines and directs acute-phase gene transcription, placing it downstream of IL-6/IL-1 signaling.\",\n      \"evidence\": \"Nuclear binding assays, EMSA/supershift, and reporter/mutagenesis at IL-6RE and complement C3 promoter in Hep3B cells\",\n      \"pmids\": [\"7680115\", \"8385337\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signal-transduction steps not yet mapped\", \"Did not address post-translational regulation of CEBPD\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Identified PU.1 as a direct CEBPD partner and mapped the interacting domains, extending the dimerization logic to cross-family transcriptional synergy.\",\n      \"evidence\": \"Far Western, deletion mutagenesis, EMSA, and reporter assays\",\n      \"pmids\": [\"7594592\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Target genes of the CEBPD/PU.1 pair not defined\", \"Cell-type specificity of the interaction unaddressed\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Defined a cell-cycle function by showing CEBPD induction is required to initiate G0 growth arrest, linking it to growth suppression.\",\n      \"evidence\": \"Antisense CEBPD with cell-cycle analysis in growth-arrested mammary epithelial cells\",\n      \"pmids\": [\"9045647\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular effectors of arrest not yet identified\", \"Antisense approach lacks single-gene specificity controls\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Distinguished CEBPD from C/EBPβ functionally by showing it is specifically required for the sustained phase of inflammatory COX-2 induction downstream of MAPK/p38.\",\n      \"evidence\": \"C/EBPβ knockout macrophages, MAPK/p38 inhibitors, and COX-2 induction assays\",\n      \"pmids\": [\"11668179\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct phosphorylation events not yet mapped\", \"Did not address transcriptional vs post-translational contributions\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Revealed that CEBPD abundance is constrained by ubiquitin-dependent nuclear degradation and short mRNA half-life, explaining its transient, immediate-early behavior.\",\n      \"evidence\": \"Pulse-chase, RACE-PAT, and proteasome inhibitor experiments in mammary epithelial cells\",\n      \"pmids\": [\"12554732\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase responsible not identified\", \"Degron sequences not mapped\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Mapped a bifunctional CEBPD domain that both transactivates and docks p38 MAPK, providing a structural basis for signal-dependent activation.\",\n      \"evidence\": \"Domain mutagenesis, p38 inhibitor, and reporter assays for haptoglobin induction\",\n      \"pmids\": [\"15694370\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphoacceptor residues not pinpointed\", \"Single-lab biochemistry without structural confirmation\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed SUMO1 modification at K120 acts as a molecular switch converting CEBPD from activator to HDAC-recruiting repressor, explaining bidirectional control of target genes.\",\n      \"evidence\": \"Sumoylation assays, K120 mutagenesis, Co-IP with HDAC1/3, and ChIP/reporter at PPARG2 in HepG2 cells\",\n      \"pmids\": [\"18619497\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMO ligase/desumoylase enzymes not identified\", \"Genome-wide scope of suCEBPD repression unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected CEBPD to the cell-cycle machinery mechanistically by showing it induces APC/C subunit CDC27 to drive cyclin D1 degradation, establishing a tumor-suppressive pathway.\",\n      \"evidence\": \"Knockout MEFs, siRNA, ChIP, reporter, and Western blot\",\n      \"pmids\": [\"20439707\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo tumor-suppressor role not tested here\", \"Crosstalk with GSK-3β pathway only partially defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Uncovered a transcription-independent role: CEBPD chaperones FANCD2 into the nucleus via IPO4, a prerequisite for FANCD2 monoubiquitination in DNA repair.\",\n      \"evidence\": \"Reciprocal Co-IP mapping separate domains, KO MEFs, siRNA, nuclear fractionation, and mitomycin C survival assays\",\n      \"pmids\": [\"20805509\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the FANCD2–CEBPD–IPO4 ternary complex unknown\", \"Whether this activity is regulated by the same signals as transcription unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated context-dependent pro-survival and pro-resistance activity by showing CEBPD transactivates SOD1 to reduce chemotherapy-induced ROS and apoptosis.\",\n      \"evidence\": \"Reporter, ChIP, ROS/apoptosis assays, and siRNA in bladder urothelial carcinoma cells\",\n      \"pmids\": [\"20385105\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation with tumor-suppressor role not addressed\", \"Single tumor-cell context\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended CEBPD into innate-immune and tissue functions through direct regulation of TLR8 and astrocytic PTX3.\",\n      \"evidence\": \"ChIP and reporter assays (TLR8); gene profiling, ChIP, siRNA, and phagocytosis assay (PTX3)\",\n      \"pmids\": [\"20829351\", \"21112127\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo immune phenotypes not established\", \"Stimulus-specific binding mechanism at TLR8 unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed CEBPD opposes RB/E2F1 repression of growth-arrest gene promoters and is itself induced via the p38/CREB pathway, reinforcing its anti-proliferative axis.\",\n      \"evidence\": \"ChIP, reporter assays, p38/CREB inhibitors, and xenograft model\",\n      \"pmids\": [\"20971808\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CEBPD–RB/E2F1 biochemical relationship not defined\", \"Single-lab data\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified Miz1/HDAC1 as the off-switch that terminates LPS-induced CEBPD transcription, defining how inflammatory CEBPD output is temporally bounded in vivo.\",\n      \"evidence\": \"Miz1 POZ-domain mutant mice, phosphorylation mapping, HDAC1 recruitment, and in vivo LPS challenge\",\n      \"pmids\": [\"23525087\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase phosphorylating Miz1 Ser178 not identified\", \"Generality beyond LPS inflammation untested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked CEBPD to hypoxia-driven lymphangiogenesis through a reciprocal HIF-1α loop controlling VEGF-C/VEGFR3.\",\n      \"evidence\": \"Mouse genetic deletion, LEC gain/loss-of-function, tube formation, and in vivo lymphangiogenesis assays\",\n      \"pmids\": [\"21666710\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of CEBPD regulation of HIF-1α not resolved\", \"Single-lab functional data\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed CEBPD can act as a tissue-specific repressor by interacting with Pit1 to suppress prolactin and downregulating proliferation drivers in pituitary tumor cells.\",\n      \"evidence\": \"siRNA, forced expression, ChIP, reporter, and microarray profiling\",\n      \"pmids\": [\"21980073\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CEBPD–Pit1 interaction interface not mapped\", \"In vivo tumor relevance untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined a cytoprotective role in pancreatic beta-cells where CEBPD restrains CHOP/BIM-mediated apoptosis and dampens chemokine output, refining its context-dependence.\",\n      \"evidence\": \"siRNA, overexpression, and caspase/apoptosis assays in rat and human islet cells\",\n      \"pmids\": [\"22347430\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CEBPD targets in this circuit not all identified\", \"Single-lab data\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established a chemoresistance pathway in which EGFR/STAT3 drive CEBPD to activate ABCB1/ABCC2 drug transporters, conferring cross-resistance.\",\n      \"evidence\": \"siRNA/shRNA, reporter, ChIP, xenograft, and pharmacological inhibitors in bladder carcinoma\",\n      \"pmids\": [\"27435393\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether STAT3 directly co-regulates the transporter promoters with CEBPD unclear\", \"Single tumor type\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed metformin stabilizes CEBPD (via reduced Src degradation and AMPK activation), which then induces autophagy genes LC3B and ATG3, linking CEBPD to autophagy-coupled apoptosis.\",\n      \"evidence\": \"Reporter, ChIP, siRNA, AMPK modulators, and apoptosis assays in hepatocellular carcinoma cells\",\n      \"pmids\": [\"28099155\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Src-mediated degradation mechanism not detailed\", \"Single-lab data\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Confirmed CEBPD as a druggable dimerization target by showing a dominant-negative leucine-zipper peptide binds CEBPD and suppresses its activity selectively in cancer cells.\",\n      \"evidence\": \"MS-based pulldown, immunoblotting, knockdown, and reporter assays\",\n      \"pmids\": [\"31676720\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous binding partners displaced by DN-ATF5 not fully mapped\", \"Selectivity mechanism for cancer cells unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended the IPO4–CEBPD axis to chemoresistance by showing IPO4-driven nuclear import of CEBPD enables transcriptional upregulation of PRKDC for cisplatin-induced DNA repair.\",\n      \"evidence\": \"shRNA, reporter, ChIP, DNA-repair assays, and xenograft\",\n      \"pmids\": [\"32661323\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NLS residues of CEBPD recognized by IPO4 not fully defined\", \"Single-lab data\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified BRD4 (bromodomain-1) as a chromatin reader required for CEBPD expression and a direct CEBPD co-factor in vascular smooth muscle inflammation.\",\n      \"evidence\": \"ChIP-seq, genomic deletion, BRD4 silencing, reciprocal Co-IP, and JQ1 inhibition\",\n      \"pmids\": [\"33768129\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of BRD4 bromodomain-1 specificity not resolved\", \"Single-lab data\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed multiple cancer/stromal circuits route through CEBPD: post-transcriptional control via PUM2 SUMOylation driving DSG2/vasculogenic mimicry, and CAF-derived SDF4 driving CXCR4/VEGFD angiogenesis, plus AR-driven CEBPD→CASP8 control of apoptosis.\",\n      \"evidence\": \"Co-IP, RIP, ChIP, reporter assays, and in vivo angiogenesis/vasculogenic mimicry models\",\n      \"pmids\": [\"32997416\", \"33953165\", \"24810056\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Integration of these parallel circuits in a single tumor unclear\", \"Each from a single lab/context\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Validated leucine-zipper decoy peptides (Dpep/Bpep) as CEBPD-disrupting agents that suppress direct targets (IL6, IL8, ASNS) and trigger cancer-selective apoptosis.\",\n      \"evidence\": \"Cell-penetrating peptides, reporter, Western blot, apoptosis assays, and xenografts\",\n      \"pmids\": [\"34065488\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Off-target effects on other bZIP factors not fully excluded\", \"Pharmacokinetics/in vivo delivery not optimized\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a hypoxia-to-invasion cascade where HIF1α/HIF2α induce CEBPD, which activates FN1 to drive EGFR/PI3K-dependent glioblastoma invasion.\",\n      \"evidence\": \"ChIP-seq/qPCR, luciferase reporter, knockdown, and in vitro/in vivo invasion assays\",\n      \"pmids\": [\"37059730\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of HIF1α vs HIF2α not resolved\", \"Single tumor model\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established CEBPD as a master regulator of engineered NK-cell anti-tumor function and metabolic fitness, expanding its role into immune-effector programming.\",\n      \"evidence\": \"CRISPR deletion, overexpression, ATAC-seq, and in vivo GBM models with cytotoxicity assays\",\n      \"pmids\": [\"39137729\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CEBPD target genes underpinning NK metabolic fitness not enumerated\", \"Single-lab data\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CEBPD's opposing roles — tumor-suppressive G0 arrest versus pro-survival chemoresistance, invasion, and angiogenesis — are selected within a given cell state remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model integrating SUMO/phosphorylation/degradation switches with context-specific output\", \"Structural basis of dimer-partner choice and its functional consequences undefined\", \"In vivo dose-dependence of CEBPD tumor-suppressor vs oncogenic behavior unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 2, 12]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 2, 11]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 2, 9, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 11, 12]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 8, 16]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [7, 12]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [13, 26]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [15, 23, 29]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CEBPB\", \"PU.1\", \"HDAC1\", \"HDAC3\", \"FANCD2\", \"IPO4\", \"BRD4\", \"Pit1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}