{"gene":"CREBZF","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2020,"finding":"CREBZF associates with the linker domain of STAT3 and represses STAT3 dimerization and transcriptional activity, thereby inhibiting cyclin gene expression and liver regeneration after partial hepatectomy and CCl4-induced injury. Hepatocyte-specific CREBZF knockout hyperactivates STAT3-driven cyclin D1 and regeneration, which is reversed by the STAT3 inhibitor cucurbitacin I.","method":"Liver-specific knockout mice, co-immunoprecipitation, adeno-associated virus overexpression, flow cytometry cell cycle analysis, STAT3 inhibitor rescue experiment","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genetic KO with defined cellular phenotype, pharmacological rescue, and AAV overexpression in two independent liver injury models in a single rigorous study","pmids":["31469186"],"is_preprint":false},{"year":2018,"finding":"CREBZF couples insulin-Akt signaling to hepatic lipogenesis by directly inhibiting transcription of Insig-2a through association with ATF4, thereby allowing SREBP-1c processing and de novo fatty acid synthesis. Liver-specific CREBZF knockout induces Insig-2a and Insig-1 and represses the lipogenic program during refeeding and in streptozotocin/insulin-treated mice.","method":"Liver-specific knockout mice, refeeding and insulin treatment models, co-immunoprecipitation with ATF4, reporter/promoter assays, western blot for Insig isoforms and lipogenic enzymes","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined metabolic phenotype, direct binding partner (ATF4) identified by Co-IP, mechanistic promoter assays, replicated across multiple in vivo models in one study","pmids":["29637572"],"is_preprint":false},{"year":2023,"finding":"CREBZF promotes osteopontin production and secretion in hepatocytes by inhibiting miR-6964-3p, which in turn activates hepatic stellate cells (HSCs) and drives liver fibrosis in diet-induced NASH. AAV-mediated osteopontin rescue in CREBZF-deficient mice restores HSC activation and NASH progression, establishing a hepatocyte-autonomous CREBZF→osteopontin→HSC axis.","method":"Diet-induced NASH mouse models, CREBZF liver-specific knockout, AAV-mediated osteopontin rescue, miRNA manipulation, HSC activation assays","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined fibrosis phenotype, miRNA mechanism identified, AAV rescue experiment confirming pathway, multiple orthogonal methods in one study","pmids":["36680394"],"is_preprint":false},{"year":2024,"finding":"Glucose induces CREBZF in white adipose tissue, where it associates with PGC-1α to repress thermogenic gene expression (including UCP1). Lys208 acetylation by CBP/p300 and deacetylation by HDAC3 regulates CREBZF protein stability by controlling proteasomal degradation. Adipose-specific CREBZF knockout mice show enhanced browning, thermogenic gene expression, and adaptive thermogenesis during cold exposure.","method":"Adipose-specific CREBZF knockout mice, acetylation site mutagenesis (Lys208), CBP/p300 and HDAC3 co-immunoprecipitation, cold exposure assays, rectal temperature measurement, chromatin/co-factor pulldown with PGC-1α","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — acetylation writer/eraser identified with mutagenesis, binding partner (PGC-1α) confirmed by Co-IP, adipose-specific KO with defined thermogenic phenotype, multiple orthogonal methods","pmids":["38588421"],"is_preprint":false},{"year":2013,"finding":"CREBZF/Zhangfei interacts with Xbp1s via its leucine zipper domain, leading to proteasomal degradation of Xbp1s. This suppresses Xbp1s-driven transcription from UPR elements and reduces UPR gene expression. siRNA knockdown of endogenous Zhangfei in thapsigargin-treated primary rat sensory neurons significantly increases UPR transcripts and proteins.","method":"Co-immunoprecipitation, leucine zipper deletion mutants, UPR reporter assays, siRNA knockdown in primary neurons, western blot and RT-PCR for UPR markers","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct protein interaction mapped to leucine zipper, proteasomal degradation mechanism confirmed, endogenous knockdown phenotype in primary neurons, multiple orthogonal methods","pmids":["24155933"],"is_preprint":false},{"year":2012,"finding":"CREBZF is a novel positive regulator of p53: it interacts in vitro with both HEY1 and p53, stabilizes p53 protein, activates p53 transcriptional activity, and cooperates synergistically with HEY1 to enhance p53-dependent transcription. CREBZF induces post-translational modifications on p53 that prevent its degradation. Partial knockdown of endogenous CREBZF diminishes p53 protein levels and inhibits HEY1-mediated p53 activation.","method":"Yeast two-hybrid screen (HEY1 as bait), in vitro binding assays, co-immunoprecipitation, p53 reporter assays, siRNA knockdown, post-translational modification analysis","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid identification with in vitro binding and reporter validation, siRNA knockdown phenotype, single lab with multiple methods","pmids":["22983008"],"is_preprint":false},{"year":2013,"finding":"The effects of Zhangfei/CREBZF on cell growth suppression and UPR inhibition require the tumor suppressor p53 as an intermediary. The bLZip domain of Zhangfei is required for interaction with p53. Zhangfei stabilizes p53 and co-localizes with it in cellular nuclei, and displaces the E3 ubiquitin ligase Mdm2 from its association with p53. siRNA suppression of p53 partially inhibits Zhangfei's effects. Zhangfei has no effect on p53-null MG63 cells but mirrors its D-17 effects in p53-expressing U2OS cells.","method":"Co-immunoprecipitation, nuclear co-localization by imaging, Mdm2 displacement assay, siRNA knockdown of p53, bLZip domain deletion mutants, p53-null cell line comparison","journal":"Cell cycle","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, domain mutagenesis, siRNA epistasis, isogenic p53-null vs p53-expressing cell line comparison, multiple orthogonal methods in one study","pmids":["24200963"],"is_preprint":false},{"year":2012,"finding":"CREBZF interacts with Smads 1, 5, and 8 (BMP-pathway R-Smads), identified through yeast two-hybrid screening using the MH2 domain of Smad8 as bait, confirmed by co-immunoprecipitation in a human prostate cancer cell line. Overexpression of CREBZF inhibits BMP response element promoter activity and abolishes BMP-6-induced cell growth inhibition.","method":"Yeast two-hybrid screen (Smad8 MH2 domain as bait), co-immunoprecipitation in human prostate cancer cells, BMP-response element reporter assay, BMP-6 cell growth inhibition assay","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP, functional reporter and growth assay, single lab with two orthogonal binding methods","pmids":["22707059"],"is_preprint":false},{"year":2019,"finding":"CREBZF promotes hCG-induced testosterone production in mouse Leydig cells by upregulating the orphan nuclear receptors Nr4a1 and Nr5a1, which subsequently drive expression of steroidogenic genes (3β-HSD, 17β-HSD, P450c17). CREBZF silencing in primary Leydig cells and MLTC-1 cells significantly inhibits hCG-stimulated testosterone production and reduces serum testosterone after lentiviral shRNA microinjection into mouse testis.","method":"Lentiviral shRNA knockdown, primary Leydig cell culture, MLTC-1 cell overexpression/knockdown, intratesticular microinjection, testosterone radioimmunoassay, RT-PCR for steroidogenic genes and nuclear receptors","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in vitro and in vivo with defined steroidogenic phenotype, pathway placement via Nr4a1/Nr5a1, single lab","pmids":["31124138"],"is_preprint":false},{"year":2018,"finding":"CREBZF overexpression induces apoptosis in mouse ovarian granulosa cells by upregulating BAX and cleaved Caspase-3, downregulating BCL-2, and inhibiting ERK1/2 and mTOR signaling pathways (reduced phosphorylation of ERK1/2 and S6K1). CREBZF also activates autophagy (increased LC3-II).","method":"CREBZF overexpression and knockdown, flow cytometry for apoptosis, western blot for apoptosis markers and pathway phosphoproteins, LC3-II autophagy marker","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — overexpression and knockdown with defined apoptotic and signaling phenotypes, pathway placement by phospho-western blots, single lab","pmids":["30413092"],"is_preprint":false},{"year":2012,"finding":"Zhangfei/CREBZF induces cell death in ONS-76 medulloblastoma cells through a mechanism involving enhanced transcription from the Brn3a promoter, subsequent TrkA upregulation, and autocrine NGF-TrkA signaling that activates the MAPK pathway, leading to differentiation and cell death. Antibodies against NGF and inhibitors of TrkA and MAPK components partially restore growth of Zhangfei-expressing cells.","method":"Adenoviral Zhangfei expression, Brn3a promoter reporter assay, NGF antibody neutralization, TrkA and MAPK inhibitors, transcript profiling, phosphorylation-based kinase activity analysis","journal":"Journal of neuro-oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter reporter assay establishes Brn3a as direct target, pharmacological rescue with antibody and inhibitors places pathway, single lab with multiple orthogonal methods","pmids":["22798206"],"is_preprint":false},{"year":2009,"finding":"CREBZF/Zhangfei expression is induced by amino acid deprivation in MDCK cells. A 9-bp AARE-like element (5'-ATTCACTCA-3') at position -1227 to -1219 in the CREBZF promoter is required for amino acid deprivation-inducible transcription, identified by deletion mapping and site-directed mutagenesis.","method":"Amino acid deprivation in MDCK cells, CREBZF promoter cloning, deletion mapping and site-directed mutagenesis, promoter-reporter assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — promoter mutagenesis identifies specific regulatory element, but single lab, single study without independent replication","pmids":["20026304"],"is_preprint":false},{"year":2013,"finding":"CREBZF (SMILE isoform) is expressed in mouse uterine luminal and glandular epithelium, is regulated by estrogen (oestrogen stimulates SMILE expression in ovariectomized mice), and its expression peaks on day 4 of pregnancy at implantation sites but is absent from decidual cells. The presence of an active blastocyst is required for SMILE expression at the implantation site.","method":"Immunohistochemistry, western blot, RT-PCR across pregnancy stages, ovariectomy/hormone treatment, pseudopregnancy model, delayed implantation model","journal":"Reproductive biology and endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by IHC with functional context (implantation), hormone regulation established by ovariectomy/rescue experiment, single lab with multiple methods","pmids":["24325733"],"is_preprint":false},{"year":2023,"finding":"miR-425-5p suppresses Crebzf expression in aging oocytes. Inhibition of miR-425-5p improves old oocyte development by restoring Crebzf levels. Crebzf regulates mRNAs targeting H3K4me3 histone methyltransferases, acting as a mediator of transcriptional regulation in GV oocytes. Overexpression of miR-425-5p hinders oocyte maturation by downregulating Crebzf and disrupting transcriptional regulation.","method":"High-throughput miRNA sequencing, microinjection of miR-425-5p inhibitors, in vivo antagomir treatment, single-cell RNA sequencing, Crebzf overexpression/knockdown in oocytes","journal":"GeroScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo antagomir treatment with oocyte development phenotype, single-cell RNA-seq for pathway targets, miR-425-5p→Crebzf axis experimentally validated, single lab","pmids":["37532927"],"is_preprint":false},{"year":2023,"finding":"CREBZF suppresses STAT3 dimerization and ADAR1 expression, which promotes circPAPD4 biogenesis (since ADAR1 suppresses circPAPD4 formation). CircPAPD4 competitively binds miR-1269a to de-repress CREBZF expression, forming a positive feedback loop (circPAPD4/miR-1269a/CREBZF/STAT3/ADAR1) that curbs breast cancer progression.","method":"RNA pull-down, dual-luciferase reporter assays, co-immunoprecipitation, RT-qPCR, in vivo tumor models with CREBZF mRNA nanoparticles, ADAR1 knockdown/overexpression","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for STAT3 dimerization, RNA pulldown for miR-1269a sponging, in vivo nanoparticle delivery confirms pathway, single lab with multiple orthogonal methods","pmids":["37264406"],"is_preprint":false},{"year":2024,"finding":"Conditional knockout of CREBZF in androgen-synthesis cells (Cyp17a1-Cre) in mice does not affect fertility or serum testosterone, but impairs testosterone secretion in isolated primary Leydig cells and decreases Star, Cyp17a1, and Hsd3b1 mRNA. CREBZF deficiency results in adrenal cortex thickening, elevated serum corticosterone and DHEA, increased StAR/Cyp11a1/17β-Hsd3 in adrenal cortex, and anxiety-like behavior and memory impairment.","method":"Cyp17a1-Cre conditional knockout, primary Leydig cell isolation, testosterone ELISA, RT-PCR for steroidogenic genes, immunohistochemistry for adrenal cortex markers, elevated plus maze and Barnes maze behavioral tests","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined steroidogenic and behavioral phenotypes, multiple endpoints measured, single lab","pmids":["38696238"],"is_preprint":false},{"year":2015,"finding":"Zhangfei/CREBZF suppresses cell growth and UPR-related transcripts in multiple independent canine osteosarcoma cell lines (Abrams, McKinley, Gracie, D-17) that express functional p53. Zhangfei also induces osteocalcin expression (a marker of osteoblast differentiation) and triggers programmed cell death in these lines. Effects depend on p53 functionality.","method":"Adenoviral Zhangfei expression in four independent OS cell lines, RT-PCR for UPR transcripts and osteocalcin, cell growth assays, apoptosis markers","journal":"BMC veterinary research","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — replicated across four independent cell lines, but OE-based with limited mechanistic depth; replication across lines elevates confidence","pmids":["25890299"],"is_preprint":false}],"current_model":"CREBZF (Zhangfei/SMILE) is a bZIP transcription factor that functions as a broad transcriptional co-repressor: it directly binds and inhibits STAT3 dimerization (suppressing liver regeneration), interacts with ATF4 to repress Insig-2a transcription (coupling insulin signaling to hepatic lipogenesis), promotes liver fibrosis via osteopontin secretion from hepatocytes, suppresses thermogenesis by associating with PGC-1α in adipose tissue (regulated by CBP/p300-HDAC3-mediated reversible Lys208 acetylation), stabilizes p53 by displacing Mdm2 and inducing protective post-translational modifications, interacts with BMP-pathway Smads 1/5/8 to inhibit BMP signaling, suppresses the UPR by binding Xbp1s via its leucine zipper and promoting its proteasomal degradation, and regulates steroidogenesis in Leydig cells through Nr4a1/Nr5a1 upregulation; its own transcription is induced by amino acid deprivation through an AARE-like promoter element and by estrogen in uterine epithelium."},"narrative":{"mechanistic_narrative":"CREBZF (Zhangfei/SMILE) is a bZIP transcriptional co-regulator that broadly restrains stress-, growth-, and metabolism-associated transcription factors through direct protein-protein contacts rather than autonomous DNA binding [PMID:31469186, PMID:29637572]. In liver, it constrains regeneration by binding the linker domain of STAT3 to block its dimerization and downstream cyclin expression [PMID:31469186], and it couples insulin signaling to lipogenesis by associating with ATF4 to repress Insig-2a, thereby licensing SREBP-1c-driven fatty acid synthesis [PMID:29637572]; it further drives diet-induced fibrosis through a hepatocyte-autonomous axis in which it suppresses miR-6964-3p to elevate osteopontin secretion and activate hepatic stellate cells [PMID:36680394]. In adipose tissue CREBZF associates with PGC-1α to repress thermogenic genes including UCP1, and its abundance is set by reversible Lys208 acetylation written by CBP/p300 and erased by HDAC3 that gates proteasomal turnover [PMID:38588421]. It governs proteostasis by binding the UPR effector Xbp1s via its leucine zipper and targeting it for proteasomal degradation [PMID:24155933], and it stabilizes p53 by displacing Mdm2 and acting through its bZIP/bLZip domain, cooperating with HEY1 to potentiate p53-dependent transcription and p53-dependent growth suppression [PMID:22983008, PMID:24200963]. CREBZF additionally inhibits BMP signaling through interaction with R-Smads 1/5/8 [PMID:22707059] and supports steroidogenesis by upregulating the nuclear receptors Nr4a1 and Nr5a1 in Leydig cells [PMID:31124138]. Its own expression is induced by amino acid deprivation via an AARE-like promoter element [PMID:20026304].","teleology":[{"year":2009,"claim":"Established how CREBZF transcription itself is controlled, placing it within the amino acid stress response.","evidence":"Promoter deletion mapping and site-directed mutagenesis of an AARE-like element under amino acid deprivation in MDCK cells","pmids":["20026304"],"confidence":"Medium","gaps":["Transcription factor binding the AARE-like element not identified","Single study without independent replication"]},{"year":2012,"claim":"Identified CREBZF as a positive regulator of p53 and a partner of HEY1, framing it as a stabilizer rather than activator-by-DNA-binding.","evidence":"Yeast two-hybrid (HEY1 bait), in vitro binding, Co-IP, p53 reporter assays and siRNA knockdown","pmids":["22983008"],"confidence":"Medium","gaps":["Identity of the protective post-translational modifications on p53 not defined","Largely in vitro/overexpression context"]},{"year":2012,"claim":"Defined CREBZF as a BMP-pathway repressor through direct R-Smad binding, broadening its co-repressor scope.","evidence":"Yeast two-hybrid (Smad8 MH2 bait), Co-IP in prostate cancer cells, BMP-response element reporter and BMP-6 growth assay","pmids":["22707059"],"confidence":"Medium","gaps":["Mechanism of Smad inhibition not resolved","In vivo relevance untested"]},{"year":2013,"claim":"Resolved the p53 stabilization mechanism as Mdm2 displacement requiring the bLZip domain, and showed p53 is the obligate intermediary for growth and UPR effects.","evidence":"Co-IP, nuclear co-localization imaging, Mdm2 displacement assay, bLZip deletion mutants and isogenic p53-null vs p53-expressing cell comparison","pmids":["24200963"],"confidence":"High","gaps":["Does not define which post-translational modifications block degradation","p53-independent CREBZF functions not addressed"]},{"year":2013,"claim":"Showed CREBZF restrains the UPR directly by degrading Xbp1s, defining a leucine-zipper-dependent proteostasis brake distinct from the p53 axis.","evidence":"Co-IP, leucine zipper deletion mutants, UPR reporter assays and siRNA knockdown in primary rat sensory neurons","pmids":["24155933"],"confidence":"High","gaps":["E3 ligase mediating Xbp1s degradation not identified","Relationship to the p53-dependent UPR effects unresolved"]},{"year":2013,"claim":"Linked CREBZF to estrogen-regulated uterine biology and blastocyst-dependent expression at implantation.","evidence":"IHC, western blot, RT-PCR across pregnancy stages, ovariectomy/hormone rescue and delayed implantation models in mice","pmids":["24325733"],"confidence":"Medium","gaps":["Functional role in implantation not tested by loss-of-function","Downstream targets in uterine epithelium unknown"]},{"year":2015,"claim":"Confirmed p53-dependent growth suppression, UPR repression and differentiation across multiple independent cell lines, strengthening the p53-coupled tumor-suppressive model.","evidence":"Adenoviral Zhangfei expression in four canine osteosarcoma lines, RT-PCR, growth and apoptosis assays","pmids":["25890299"],"confidence":"Medium","gaps":["Overexpression-based with limited mechanistic depth","Differentiation pathway to osteocalcin induction not mapped"]},{"year":2018,"claim":"Defined the in vivo metabolic role of CREBZF as coupling insulin-Akt signaling to hepatic lipogenesis via ATF4-dependent Insig-2a repression.","evidence":"Liver-specific knockout mice, refeeding/insulin models, ATF4 Co-IP, promoter/reporter assays","pmids":["29637572"],"confidence":"High","gaps":["How insulin signaling regulates CREBZF activity not defined","Direct DNA contact at Insig-2a vs ATF4-mediated recruitment not distinguished"]},{"year":2018,"claim":"Showed CREBZF can promote apoptosis and autophagy and modulate ERK/mTOR signaling in granulosa cells, extending its pro-death activity to the ovary.","evidence":"Overexpression/knockdown, flow cytometry, phospho-western blots and LC3-II in mouse ovarian granulosa cells","pmids":["30413092"],"confidence":"Medium","gaps":["Mechanism connecting CREBZF to ERK/mTOR not defined","Single lab, overexpression-weighted"]},{"year":2019,"claim":"Placed CREBZF as a positive driver of Leydig cell steroidogenesis acting through Nr4a1/Nr5a1.","evidence":"Lentiviral shRNA, primary Leydig and MLTC-1 cells, intratesticular microinjection, testosterone radioimmunoassay, RT-PCR","pmids":["31124138"],"confidence":"Medium","gaps":["Direct vs indirect control of Nr4a1/Nr5a1 unresolved","In vivo fertility consequence not tested here"]},{"year":2020,"claim":"Established CREBZF as a brake on liver regeneration by directly inhibiting STAT3 dimerization, with a pharmacological rescue confirming the axis.","evidence":"Liver-specific KO mice, reciprocal Co-IP, AAV overexpression, cell-cycle flow cytometry and STAT3 inhibitor rescue in two injury models","pmids":["31469186"],"confidence":"High","gaps":["Structural basis of linker-domain binding not solved","Signals controlling CREBZF during regeneration unknown"]},{"year":2023,"claim":"Defined a hepatocyte-autonomous CREBZF→osteopontin→stellate cell axis driving NASH fibrosis through miR-6964-3p suppression.","evidence":"Diet-induced NASH models, liver-specific KO, AAV osteopontin rescue, miRNA manipulation and HSC activation assays","pmids":["36680394"],"confidence":"High","gaps":["How CREBZF represses miR-6964-3p not defined","Relationship to its lipogenic role in the same tissue unintegrated"]},{"year":2023,"claim":"Embedded the CREBZF-STAT3 axis in a circPAPD4/miR-1269a/ADAR1 feedback loop constraining breast cancer progression.","evidence":"RNA pull-down, dual-luciferase reporters, Co-IP, in vivo CREBZF mRNA nanoparticle delivery and ADAR1 manipulation","pmids":["37264406"],"confidence":"Medium","gaps":["Directness of CREBZF effect on ADAR1 expression unclear","Single lab"]},{"year":2023,"claim":"Linked CREBZF to oocyte transcriptional competence and aging via a miR-425-5p axis affecting H3K4me3 methyltransferase regulation.","evidence":"miRNA-seq, microinjection of miR-425-5p inhibitors, in vivo antagomir, single-cell RNA-seq and Crebzf manipulation in oocytes","pmids":["37532927"],"confidence":"Medium","gaps":["Direct targets through which CREBZF controls H3K4me3 enzymes not defined","Single lab"]},{"year":2024,"claim":"Identified glucose-induced CREBZF as a thermogenic suppressor acting through PGC-1α, with Lys208 acetylation as the stability switch governing its abundance.","evidence":"Adipose-specific KO mice, Lys208 mutagenesis, CBP/p300 and HDAC3 Co-IP, cold exposure and PGC-1α co-factor pulldown","pmids":["38588421"],"confidence":"High","gaps":["Whether acetylation control generalizes to other CREBZF functions untested","Direct PGC-1α binding interface not mapped"]},{"year":2024,"claim":"Refined the steroidogenic role using cell-type-specific knockout, revealing intrinsic Leydig defects and adrenal/behavioral consequences despite preserved fertility.","evidence":"Cyp17a1-Cre conditional KO, primary Leydig cell testosterone ELISA, RT-PCR, adrenal IHC and behavioral testing","pmids":["38696238"],"confidence":"Medium","gaps":["Mechanism linking CREBZF loss to adrenal cortex thickening unknown","Cause of anxiety/memory phenotype not resolved"]},{"year":null,"claim":"It remains unresolved how a single bZIP co-regulator selects among its many partners (STAT3, ATF4, Xbp1s, p53, R-Smads, PGC-1α) in a tissue- and signal-specific manner, and what structural determinants and post-translational switches dictate each interaction.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of any CREBZF-partner interface","Logic of partner selection across tissues undefined","Whether CREBZF binds DNA directly at any target remains unestablished"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,3,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,4,5,6]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,7,14]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,3]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[4,11]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4,6]}],"complexes":[],"partners":["STAT3","ATF4","XBP1","TP53","MDM2","HEY1","PPARGC1A","SMAD8"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NS37","full_name":"CREB/ATF bZIP transcription factor","aliases":["Host cell factor-binding transcription factor Zhangfei","HCF-binding transcription factor Zhangfei"],"length_aa":354,"mass_kda":37.1,"function":"Strongly activates transcription when bound to HCFC1. Suppresses the expression of HSV proteins in cells infected with the virus in a HCFC1-dependent manner. Also suppresses the HCFC1-dependent transcriptional activation by CREB3 and reduces the amount of CREB3 in the cell. Able to down-regulate expression of some cellular genes in CREBZF-expressing cells","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9NS37/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CREBZF","classification":"Not Classified","n_dependent_lines":10,"n_total_lines":1208,"dependency_fraction":0.008278145695364239},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CREBZF","total_profiled":1310},"omim":[{"mim_id":"606444","title":"CREB/ATF BASIC LEUCINE ZIPPER TRANSCRIPTION FACTOR; CREBZF","url":"https://www.omim.org/entry/606444"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Mitochondria","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CREBZF"},"hgnc":{"alias_symbol":["ZF","SMILE"],"prev_symbol":[]},"alphafold":{"accession":"Q9NS37","domains":[{"cath_id":"3.90.20","chopping":"211-294_324-354","consensus_level":"medium","plddt":85.5163,"start":211,"end":354}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NS37","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NS37-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NS37-F1-predicted_aligned_error_v6.png","plddt_mean":61.47},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CREBZF","jax_strain_url":"https://www.jax.org/strain/search?query=CREBZF"},"sequence":{"accession":"Q9NS37","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NS37.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NS37/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NS37"}},"corpus_meta":[{"pmid":"1811936","id":"PMC_1811936","title":"Expression of the zebrafish paired box gene pax[zf-b] during early neurogenesis.","date":"1991","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/1811936","citation_count":419,"is_preprint":false},{"pmid":"16996269","id":"PMC_16996269","title":"POZ for effect--POZ-ZF transcription factors in cancer and development.","date":"2006","source":"Trends in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16996269","citation_count":216,"is_preprint":false},{"pmid":"1718739","id":"PMC_1718739","title":"Zebrafish pax[zf-a]: a paired box-containing gene expressed in the neural tube.","date":"1991","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/1718739","citation_count":201,"is_preprint":false},{"pmid":"23697932","id":"PMC_23697932","title":"ZF-CxxC domain-containing proteins, CpG islands and the chromatin connection.","date":"2013","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/23697932","citation_count":180,"is_preprint":false},{"pmid":"22894929","id":"PMC_22894929","title":"The BTB-ZF transcription factors.","date":"2012","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/22894929","citation_count":108,"is_preprint":false},{"pmid":"24711583","id":"PMC_24711583","title":"The BTB-ZF transcription factor Zbtb20 is driven by Irf4 to promote plasma cell differentiation and longevity.","date":"2014","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24711583","citation_count":90,"is_preprint":false},{"pmid":"23086144","id":"PMC_23086144","title":"BTB-ZF factors recruit the E3 ligase cullin 3 to regulate lymphoid effector programs.","date":"2012","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/23086144","citation_count":88,"is_preprint":false},{"pmid":"21900183","id":"PMC_21900183","title":"The BTB-ZF family of transcription factors: key regulators of lineage commitment and effector function development in the immune system.","date":"2011","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/21900183","citation_count":79,"is_preprint":false},{"pmid":"25605927","id":"PMC_25605927","title":"BTB-ZF transcriptional regulator PLZF modifies chromatin to restrain inflammatory signaling programs.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25605927","citation_count":61,"is_preprint":false},{"pmid":"28028224","id":"PMC_28028224","title":"APE2 Zf-GRF facilitates 3'-5' resection of DNA damage following oxidative stress.","date":"2016","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28028224","citation_count":54,"is_preprint":false},{"pmid":"31469186","id":"PMC_31469186","title":"CREBZF as a Key Regulator of STAT3 Pathway in the Control of Liver Regeneration in Mice.","date":"2020","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/31469186","citation_count":47,"is_preprint":false},{"pmid":"12021275","id":"PMC_12021275","title":"Aph2, a protein with a zf-DHHC motif, interacts with c-Abl and has pro-apoptotic activity.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12021275","citation_count":47,"is_preprint":false},{"pmid":"26546019","id":"PMC_26546019","title":"Genome-wide analysis and expression patterns of ZF-HD transcription factors under different developmental tissues and abiotic stresses in Chinese cabbage.","date":"2015","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/26546019","citation_count":46,"is_preprint":false},{"pmid":"29637572","id":"PMC_29637572","title":"Hepatic CREBZF couples insulin to lipogenesis by inhibiting insig activity and contributes to hepatic steatosis in diet-induced insulin-resistant mice.","date":"2018","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/29637572","citation_count":45,"is_preprint":false},{"pmid":"10075714","id":"PMC_10075714","title":"RIN ZF, a novel zinc finger gene, encodes proteins that bind to the CACC element of the gastrin promoter.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10075714","citation_count":42,"is_preprint":false},{"pmid":"24186071","id":"PMC_24186071","title":"CpG island chromatin is shaped by recruitment of ZF-CxxC proteins.","date":"2013","source":"Cold Spring Harbor perspectives in biology","url":"https://pubmed.ncbi.nlm.nih.gov/24186071","citation_count":35,"is_preprint":false},{"pmid":"7875601","id":"PMC_7875601","title":"The zebrafish Zf-Sox 19 protein: a novel member of the Sox family which reveals highly conserved motifs outside of the DNA-binding domain.","date":"1995","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/7875601","citation_count":33,"is_preprint":false},{"pmid":"31185913","id":"PMC_31185913","title":"Genome-wide investigation of the ZF-HD gene family in Tartary buckwheat (Fagopyrum tataricum).","date":"2019","source":"BMC plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/31185913","citation_count":32,"is_preprint":false},{"pmid":"22983008","id":"PMC_22983008","title":"The transcription factor CREBZF is a novel positive regulator of p53.","date":"2012","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/22983008","citation_count":31,"is_preprint":false},{"pmid":"24638067","id":"PMC_24638067","title":"BTB-ZF transcription factors, a growing family of regulators of early and late B-cell development.","date":"2014","source":"Immunology and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/24638067","citation_count":31,"is_preprint":false},{"pmid":"20658568","id":"PMC_20658568","title":"Interaction identification of Zif268 and TATA(ZF) proteins with GC-/AT-rich DNA sequence: A theoretical study.","date":"2011","source":"Journal of computational chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20658568","citation_count":30,"is_preprint":false},{"pmid":"2902580","id":"PMC_2902580","title":"Primary structure, developmentally regulated expression and potential duplication of the zebrafish homeobox gene ZF-21.","date":"1988","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/2902580","citation_count":30,"is_preprint":false},{"pmid":"30419310","id":"PMC_30419310","title":"Dancing from bottoms up - Roles of the POZ-ZF transcription factor Kaiso in Cancer.","date":"2018","source":"Biochimica et biophysica acta. Reviews on cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30419310","citation_count":29,"is_preprint":false},{"pmid":"29990732","id":"PMC_29990732","title":"Toxicity induced by glyphosate and glyphosate-based herbicides in the zebrafish hepatocyte cell line (ZF-L).","date":"2018","source":"Ecotoxicology and environmental safety","url":"https://pubmed.ncbi.nlm.nih.gov/29990732","citation_count":27,"is_preprint":false},{"pmid":"27401554","id":"PMC_27401554","title":"The C2H2-ZF transcription factor Zfp335 recognizes two consensus motifs using separate zinc finger arrays.","date":"2016","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/27401554","citation_count":24,"is_preprint":false},{"pmid":"31442592","id":"PMC_31442592","title":"Environmental chemicals differentially affect epigenetic-related mechanisms in the zebrafish liver (ZF-L) cell line and in zebrafish embryos.","date":"2019","source":"Aquatic toxicology (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/31442592","citation_count":23,"is_preprint":false},{"pmid":"33554320","id":"PMC_33554320","title":"Identification and Transcriptional Analysis of Zinc Finger-Homeodomain (ZF-HD) Family Genes in Cucumber.","date":"2021","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33554320","citation_count":21,"is_preprint":false},{"pmid":"21124861","id":"PMC_21124861","title":"A novel zf-MYND protein, CHB-3, mediates guanylyl cyclase localization to sensory cilia and controls body size of Caenorhabditis elegans.","date":"2010","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21124861","citation_count":21,"is_preprint":false},{"pmid":"18206344","id":"PMC_18206344","title":"The use of primary hepatocytes from brown trout (Salmo trutta lacustris) and the fish cell lines RTH-149 and ZF-L for in vitro screening of (anti)estrogenic activity of wood extractives.","date":"2007","source":"Toxicology in vitro : an international journal published in association with BIBRA","url":"https://pubmed.ncbi.nlm.nih.gov/18206344","citation_count":21,"is_preprint":false},{"pmid":"25953800","id":"PMC_25953800","title":"Identification of C2H2-ZF binding preferences from ChIP-seq data using RCADE.","date":"2015","source":"Bioinformatics (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/25953800","citation_count":20,"is_preprint":false},{"pmid":"25195838","id":"PMC_25195838","title":"Construction and expression of lentiviral vectors encoding recombinant mouse CREBZF in NIH 3T3 cells.","date":"2014","source":"Plasmid","url":"https://pubmed.ncbi.nlm.nih.gov/25195838","citation_count":18,"is_preprint":false},{"pmid":"24155933","id":"PMC_24155933","title":"Zhangfei/CREB-ZF - a potential regulator of the unfolded protein response.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24155933","citation_count":18,"is_preprint":false},{"pmid":"24553073","id":"PMC_24553073","title":"CxxC-ZF domain is needed for KDM2A to demethylate histone in rDNA promoter in response to starvation.","date":"2014","source":"Cell structure and function","url":"https://pubmed.ncbi.nlm.nih.gov/24553073","citation_count":18,"is_preprint":false},{"pmid":"24040197","id":"PMC_24040197","title":"The POZ-ZF transcription factor Kaiso (ZBTB33) induces inflammation and progenitor cell differentiation in the murine intestine.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24040197","citation_count":18,"is_preprint":false},{"pmid":"30413092","id":"PMC_30413092","title":"Activation of CREBZF Increases Cell Apoptosis in Mouse Ovarian Granulosa Cells by Regulating the ERK1/2 and mTOR Signaling Pathways.","date":"2018","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30413092","citation_count":17,"is_preprint":false},{"pmid":"25890299","id":"PMC_25890299","title":"The effect of Zhangfei/CREBZF on cell growth, differentiation, apoptosis, migration, and the unfolded protein response in several canine osteosarcoma cell lines.","date":"2015","source":"BMC veterinary research","url":"https://pubmed.ncbi.nlm.nih.gov/25890299","citation_count":17,"is_preprint":false},{"pmid":"22798206","id":"PMC_22798206","title":"Mechanism for the induction of cell death in ONS-76 medulloblastoma cells by Zhangfei/CREB-ZF.","date":"2012","source":"Journal of neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/22798206","citation_count":17,"is_preprint":false},{"pmid":"26065625","id":"PMC_26065625","title":"Cytotoxicity of the association of pesticides Roundup Transorb® and Furadan 350 SC® on the zebrafish cell line, ZF-L.","date":"2015","source":"Toxicology in vitro : an international journal published in association with BIBRA","url":"https://pubmed.ncbi.nlm.nih.gov/26065625","citation_count":17,"is_preprint":false},{"pmid":"35094653","id":"PMC_35094653","title":"Up-regulation of long noncoding RNA MBNL1-AS1 suppresses breast cancer progression by modulating miR-423-5p/CREBZF axis.","date":"2022","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/35094653","citation_count":16,"is_preprint":false},{"pmid":"37264406","id":"PMC_37264406","title":"CREBZF mRNA nanoparticles suppress breast cancer progression through a positive feedback loop boosted by circPAPD4.","date":"2023","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/37264406","citation_count":16,"is_preprint":false},{"pmid":"32218690","id":"PMC_32218690","title":"miRNAs as potential biomarkers for the progression of gastric cancer inhibit CREBZF and regulate migration of gastric adenocarcinoma cells.","date":"2020","source":"International journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32218690","citation_count":16,"is_preprint":false},{"pmid":"37821819","id":"PMC_37821819","title":"In silico and computational analysis of zinc finger motif-associated homeodomain (ZF-HD) family genes in chilli (Capsicum annuum L).","date":"2023","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/37821819","citation_count":16,"is_preprint":false},{"pmid":"31029961","id":"PMC_31029961","title":"Modulation of the multixenobiotic resistance mechanism in Danio rerio hepatocyte culture (ZF-L) after exposure to glyphosate and Roundup®.","date":"2019","source":"Chemosphere","url":"https://pubmed.ncbi.nlm.nih.gov/31029961","citation_count":16,"is_preprint":false},{"pmid":"24325733","id":"PMC_24325733","title":"CREBZF expression and hormonal regulation in the mouse uterus.","date":"2013","source":"Reproductive biology and endocrinology : RB&E","url":"https://pubmed.ncbi.nlm.nih.gov/24325733","citation_count":15,"is_preprint":false},{"pmid":"20026304","id":"PMC_20026304","title":"Amino acid deprivation induces CREBZF/Zhangfei expression via an AARE-like element in the promoter.","date":"2009","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/20026304","citation_count":15,"is_preprint":false},{"pmid":"32380589","id":"PMC_32380589","title":"Biochemical and genotoxic biomarkers and cell cycle assessment in the zebrafish liver (ZF-L) cell line exposed to the novel metal-insecticide magnesium-hespiridin complex.","date":"2020","source":"Chemosphere","url":"https://pubmed.ncbi.nlm.nih.gov/32380589","citation_count":15,"is_preprint":false},{"pmid":"36680394","id":"PMC_36680394","title":"Intrahepatic osteopontin signaling by CREBZF defines a checkpoint for steatosis-to-NASH progression.","date":"2023","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/36680394","citation_count":14,"is_preprint":false},{"pmid":"24200963","id":"PMC_24200963","title":"Effects of cyclic AMP response element binding protein-Zhangfei (CREBZF) on the unfolded protein response and cell growth are exerted through the tumor suppressor p53.","date":"2013","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/24200963","citation_count":14,"is_preprint":false},{"pmid":"8425549","id":"PMC_8425549","title":"Chemical assay for cyst(e)ine-rich peptides detects a novel intestinal peptide ZF-1, homologous to a single zinc-finger motif.","date":"1993","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8425549","citation_count":14,"is_preprint":false},{"pmid":"31124138","id":"PMC_31124138","title":"CREBZF regulates testosterone production in mouse Leydig cells.","date":"2019","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/31124138","citation_count":13,"is_preprint":false},{"pmid":"30855222","id":"PMC_30855222","title":"ZF-Mapper: Simple and Complete Freeware for Fluorescence Quantification in Zebrafish Images.","date":"2019","source":"Zebrafish","url":"https://pubmed.ncbi.nlm.nih.gov/30855222","citation_count":13,"is_preprint":false},{"pmid":"37839588","id":"PMC_37839588","title":"Diverse indole-diterpenoids with protein tyrosine phosphatase 1B inhibitory activities from the marine coral-derived fungus Aspergillus sp. ZF-104.","date":"2023","source":"Phytochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37839588","citation_count":13,"is_preprint":false},{"pmid":"35189832","id":"PMC_35189832","title":"Genome-wide investigation of the ZF-HD gene family in two varieties of alfalfa (Medicago sativa L.) and its expression pattern under alkaline stress.","date":"2022","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/35189832","citation_count":12,"is_preprint":false},{"pmid":"22707059","id":"PMC_22707059","title":"CREBZF, a novel Smad8-binding protein.","date":"2012","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22707059","citation_count":11,"is_preprint":false},{"pmid":"1356006","id":"PMC_1356006","title":"The zebrafish homeobox gene hox[zf-114]: primary structure, expression pattern and evolutionary aspects.","date":"1992","source":"The International journal of developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/1356006","citation_count":11,"is_preprint":false},{"pmid":"17306895","id":"PMC_17306895","title":"Nuclear trafficking of the POZ-ZF protein Znf131.","date":"2006","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/17306895","citation_count":11,"is_preprint":false},{"pmid":"36685917","id":"PMC_36685917","title":"Genome-wide identification and expression analysis of the ZF-HD gene family in pea (Pisum sativum L.).","date":"2023","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36685917","citation_count":10,"is_preprint":false},{"pmid":"36369302","id":"PMC_36369302","title":"Genome-wide analysis of zinc finger-homeodomain (ZF-HD) transcription factors in diploid and tetraploid cotton.","date":"2022","source":"Functional & integrative genomics","url":"https://pubmed.ncbi.nlm.nih.gov/36369302","citation_count":10,"is_preprint":false},{"pmid":"38587455","id":"PMC_38587455","title":"The BTB-ZF gene Bm-mamo regulates pigmentation in silkworm caterpillars.","date":"2024","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/38587455","citation_count":9,"is_preprint":false},{"pmid":"26136427","id":"PMC_26136427","title":"BTB-ZF Protein Znf131 Regulates Cell Growth of Developing and Mature T Cells.","date":"2015","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/26136427","citation_count":9,"is_preprint":false},{"pmid":"38588421","id":"PMC_38588421","title":"Glucose regulation of adipose tissue browning by CBP/p300- and HDAC3-mediated reversible acetylation of CREBZF.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/38588421","citation_count":8,"is_preprint":false},{"pmid":"28882591","id":"PMC_28882591","title":"The POZ-ZF transcription factor Znf131 is implicated as a regulator of Kaiso-mediated biological processes.","date":"2017","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/28882591","citation_count":8,"is_preprint":false},{"pmid":"33575598","id":"PMC_33575598","title":"On the prediction of DNA-binding preferences of C2H2-ZF domains using structural models: application on human CTCF.","date":"2020","source":"NAR genomics and bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/33575598","citation_count":8,"is_preprint":false},{"pmid":"22544070","id":"PMC_22544070","title":"The BTB/POZ-ZF transcription factor dPLZF is involved in Ras/ERK signaling during Drosophila wing development.","date":"2012","source":"Molecules and cells","url":"https://pubmed.ncbi.nlm.nih.gov/22544070","citation_count":8,"is_preprint":false},{"pmid":"37532927","id":"PMC_37532927","title":"MiR-425-5p suppression of Crebzf regulates oocyte aging via chromatin modification.","date":"2023","source":"GeroScience","url":"https://pubmed.ncbi.nlm.nih.gov/37532927","citation_count":7,"is_preprint":false},{"pmid":"37414528","id":"PMC_37414528","title":"Characterizing control of memory CD8 T cell differentiation by BTB-ZF transcription factor Zbtb20.","date":"2023","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/37414528","citation_count":6,"is_preprint":false},{"pmid":"25827285","id":"PMC_25827285","title":"Identification and characterization of reproductive KRAB-ZF genes in mice.","date":"2015","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/25827285","citation_count":6,"is_preprint":false},{"pmid":"31071334","id":"PMC_31071334","title":"Mitochondrial and lysosomal dysfunction induced by the novel metal-insecticide [Mg(hesp)2(phen)] in the zebrafish (Danio rerio) hepatocyte cell line (ZF-L).","date":"2019","source":"Chemico-biological interactions","url":"https://pubmed.ncbi.nlm.nih.gov/31071334","citation_count":6,"is_preprint":false},{"pmid":"38068699","id":"PMC_38068699","title":"Genome-Wide Identification and Analysis of ZF-HD Gene Family in Moso Bamboo (Phyllostachys edulis).","date":"2023","source":"Plants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/38068699","citation_count":5,"is_preprint":false},{"pmid":"11196436","id":"PMC_11196436","title":"Effects of cellular mediator agonists on cortisol and steroid acute regulatory (StAR) protein in bovine zona fasciculata (ZF) cells.","date":"2000","source":"Endocrine research","url":"https://pubmed.ncbi.nlm.nih.gov/11196436","citation_count":5,"is_preprint":false},{"pmid":"29870745","id":"PMC_29870745","title":"Genetically engineered zebrafish liver (ZF-L) cells as an in vitro source for zebrafish acetylcholinesterase (zfAChE) for the use in AChE inhibition assays.","date":"2018","source":"Toxicology in vitro : an international journal published in association with BIBRA","url":"https://pubmed.ncbi.nlm.nih.gov/29870745","citation_count":5,"is_preprint":false},{"pmid":"15158598","id":"PMC_15158598","title":"Phage display of the Equine arteritis virus nsp1 ZF domain and examination of its metal interactions.","date":"2004","source":"Journal of virological methods","url":"https://pubmed.ncbi.nlm.nih.gov/15158598","citation_count":5,"is_preprint":false},{"pmid":"39329271","id":"PMC_39329271","title":"DNA-binding proteins from MBD through ZF to BEN: recognition of cytosine methylation status by one arginine with two conformations.","date":"2024","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/39329271","citation_count":4,"is_preprint":false},{"pmid":"14681021","id":"PMC_14681021","title":"Transcriptional and translational regulation of zebrafish connexin 55.5 (zf.Cx.55.5) and connexin 52.6 (zf.Cx52.6).","date":"2003","source":"Cell communication & adhesion","url":"https://pubmed.ncbi.nlm.nih.gov/14681021","citation_count":4,"is_preprint":false},{"pmid":"27794434","id":"PMC_27794434","title":"Who knows not where an anemone does wear his sting? Could polypeptides released from the columnar vesicles of Bunodosoma cangicum induce apoptosis in the ZF-L cell line?","date":"2016","source":"Toxicon : official journal of the International Society on Toxinology","url":"https://pubmed.ncbi.nlm.nih.gov/27794434","citation_count":4,"is_preprint":false},{"pmid":"29750959","id":"PMC_29750959","title":"A BTB-ZF protein, ZNF131, is required for early B cell development.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/29750959","citation_count":3,"is_preprint":false},{"pmid":"29707688","id":"PMC_29707688","title":"Regulation of Cyclic AMP-Response Element Binding Protein Zhangfei (CREBZF) Expression by Estrogen in Mouse Uterus.","date":"2018","source":"Development & reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/29707688","citation_count":3,"is_preprint":false},{"pmid":"31504764","id":"PMC_31504764","title":"Functional analysis of Cwc24 ZF-domain in 5' splice site selection.","date":"2019","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/31504764","citation_count":3,"is_preprint":false},{"pmid":"36271106","id":"PMC_36271106","title":"Structure of the pre-mRNA leakage 39-kDa protein reveals a single domain of integrated zf-C3HC and Rsm1 modules.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/36271106","citation_count":3,"is_preprint":false},{"pmid":"20680338","id":"PMC_20680338","title":"Molecular characterization and expression of the MYND-ZF gene from Clonorchis sinensis.","date":"2010","source":"Parasitology research","url":"https://pubmed.ncbi.nlm.nih.gov/20680338","citation_count":3,"is_preprint":false},{"pmid":"39179062","id":"PMC_39179062","title":"Molecular characterization of cassava zinc finger-homeodomain (ZF-HD) transcription factors reveals their role in disease resistance.","date":"2024","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/39179062","citation_count":3,"is_preprint":false},{"pmid":"35789966","id":"PMC_35789966","title":"Milk of Cow and Goat, Immunized by Recombinant Protein Vaccine ZF-UZ-VAC2001(Zifivax), Contains Neutralizing Antibodies Against SARS-CoV-2 and Remains Active After Standard Milk Pasteurization.","date":"2022","source":"Frontiers in nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/35789966","citation_count":3,"is_preprint":false},{"pmid":"12812053","id":"PMC_12812053","title":"[Cloning, genomic organization and promoter activity of the mouse zinc finger protein gene ZF-12].","date":"2003","source":"Yi chuan xue bao = Acta genetica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/12812053","citation_count":3,"is_preprint":false},{"pmid":"29707685","id":"PMC_29707685","title":"Differential Expression of Cyclic AMP-Response Element Binding Protein Zhangfei (CREBZF) in the Mouse Testis during Postnatal Development.","date":"2018","source":"Development & reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/29707685","citation_count":2,"is_preprint":false},{"pmid":"39639240","id":"PMC_39639240","title":"ZF-HD gene family in rapeseed (Brassica napus L.): genome-wide identification, phylogeny, evolutionary expansion and expression analyses.","date":"2024","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/39639240","citation_count":2,"is_preprint":false},{"pmid":"31073020","id":"PMC_31073020","title":"Shaping of Drosophila Neural Cell Lineages Through Coordination of Cell Proliferation and Cell Fate by the BTB-ZF Transcription Factor Tramtrack-69.","date":"2019","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31073020","citation_count":2,"is_preprint":false},{"pmid":"39894816","id":"PMC_39894816","title":"Genome-wide identification and expression analysis of ZF-HD family in sunflower (Helianthus annuus L.) under drought and salt stresses.","date":"2025","source":"BMC plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/39894816","citation_count":2,"is_preprint":false},{"pmid":"39516047","id":"PMC_39516047","title":"Improved treatment of coking wastewater and higher biodiversity through immobilization of Comamonas sp. ZF-3 supplemented microbial community.","date":"2024","source":"FEMS microbiology letters","url":"https://pubmed.ncbi.nlm.nih.gov/39516047","citation_count":2,"is_preprint":false},{"pmid":"39810081","id":"PMC_39810081","title":"The members of zinc finger-homeodomain (ZF-HD) transcription factors are associated with abiotic stresses in soybean: insights from genomics and expression analysis.","date":"2025","source":"BMC plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/39810081","citation_count":2,"is_preprint":false},{"pmid":"32980066","id":"PMC_32980066","title":"Identification and effect of Zf-AD-containing C2H2 zinc finger genes on BmNPV replication in the silkworm (Bombyx mori).","date":"2020","source":"Pesticide biochemistry and physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32980066","citation_count":2,"is_preprint":false},{"pmid":"38696238","id":"PMC_38696238","title":"Androgen synthesis cell-specific CREBZF deficiency alters adrenal cortex steroid secretion and develops behavioral abnormalities in adult male mice.","date":"2024","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/38696238","citation_count":1,"is_preprint":false},{"pmid":"37356736","id":"PMC_37356736","title":"Disruption of a BTB-ZF transcription factor causes female sterility and melanization in the larval body of the silkworm, Bombyx mori.","date":"2023","source":"Insect biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/37356736","citation_count":1,"is_preprint":false},{"pmid":"41754257","id":"PMC_41754257","title":"Genome-Wide Identification of the ZF-HD Gene Family in Melon and Functional Characterization of CmZHD8 in Salt Stress Tolerance.","date":"2026","source":"Plants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/41754257","citation_count":1,"is_preprint":false},{"pmid":"19048285","id":"PMC_19048285","title":"Zf-and-Hsys-based Cm measurement under the whole-cell patch-clamp recording.","date":"2008","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/19048285","citation_count":1,"is_preprint":false},{"pmid":"41386884","id":"PMC_41386884","title":"DeepBovC2H2-ZF: deep learning-guided prediction and molecular dynamics validation of C2H2 zinc finger transcription factors in Bovidae.","date":"2025","source":"Journal, genetic engineering & biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/41386884","citation_count":0,"is_preprint":false},{"pmid":"15344332","id":"PMC_15344332","title":"[Cloning and identification of a mouse zinc finger protein gene ZF-12-related pseudogene].","date":"2002","source":"Shi yan sheng wu xue bao","url":"https://pubmed.ncbi.nlm.nih.gov/15344332","citation_count":0,"is_preprint":false},{"pmid":"42095833","id":"PMC_42095833","title":"The ZF-HD1/9 targets CdSQS to promote squalene biosynthesis in Camellia drupifera.","date":"2026","source":"Journal of experimental botany","url":"https://pubmed.ncbi.nlm.nih.gov/42095833","citation_count":0,"is_preprint":false},{"pmid":"41595509","id":"PMC_41595509","title":"Genome-Wide Identification of the Zinc Finger-Homeodomain (ZF-HD) Gene Family and Their Response to Cold Stress in Rosa chinensis.","date":"2026","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/41595509","citation_count":0,"is_preprint":false},{"pmid":"41893653","id":"PMC_41893653","title":"African Swine Fever Virus R238L and R298L Disrupt Lung Cell Collagen Formation and Cell Adhesion Pathway by Targeting Transcription Factors Containing zf-C2H2 Domain.","date":"2026","source":"Veterinary sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41893653","citation_count":0,"is_preprint":false},{"pmid":"12561468","id":"PMC_12561468","title":"[Establishment of mouse ZF-12+/- embryonic stem cells].","date":"2002","source":"Yi chuan xue bao = Acta genetica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/12561468","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47816,"output_tokens":5353,"usd":0.111871,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13471,"output_tokens":4705,"usd":0.09249,"stage2_stop_reason":"end_turn"},"total_usd":0.204361,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about the canonical CREBZF protein (also known as ZF, Zhangfei, SMILE). Many papers in this corpus are about unrelated genes with \"ZF\" in their names (zebrafish genes, plant ZF-HD family, BTB-ZF family members like PLZF/BCL6/Kaiso, etc.). I'll focus only on papers describing CREBZF/Zhangfei/SMILE.\n\nRelevant papers: [11], [14], [19], [31], [32], [35], [36], [37], [40], [41], [44], [45], [47], [48], [50], [54], [61], [65], [77], [84], [91]\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"CREBZF associates with the linker domain of STAT3 and represses STAT3 dimerization and transcriptional activity, thereby inhibiting cyclin gene expression and liver regeneration after partial hepatectomy and CCl4-induced injury. Hepatocyte-specific CREBZF knockout hyperactivates STAT3-driven cyclin D1 and regeneration, which is reversed by the STAT3 inhibitor cucurbitacin I.\",\n      \"method\": \"Liver-specific knockout mice, co-immunoprecipitation, adeno-associated virus overexpression, flow cytometry cell cycle analysis, STAT3 inhibitor rescue experiment\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genetic KO with defined cellular phenotype, pharmacological rescue, and AAV overexpression in two independent liver injury models in a single rigorous study\",\n      \"pmids\": [\"31469186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CREBZF couples insulin-Akt signaling to hepatic lipogenesis by directly inhibiting transcription of Insig-2a through association with ATF4, thereby allowing SREBP-1c processing and de novo fatty acid synthesis. Liver-specific CREBZF knockout induces Insig-2a and Insig-1 and represses the lipogenic program during refeeding and in streptozotocin/insulin-treated mice.\",\n      \"method\": \"Liver-specific knockout mice, refeeding and insulin treatment models, co-immunoprecipitation with ATF4, reporter/promoter assays, western blot for Insig isoforms and lipogenic enzymes\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined metabolic phenotype, direct binding partner (ATF4) identified by Co-IP, mechanistic promoter assays, replicated across multiple in vivo models in one study\",\n      \"pmids\": [\"29637572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CREBZF promotes osteopontin production and secretion in hepatocytes by inhibiting miR-6964-3p, which in turn activates hepatic stellate cells (HSCs) and drives liver fibrosis in diet-induced NASH. AAV-mediated osteopontin rescue in CREBZF-deficient mice restores HSC activation and NASH progression, establishing a hepatocyte-autonomous CREBZF→osteopontin→HSC axis.\",\n      \"method\": \"Diet-induced NASH mouse models, CREBZF liver-specific knockout, AAV-mediated osteopontin rescue, miRNA manipulation, HSC activation assays\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined fibrosis phenotype, miRNA mechanism identified, AAV rescue experiment confirming pathway, multiple orthogonal methods in one study\",\n      \"pmids\": [\"36680394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Glucose induces CREBZF in white adipose tissue, where it associates with PGC-1α to repress thermogenic gene expression (including UCP1). Lys208 acetylation by CBP/p300 and deacetylation by HDAC3 regulates CREBZF protein stability by controlling proteasomal degradation. Adipose-specific CREBZF knockout mice show enhanced browning, thermogenic gene expression, and adaptive thermogenesis during cold exposure.\",\n      \"method\": \"Adipose-specific CREBZF knockout mice, acetylation site mutagenesis (Lys208), CBP/p300 and HDAC3 co-immunoprecipitation, cold exposure assays, rectal temperature measurement, chromatin/co-factor pulldown with PGC-1α\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — acetylation writer/eraser identified with mutagenesis, binding partner (PGC-1α) confirmed by Co-IP, adipose-specific KO with defined thermogenic phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"38588421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CREBZF/Zhangfei interacts with Xbp1s via its leucine zipper domain, leading to proteasomal degradation of Xbp1s. This suppresses Xbp1s-driven transcription from UPR elements and reduces UPR gene expression. siRNA knockdown of endogenous Zhangfei in thapsigargin-treated primary rat sensory neurons significantly increases UPR transcripts and proteins.\",\n      \"method\": \"Co-immunoprecipitation, leucine zipper deletion mutants, UPR reporter assays, siRNA knockdown in primary neurons, western blot and RT-PCR for UPR markers\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct protein interaction mapped to leucine zipper, proteasomal degradation mechanism confirmed, endogenous knockdown phenotype in primary neurons, multiple orthogonal methods\",\n      \"pmids\": [\"24155933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CREBZF is a novel positive regulator of p53: it interacts in vitro with both HEY1 and p53, stabilizes p53 protein, activates p53 transcriptional activity, and cooperates synergistically with HEY1 to enhance p53-dependent transcription. CREBZF induces post-translational modifications on p53 that prevent its degradation. Partial knockdown of endogenous CREBZF diminishes p53 protein levels and inhibits HEY1-mediated p53 activation.\",\n      \"method\": \"Yeast two-hybrid screen (HEY1 as bait), in vitro binding assays, co-immunoprecipitation, p53 reporter assays, siRNA knockdown, post-translational modification analysis\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid identification with in vitro binding and reporter validation, siRNA knockdown phenotype, single lab with multiple methods\",\n      \"pmids\": [\"22983008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The effects of Zhangfei/CREBZF on cell growth suppression and UPR inhibition require the tumor suppressor p53 as an intermediary. The bLZip domain of Zhangfei is required for interaction with p53. Zhangfei stabilizes p53 and co-localizes with it in cellular nuclei, and displaces the E3 ubiquitin ligase Mdm2 from its association with p53. siRNA suppression of p53 partially inhibits Zhangfei's effects. Zhangfei has no effect on p53-null MG63 cells but mirrors its D-17 effects in p53-expressing U2OS cells.\",\n      \"method\": \"Co-immunoprecipitation, nuclear co-localization by imaging, Mdm2 displacement assay, siRNA knockdown of p53, bLZip domain deletion mutants, p53-null cell line comparison\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, domain mutagenesis, siRNA epistasis, isogenic p53-null vs p53-expressing cell line comparison, multiple orthogonal methods in one study\",\n      \"pmids\": [\"24200963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CREBZF interacts with Smads 1, 5, and 8 (BMP-pathway R-Smads), identified through yeast two-hybrid screening using the MH2 domain of Smad8 as bait, confirmed by co-immunoprecipitation in a human prostate cancer cell line. Overexpression of CREBZF inhibits BMP response element promoter activity and abolishes BMP-6-induced cell growth inhibition.\",\n      \"method\": \"Yeast two-hybrid screen (Smad8 MH2 domain as bait), co-immunoprecipitation in human prostate cancer cells, BMP-response element reporter assay, BMP-6 cell growth inhibition assay\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP, functional reporter and growth assay, single lab with two orthogonal binding methods\",\n      \"pmids\": [\"22707059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CREBZF promotes hCG-induced testosterone production in mouse Leydig cells by upregulating the orphan nuclear receptors Nr4a1 and Nr5a1, which subsequently drive expression of steroidogenic genes (3β-HSD, 17β-HSD, P450c17). CREBZF silencing in primary Leydig cells and MLTC-1 cells significantly inhibits hCG-stimulated testosterone production and reduces serum testosterone after lentiviral shRNA microinjection into mouse testis.\",\n      \"method\": \"Lentiviral shRNA knockdown, primary Leydig cell culture, MLTC-1 cell overexpression/knockdown, intratesticular microinjection, testosterone radioimmunoassay, RT-PCR for steroidogenic genes and nuclear receptors\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in vitro and in vivo with defined steroidogenic phenotype, pathway placement via Nr4a1/Nr5a1, single lab\",\n      \"pmids\": [\"31124138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CREBZF overexpression induces apoptosis in mouse ovarian granulosa cells by upregulating BAX and cleaved Caspase-3, downregulating BCL-2, and inhibiting ERK1/2 and mTOR signaling pathways (reduced phosphorylation of ERK1/2 and S6K1). CREBZF also activates autophagy (increased LC3-II).\",\n      \"method\": \"CREBZF overexpression and knockdown, flow cytometry for apoptosis, western blot for apoptosis markers and pathway phosphoproteins, LC3-II autophagy marker\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — overexpression and knockdown with defined apoptotic and signaling phenotypes, pathway placement by phospho-western blots, single lab\",\n      \"pmids\": [\"30413092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Zhangfei/CREBZF induces cell death in ONS-76 medulloblastoma cells through a mechanism involving enhanced transcription from the Brn3a promoter, subsequent TrkA upregulation, and autocrine NGF-TrkA signaling that activates the MAPK pathway, leading to differentiation and cell death. Antibodies against NGF and inhibitors of TrkA and MAPK components partially restore growth of Zhangfei-expressing cells.\",\n      \"method\": \"Adenoviral Zhangfei expression, Brn3a promoter reporter assay, NGF antibody neutralization, TrkA and MAPK inhibitors, transcript profiling, phosphorylation-based kinase activity analysis\",\n      \"journal\": \"Journal of neuro-oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter reporter assay establishes Brn3a as direct target, pharmacological rescue with antibody and inhibitors places pathway, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22798206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CREBZF/Zhangfei expression is induced by amino acid deprivation in MDCK cells. A 9-bp AARE-like element (5'-ATTCACTCA-3') at position -1227 to -1219 in the CREBZF promoter is required for amino acid deprivation-inducible transcription, identified by deletion mapping and site-directed mutagenesis.\",\n      \"method\": \"Amino acid deprivation in MDCK cells, CREBZF promoter cloning, deletion mapping and site-directed mutagenesis, promoter-reporter assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — promoter mutagenesis identifies specific regulatory element, but single lab, single study without independent replication\",\n      \"pmids\": [\"20026304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CREBZF (SMILE isoform) is expressed in mouse uterine luminal and glandular epithelium, is regulated by estrogen (oestrogen stimulates SMILE expression in ovariectomized mice), and its expression peaks on day 4 of pregnancy at implantation sites but is absent from decidual cells. The presence of an active blastocyst is required for SMILE expression at the implantation site.\",\n      \"method\": \"Immunohistochemistry, western blot, RT-PCR across pregnancy stages, ovariectomy/hormone treatment, pseudopregnancy model, delayed implantation model\",\n      \"journal\": \"Reproductive biology and endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by IHC with functional context (implantation), hormone regulation established by ovariectomy/rescue experiment, single lab with multiple methods\",\n      \"pmids\": [\"24325733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"miR-425-5p suppresses Crebzf expression in aging oocytes. Inhibition of miR-425-5p improves old oocyte development by restoring Crebzf levels. Crebzf regulates mRNAs targeting H3K4me3 histone methyltransferases, acting as a mediator of transcriptional regulation in GV oocytes. Overexpression of miR-425-5p hinders oocyte maturation by downregulating Crebzf and disrupting transcriptional regulation.\",\n      \"method\": \"High-throughput miRNA sequencing, microinjection of miR-425-5p inhibitors, in vivo antagomir treatment, single-cell RNA sequencing, Crebzf overexpression/knockdown in oocytes\",\n      \"journal\": \"GeroScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo antagomir treatment with oocyte development phenotype, single-cell RNA-seq for pathway targets, miR-425-5p→Crebzf axis experimentally validated, single lab\",\n      \"pmids\": [\"37532927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CREBZF suppresses STAT3 dimerization and ADAR1 expression, which promotes circPAPD4 biogenesis (since ADAR1 suppresses circPAPD4 formation). CircPAPD4 competitively binds miR-1269a to de-repress CREBZF expression, forming a positive feedback loop (circPAPD4/miR-1269a/CREBZF/STAT3/ADAR1) that curbs breast cancer progression.\",\n      \"method\": \"RNA pull-down, dual-luciferase reporter assays, co-immunoprecipitation, RT-qPCR, in vivo tumor models with CREBZF mRNA nanoparticles, ADAR1 knockdown/overexpression\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for STAT3 dimerization, RNA pulldown for miR-1269a sponging, in vivo nanoparticle delivery confirms pathway, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37264406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Conditional knockout of CREBZF in androgen-synthesis cells (Cyp17a1-Cre) in mice does not affect fertility or serum testosterone, but impairs testosterone secretion in isolated primary Leydig cells and decreases Star, Cyp17a1, and Hsd3b1 mRNA. CREBZF deficiency results in adrenal cortex thickening, elevated serum corticosterone and DHEA, increased StAR/Cyp11a1/17β-Hsd3 in adrenal cortex, and anxiety-like behavior and memory impairment.\",\n      \"method\": \"Cyp17a1-Cre conditional knockout, primary Leydig cell isolation, testosterone ELISA, RT-PCR for steroidogenic genes, immunohistochemistry for adrenal cortex markers, elevated plus maze and Barnes maze behavioral tests\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined steroidogenic and behavioral phenotypes, multiple endpoints measured, single lab\",\n      \"pmids\": [\"38696238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Zhangfei/CREBZF suppresses cell growth and UPR-related transcripts in multiple independent canine osteosarcoma cell lines (Abrams, McKinley, Gracie, D-17) that express functional p53. Zhangfei also induces osteocalcin expression (a marker of osteoblast differentiation) and triggers programmed cell death in these lines. Effects depend on p53 functionality.\",\n      \"method\": \"Adenoviral Zhangfei expression in four independent OS cell lines, RT-PCR for UPR transcripts and osteocalcin, cell growth assays, apoptosis markers\",\n      \"journal\": \"BMC veterinary research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — replicated across four independent cell lines, but OE-based with limited mechanistic depth; replication across lines elevates confidence\",\n      \"pmids\": [\"25890299\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CREBZF (Zhangfei/SMILE) is a bZIP transcription factor that functions as a broad transcriptional co-repressor: it directly binds and inhibits STAT3 dimerization (suppressing liver regeneration), interacts with ATF4 to repress Insig-2a transcription (coupling insulin signaling to hepatic lipogenesis), promotes liver fibrosis via osteopontin secretion from hepatocytes, suppresses thermogenesis by associating with PGC-1α in adipose tissue (regulated by CBP/p300-HDAC3-mediated reversible Lys208 acetylation), stabilizes p53 by displacing Mdm2 and inducing protective post-translational modifications, interacts with BMP-pathway Smads 1/5/8 to inhibit BMP signaling, suppresses the UPR by binding Xbp1s via its leucine zipper and promoting its proteasomal degradation, and regulates steroidogenesis in Leydig cells through Nr4a1/Nr5a1 upregulation; its own transcription is induced by amino acid deprivation through an AARE-like promoter element and by estrogen in uterine epithelium.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CREBZF (Zhangfei/SMILE) is a bZIP transcriptional co-regulator that broadly restrains stress-, growth-, and metabolism-associated transcription factors through direct protein-protein contacts rather than autonomous DNA binding [#0, #1]. In liver, it constrains regeneration by binding the linker domain of STAT3 to block its dimerization and downstream cyclin expression [#0], and it couples insulin signaling to lipogenesis by associating with ATF4 to repress Insig-2a, thereby licensing SREBP-1c-driven fatty acid synthesis [#1]; it further drives diet-induced fibrosis through a hepatocyte-autonomous axis in which it suppresses miR-6964-3p to elevate osteopontin secretion and activate hepatic stellate cells [#2]. In adipose tissue CREBZF associates with PGC-1\\u03b1 to repress thermogenic genes including UCP1, and its abundance is set by reversible Lys208 acetylation written by CBP/p300 and erased by HDAC3 that gates proteasomal turnover [#3]. It governs proteostasis by binding the UPR effector Xbp1s via its leucine zipper and targeting it for proteasomal degradation [#4], and it stabilizes p53 by displacing Mdm2 and acting through its bZIP/bLZip domain, cooperating with HEY1 to potentiate p53-dependent transcription and p53-dependent growth suppression [#5, #6]. CREBZF additionally inhibits BMP signaling through interaction with R-Smads 1/5/8 [#7] and supports steroidogenesis by upregulating the nuclear receptors Nr4a1 and Nr5a1 in Leydig cells [#8]. Its own expression is induced by amino acid deprivation via an AARE-like promoter element [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established how CREBZF transcription itself is controlled, placing it within the amino acid stress response.\",\n      \"evidence\": \"Promoter deletion mapping and site-directed mutagenesis of an AARE-like element under amino acid deprivation in MDCK cells\",\n      \"pmids\": [\"20026304\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcription factor binding the AARE-like element not identified\", \"Single study without independent replication\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified CREBZF as a positive regulator of p53 and a partner of HEY1, framing it as a stabilizer rather than activator-by-DNA-binding.\",\n      \"evidence\": \"Yeast two-hybrid (HEY1 bait), in vitro binding, Co-IP, p53 reporter assays and siRNA knockdown\",\n      \"pmids\": [\"22983008\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the protective post-translational modifications on p53 not defined\", \"Largely in vitro/overexpression context\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined CREBZF as a BMP-pathway repressor through direct R-Smad binding, broadening its co-repressor scope.\",\n      \"evidence\": \"Yeast two-hybrid (Smad8 MH2 bait), Co-IP in prostate cancer cells, BMP-response element reporter and BMP-6 growth assay\",\n      \"pmids\": [\"22707059\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of Smad inhibition not resolved\", \"In vivo relevance untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved the p53 stabilization mechanism as Mdm2 displacement requiring the bLZip domain, and showed p53 is the obligate intermediary for growth and UPR effects.\",\n      \"evidence\": \"Co-IP, nuclear co-localization imaging, Mdm2 displacement assay, bLZip deletion mutants and isogenic p53-null vs p53-expressing cell comparison\",\n      \"pmids\": [\"24200963\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define which post-translational modifications block degradation\", \"p53-independent CREBZF functions not addressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed CREBZF restrains the UPR directly by degrading Xbp1s, defining a leucine-zipper-dependent proteostasis brake distinct from the p53 axis.\",\n      \"evidence\": \"Co-IP, leucine zipper deletion mutants, UPR reporter assays and siRNA knockdown in primary rat sensory neurons\",\n      \"pmids\": [\"24155933\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase mediating Xbp1s degradation not identified\", \"Relationship to the p53-dependent UPR effects unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linked CREBZF to estrogen-regulated uterine biology and blastocyst-dependent expression at implantation.\",\n      \"evidence\": \"IHC, western blot, RT-PCR across pregnancy stages, ovariectomy/hormone rescue and delayed implantation models in mice\",\n      \"pmids\": [\"24325733\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role in implantation not tested by loss-of-function\", \"Downstream targets in uterine epithelium unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Confirmed p53-dependent growth suppression, UPR repression and differentiation across multiple independent cell lines, strengthening the p53-coupled tumor-suppressive model.\",\n      \"evidence\": \"Adenoviral Zhangfei expression in four canine osteosarcoma lines, RT-PCR, growth and apoptosis assays\",\n      \"pmids\": [\"25890299\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression-based with limited mechanistic depth\", \"Differentiation pathway to osteocalcin induction not mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the in vivo metabolic role of CREBZF as coupling insulin-Akt signaling to hepatic lipogenesis via ATF4-dependent Insig-2a repression.\",\n      \"evidence\": \"Liver-specific knockout mice, refeeding/insulin models, ATF4 Co-IP, promoter/reporter assays\",\n      \"pmids\": [\"29637572\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How insulin signaling regulates CREBZF activity not defined\", \"Direct DNA contact at Insig-2a vs ATF4-mediated recruitment not distinguished\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed CREBZF can promote apoptosis and autophagy and modulate ERK/mTOR signaling in granulosa cells, extending its pro-death activity to the ovary.\",\n      \"evidence\": \"Overexpression/knockdown, flow cytometry, phospho-western blots and LC3-II in mouse ovarian granulosa cells\",\n      \"pmids\": [\"30413092\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting CREBZF to ERK/mTOR not defined\", \"Single lab, overexpression-weighted\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed CREBZF as a positive driver of Leydig cell steroidogenesis acting through Nr4a1/Nr5a1.\",\n      \"evidence\": \"Lentiviral shRNA, primary Leydig and MLTC-1 cells, intratesticular microinjection, testosterone radioimmunoassay, RT-PCR\",\n      \"pmids\": [\"31124138\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect control of Nr4a1/Nr5a1 unresolved\", \"In vivo fertility consequence not tested here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established CREBZF as a brake on liver regeneration by directly inhibiting STAT3 dimerization, with a pharmacological rescue confirming the axis.\",\n      \"evidence\": \"Liver-specific KO mice, reciprocal Co-IP, AAV overexpression, cell-cycle flow cytometry and STAT3 inhibitor rescue in two injury models\",\n      \"pmids\": [\"31469186\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of linker-domain binding not solved\", \"Signals controlling CREBZF during regeneration unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a hepatocyte-autonomous CREBZF\\u2192osteopontin\\u2192stellate cell axis driving NASH fibrosis through miR-6964-3p suppression.\",\n      \"evidence\": \"Diet-induced NASH models, liver-specific KO, AAV osteopontin rescue, miRNA manipulation and HSC activation assays\",\n      \"pmids\": [\"36680394\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CREBZF represses miR-6964-3p not defined\", \"Relationship to its lipogenic role in the same tissue unintegrated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Embedded the CREBZF-STAT3 axis in a circPAPD4/miR-1269a/ADAR1 feedback loop constraining breast cancer progression.\",\n      \"evidence\": \"RNA pull-down, dual-luciferase reporters, Co-IP, in vivo CREBZF mRNA nanoparticle delivery and ADAR1 manipulation\",\n      \"pmids\": [\"37264406\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Directness of CREBZF effect on ADAR1 expression unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked CREBZF to oocyte transcriptional competence and aging via a miR-425-5p axis affecting H3K4me3 methyltransferase regulation.\",\n      \"evidence\": \"miRNA-seq, microinjection of miR-425-5p inhibitors, in vivo antagomir, single-cell RNA-seq and Crebzf manipulation in oocytes\",\n      \"pmids\": [\"37532927\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct targets through which CREBZF controls H3K4me3 enzymes not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified glucose-induced CREBZF as a thermogenic suppressor acting through PGC-1\\u03b1, with Lys208 acetylation as the stability switch governing its abundance.\",\n      \"evidence\": \"Adipose-specific KO mice, Lys208 mutagenesis, CBP/p300 and HDAC3 Co-IP, cold exposure and PGC-1\\u03b1 co-factor pulldown\",\n      \"pmids\": [\"38588421\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether acetylation control generalizes to other CREBZF functions untested\", \"Direct PGC-1\\u03b1 binding interface not mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Refined the steroidogenic role using cell-type-specific knockout, revealing intrinsic Leydig defects and adrenal/behavioral consequences despite preserved fertility.\",\n      \"evidence\": \"Cyp17a1-Cre conditional KO, primary Leydig cell testosterone ELISA, RT-PCR, adrenal IHC and behavioral testing\",\n      \"pmids\": [\"38696238\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking CREBZF loss to adrenal cortex thickening unknown\", \"Cause of anxiety/memory phenotype not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single bZIP co-regulator selects among its many partners (STAT3, ATF4, Xbp1s, p53, R-Smads, PGC-1\\u03b1) in a tissue- and signal-specific manner, and what structural determinants and post-translational switches dictate each interaction.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of any CREBZF-partner interface\", \"Logic of partner selection across tissues undefined\", \"Whether CREBZF binds DNA directly at any target remains unestablished\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 3, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 4, 5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 7, 14]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [4, 11]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"STAT3\", \"ATF4\", \"XBP1\", \"TP53\", \"MDM2\", \"HEY1\", \"PPARGC1A\", \"SMAD8\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}