{"gene":"ZFP36","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":1989,"finding":"TIS11 (ZFP36) is a primary response gene rapidly and transiently induced in Swiss 3T3 cells by the tumor promoter TPA; cDNA sequence and deduced amino acid sequence were determined.","method":"cDNA cloning and sequencing","journal":"Oncogene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single descriptive cDNA cloning study, no functional mechanistic follow-up in this paper","pmids":["2915901"],"is_preprint":false},{"year":1991,"finding":"TIS11/ZFP36 protein contains two tandemly repeated CCCH-type Cys3His zinc-finger motifs (YKTELC repeat) that are highly conserved across a gene family including TIS11b and TIS11d.","method":"cDNA cloning, sequence comparison","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — conserved domain identified across multiple family members and replicated by multiple labs","pmids":["1996120"],"is_preprint":false},{"year":1991,"finding":"IL-6 signal transduction in B-cell hybridoma activates TIS11 gene transcription through a novel protein kinase cascade requiring tyrosine kinase activity and an H7-sensitive kinase, independently of cycloheximide-sensitive protein synthesis.","method":"Pharmacological inhibition (cycloheximide, H7), tyrosine phosphorylation assays, primary response gene induction","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological tools used, tyrosine phosphorylation of p160 measured, pathway characterized in single lab","pmids":["1705005"],"is_preprint":false},{"year":1995,"finding":"The Zfp-36 promoter requires 77 bp 5' of the transcription start site for full serum inducibility; cis-acting elements for EGR-1, AP2, Sp1, and a novel TPE1 palindrome each contribute to serum-induced transcription.","method":"Promoter deletion analysis, gel mobility shift assay (EMSA), reporter gene assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple deletion constructs, EMSA, and heterologous promoter assays in single lab","pmids":["7559666"],"is_preprint":false},{"year":1996,"finding":"The Nup475/ZFP36 Cys3His repeats each bind one equivalent of zinc (or cobalt) with tetrahedral coordination; NMR structural data indicate the zinc ion is coordinated by conserved cysteines and histidine, with the conserved YKTEL motif forming a parallel sheet-like structure.","method":"Metal-binding titration (Co2+ spectroscopy), NMR spectroscopy, synthetic peptides","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with metal binding quantification, in vitro biochemical characterization, single lab but multiple orthogonal methods","pmids":["8943007"],"is_preprint":false},{"year":1998,"finding":"Full serum-induced expression of Zfp-36 requires both promoter elements and an intronic element; a Sp1-binding sequence (bp 618-626) within the intron contributes ~70% of serum-induced expression.","method":"Intron replacement/deletion analysis, site-directed mutagenesis of Sp1 binding site, reporter gene assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of specific Sp1 site combined with multiple deletion constructs, single lab","pmids":["9417109"],"is_preprint":false},{"year":2000,"finding":"TIS11/ZFP36 functions as a positive transcriptional activator when fused to a GAL4 DNA-binding domain; the N-terminal 101 amino acid region contains the major transactivation domain, and PMA negatively regulates this activity via protein kinase C/MAP kinase cascade.","method":"GAL4 fusion transactivation assay, deletion mutagenesis, pharmacological inhibition (calphostin C, PD98059)","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional transactivation assay with domain mapping and signaling inhibitors, single lab","pmids":["10913371"],"is_preprint":false},{"year":2000,"finding":"Continuous expression of TTP/ZFP36 at physiological levels causes apoptotic cell death dependent on the zinc finger domains; TTP but not TIS11b or TIS11d sensitizes cells to TNF-alpha-induced apoptosis.","method":"Stable transfection, apoptosis assays, zinc finger domain mutants","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-dependence established by mutagenesis, apoptosis phenotype measured by multiple criteria, single lab","pmids":["10763822"],"is_preprint":false},{"year":2002,"finding":"Recombinant Nup475/ZFP36 protein binds the TNF AU-rich element via SELEX-determined optimal sequence UUAUUUAUU; zinc excess inhibits binding; the protein also shows weaker binding to poly(A) sequences.","method":"RNA gel shift (EMSA), RNA SELEX, site-directed mutagenesis of TNF ARE, recombinant protein from E. coli","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with recombinant protein, SELEX to define binding consensus, mutagenesis validation, multiple orthogonal methods","pmids":["12324455"],"is_preprint":false},{"year":2002,"finding":"TIS11/ZFP36 contains a functional nuclear localization signal (NLS) in the tandem zinc-finger region (requiring Arg127 and Arg131) and a CRM1-dependent Leu-rich nuclear export signal (NES) in the N-terminal region, enabling nucleocytoplasmic shuttling.","method":"GFP fusion constructs, leptomycin B treatment, deletion analysis, site-directed mutagenesis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — localization mapped by deletion and mutagenesis with pharmacological validation (leptomycin B), single lab","pmids":["12054509"],"is_preprint":false},{"year":2003,"finding":"A single CCCH zinc-binding domain of Nup475/ZFP36 is sufficient for selective RNA binding; the zinc(II)-complexed first domain binds UUUAUUU with ~5 µM affinity and discriminates against sequences lacking the central A or flanking U residues.","method":"Fluorescence-based binding assay with synthetic peptide, metal ion binding characterization","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with defined peptide, quantitative binding assay, sequence selectivity probed, single rigorous study","pmids":["12705825"],"is_preprint":false},{"year":2004,"finding":"TIS11/ZFP36 is recruited to stress granules (SGs) upon heat shock; recruitment requires the tandem zinc-finger domain, with specific residues Tyr105/Tyr113, Gly109/Gly114, Phe119 and zinc-chelating Cys residues in both fingers being critical.","method":"GFP fusion constructs, deletion analysis, site-directed mutagenesis, heat shock treatment, co-localization with SG markers","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping with mutagenesis and co-localization, single lab","pmids":["15652343"],"is_preprint":false},{"year":2006,"finding":"Iron (Fe2+ and Fe3+) can substitute for zinc in the TTP-2D (ZFP36 two-domain) protein; iron-substituted TTP-2D binds the canonical UUUAUUUAUUU RNA sequence with nanomolar affinity and retains selectivity for adenine-containing sequences.","method":"Metal ion titration, fluorescence-based RNA binding assay, Fe2+/Fe3+ reconstitution of recombinant protein","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution with quantitative binding, but single lab study","pmids":["17087518"],"is_preprint":false},{"year":2013,"finding":"A cryptic Transportin-dependent PY-NLS overlapping the second zinc finger (ZnF2) is conserved across TIS11/ZFP36 family; mutations disrupting ZnF2 zinc coordination unmask this NLS and promote nuclear import; nuclear export in Drosophila dTIS11 is CRM1-dependent via a divergent NES.","method":"Deletion mutagenesis, zinc finger mutation, nuclear import/export assays, leptomycin B treatment, Drosophila and mammalian cell systems","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of zinc coordination residues unmasks NLS, validated in two species, single lab","pmids":["23951221"],"is_preprint":false},{"year":2014,"finding":"ZFP36 globally binds AU-rich sequences in vivo; CLIP-seq defined in vivo binding preferences in human embryonic kidney cells; ZFP36 degrades target transcripts through specific AU-rich sequences representing a subset of U-rich sequences; targets include immune function and cancer transcripts; ZFP36 and ELAVL1 share overlapping binding sites in 1,313 genes but with differential relative preferences.","method":"HITS-CLIP (cross-linking and immunoprecipitation), mRNA half-life analysis in ZFP36 knockout mouse cells, partial correlation analysis","journal":"Genome biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide CLIP with orthogonal validation using ZFP36 KO mRNA half-lives, quantitative binding-activity correlation","pmids":["24401661"],"is_preprint":false},{"year":2014,"finding":"Rapid proteasomal degradation of ZFP36/TTP is ubiquitin-independent and driven by intrinsically disordered N- and C-terminal domains; phosphorylation inhibits proteasomal degradation of TTP in vitro.","method":"Proteasome inhibitor assays, ubiquitin-independent degradation assays, in vitro degradation with phosphorylation manipulation, Drosophila dTIS11 and mammalian TTP","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitin independence demonstrated directly, in vitro degradation assay, conserved mechanism shown in two species, single lab","pmids":["25246635"],"is_preprint":false},{"year":2015,"finding":"ZFP36 exerts negative feed-forward control of TNF mRNA expression via ARE-mediated mRNA degradation; DUSP1-dependent negative feedback on MAPKs reduces ZFP36 expression, limiting this feed-forward control; dexamethasone represses TNF independently of ZFP36.","method":"siRNA silencing of DUSP1 and ZFP36, DUSP1 overexpression, MAPK inhibition, TNF mRNA stability assays in primary human bronchial epithelial cells and A549 cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via dual knockdown with mRNA stability readout, primary cells used, single lab","pmids":["26546680"],"is_preprint":false},{"year":2015,"finding":"ZFP36 promotes assembly of the Ripoptosome death complex by depleting XIAP and cIAP2 ubiquitin ligases (via destabilizing their mRNAs), leading to RIP1 stabilization, association of RIP1 with caspase-8 and FADD, and RIP1-dependent cell death/necroptosis.","method":"Co-immunoprecipitation, size exclusion chromatography, shRNA lentivectors, cell death assays in glioma neural stem cells","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirmed complex, shRNA depletion with specific phenotypic rescue, single lab","pmids":["25939870"],"is_preprint":false},{"year":2018,"finding":"ZFP36 represses mRNA target abundance and translation in T cells, including through novel AU-rich sites in coding sequences; ZFP36 regulates early T-cell activation kinetics by attenuating activation marker expression, limiting expansion, and promoting apoptosis; loss of ZFP36 in vivo accelerates T cell responses to acute viral infection.","method":"HITS-CLIP in mouse T cells, ribosome profiling, transcriptome analysis, in vivo viral infection model with ZFP36 conditional knockout","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — HITS-CLIP target identification combined with ribosome profiling and in vivo KO phenotype, multiple orthogonal methods","pmids":["29848443"],"is_preprint":false},{"year":2019,"finding":"ZFP36/TTP promotes ATG16L1 mRNA decay by binding AU-rich elements in its 3'-UTR; internal mutation of the ARE region abrogates ZFP36-mediated ATG16L1 mRNA instability; FBXW7 ubiquitin ligase degrades ZFP36 protein by recognizing a SFSGLPS motif, linking ZFP36 to ferroptosis resistance through autophagy inhibition.","method":"ARE mutagenesis, mRNA decay assays, plasmid overexpression, FBXW7 recognition motif identification, in vivo HSC-specific Zfp36 overexpression mouse model","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ARE mutagenesis abrogates binding, FBXW7 motif identified, in vivo validation, single lab","pmids":["31679460"],"is_preprint":false},{"year":2021,"finding":"ZFP36 directly binds AU-rich elements in the NOX4 mRNA 3'-UTR to inhibit NOX4 expression, thereby suppressing NOX4-mediated DRP1 activation and mitochondrial fragmentation in neurons under OGD/R conditions.","method":"RNA immunoprecipitation (RIP), 3'-UTR binding assay, siRNA knockdown, ZFP36 overexpression, NOX4 inhibitor experiments","journal":"Brain research bulletin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP confirmed direct mRNA binding, epistasis with NOX4 inhibitor, single lab","pmids":["34896479"],"is_preprint":false},{"year":2021,"finding":"ZFP36 directly binds ARE sequences in the CREBBP mRNA 3'-UTR to promote its degradation, as confirmed by pull-down and RIP assays; ZFP36 deficiency upregulates CREBBP and enhances I/R-induced lung injury via CREBBP/p53/p21/Bax pathway.","method":"RIP assay, pull-down assay, in silico prediction, Western blot, in vivo ZFP36 knockdown mouse model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP and pull-down confirm direct mRNA interaction, pathway epistasis, single lab","pmids":["34238924"],"is_preprint":false},{"year":2020,"finding":"ZFP36 binds AU-rich elements in the PRC1 mRNA 3'-UTR to downregulate PRC1 expression, suppressing HCC tumor growth and increasing 5-Fu sensitivity, as demonstrated by luciferase reporter and RIP assays.","method":"Luciferase reporter assay, RIP assay, ZFP36 overexpression, xenograft mouse model","journal":"Frontiers in molecular biosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter and RIP confirm direct 3'UTR binding, in vivo validation, single lab","pmids":["32766276"],"is_preprint":false},{"year":2023,"finding":"ZFP36 directly promotes mRNA decay of Enolase 2 (Eno2), altering Eno2 protein expression and enzymatic activity; ZFP36/L1/L2 family proteins are key drivers of metabolic regulation downstream of acute growth factor signaling, with ZFP36 binding catalogued against metabolic enzyme and nutrient transporter mRNAs.","method":"CLIP-seq, mRNA stability assays, Eno2 enzymatic activity measurement, VEGF-stimulated retinal angiogenesis model","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CLIP-seq with functional mRNA decay validation and enzymatic activity readout, in vivo tissue evidence, single lab","pmids":["37086408"],"is_preprint":false},{"year":2023,"finding":"Jag1 mRNA is a direct target of ZFP36-mediated decay; VEGF induces ZFP36 in endothelial cells creating a feedforward loop that suppresses Jag1 to enable adequate Notch signaling; endothelial Zfp36 knockout mice show mispatterned JAG1 and increased tip cell numbers, rescued by Jag1 haploinsufficiency.","method":"ZFP36 CLIP, mRNA decay assays, endothelial-specific Zfp36 knockout mice, retinal vascular plexus imaging, Jag1 haploinsufficiency rescue","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct CLIP evidence for Jag1 binding, in vivo KO with specific phenotype and genetic rescue by Jag1 haploinsufficiency","pmids":["38157296"],"is_preprint":false},{"year":2023,"finding":"ZFP36 associates with RIG-I and promotes K63-linked polyubiquitination of RIG-I at K154/K164/K172, facilitating RIG-I activation and IFN-β production during viral infection; a ZFP36 zinc-finger mutant (C118S/C162S) fails to promote RIG-I ubiquitination.","method":"Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis of RIG-I ubiquitination sites, ZFP36 zinc-finger domain mutagenesis, SeV infection model","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirmed association, ubiquitination site mutagenesis, zinc-finger mutant abolishes activity, single lab","pmids":["37565597"],"is_preprint":false},{"year":2024,"finding":"ZFP36 binds the 3'-UTR of RGS2 mRNA and promotes its degradation, thereby regulating GPCR-mediated intracellular calcium increases in vascular smooth muscle cells; VSMC-specific ZFP36 deletion reduces vessel contractility, blood pressure, and attenuates AngII-induced hypertension in mice; AngII activates ZFP36 transcription via PARP1.","method":"mRNA stability assays, VSMC-specific ZFP36 knockout mice, blood pressure measurement, calcium signaling assays, AAV-mediated knockdown in spontaneously hypertensive rats, PARP1 inhibitor experiments","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific KO with defined hemodynamic phenotype, in vivo rat AAV validation, mechanistic pathway through RGS2 mRNA target, multiple orthogonal methods","pmids":["39589932"],"is_preprint":false},{"year":2024,"finding":"ZFP36 binds to the 3'-UTR of CREBBP/NLRP3 mRNAs to promote their decay; ZFP36 directly targets NLRP3 mRNA for degradation in fibroblasts, reducing inflammasome activation; ZFP36 gene undergoes promoter methylation in psoriatic fibroblasts reducing its expression.","method":"RIP assay, mRNA stability assay, ZFP36 restoration experiments, promoter methylation analysis, NLRP3 inflammasome activity assay","journal":"Frontiers in medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP confirms direct binding, functional rescue experiment, single lab","pmids":["33585499"],"is_preprint":false},{"year":2024,"finding":"IFNβ-induced ISGF3 transcription factor complex drives ZFP36 expression during necroptosis, and ZFP36 then post-transcriptionally degrades mRNAs of inflammatory cytokines (IL-6, IL-8, DUSP1, PTGS2, TNFAIP3) through ARE recognition; the MKK3-p38-MK2 axis regulates ZFP36 expression upstream.","method":"Transcriptomics, ISGF3 and MK2/MKK3 overexpression/knockdown, mRNA stability assays, ZFP36 knockdown validation, coronavirus infection models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via multiple kinase KD/OE with mRNA stability readout, multiple cytokine targets validated, single lab","pmids":["39117638"],"is_preprint":false},{"year":2024,"finding":"dsRNA/poly(I:C) activates p38 MAPK-MK2 signaling to phosphorylate ZFP36/TTP, inactivating it and stabilizing AU-rich cytokine mRNAs (TNF, IL-6, COX-2, IL-8); hydroxychloroquine reduces ZFP36 phosphorylation by suppressing p38/MK2, thereby reducing phosphorylated TTP abundance and destabilizing these inflammatory mRNAs.","method":"p38/MK2 phosphorylation assays, mRNA stability assays, hydroxychloroquine treatment, THP-1 and primary blood monocytes","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphorylation state linked to mRNA stability outcome with pharmacological manipulation, single lab","pmids":["39046234"],"is_preprint":false},{"year":2025,"finding":"Adipose ZFP36 represses RNF128 mRNA stability and translation; loss of ZFP36 in adipose tissue increases RNF128, which negatively regulates Sirt1, promoting adipocyte hypertrophy and obesity; adipose-specific ZFP36 knockout mice show decreased PLIN1, ATGL, and HSL expression and increased susceptibility to diet-induced obesity.","method":"Adipose-specific ZFP36 knockout mice, gene array assay, mRNA stability assay, in vivo metabolic phenotyping","journal":"Metabolism: clinical and experimental","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific KO with defined metabolic phenotype, pathway through RNF128/Sirt1 identified, single lab","pmids":["39761791"],"is_preprint":false},{"year":2025,"finding":"ZFP36 binds to the 3'-UTR of Ythdc2 mRNA to promote its degradation; loss of this suppression allows Ythdc2 to degrade SLC7A11 mRNA, reducing glutathione and promoting ferroptosis and cardiac hypertrophy; Ythdc2 overexpression reverses ZFP36-mediated protection.","method":"3'-UTR binding assays, Ythdc2/SLC7A11 mRNA stability measurements, ZFP36 overexpression/knockdown in cardiomyocytes, transverse aortic constriction mouse model, epistasis rescue experiments","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'UTR binding established, pathway epistasis via Ythdc2 rescue, in vivo model, single lab","pmids":["40000392"],"is_preprint":false},{"year":2025,"finding":"Smooth muscle ZFP36 binds CEMIP mRNA and promotes its degradation, reducing CEMIP protein and limiting VSMC proliferation and migration; smooth muscle-specific Zfp36 knockout accelerates neointimal hyperplasia; PDGF-BB downregulates ZFP36 in VSMCs via KLF4 binding to the Zfp36 promoter.","method":"Smooth muscle-specific ZFP36 knockout mice, carotid artery ligation model, mRNA stability assay for CEMIP, Cemip knockdown rescue, KLF4 promoter binding analysis","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific KO with in vivo vascular phenotype, CEMIP mRNA target validated by rescue, single lab","pmids":["39890944"],"is_preprint":false},{"year":2021,"finding":"ZFP36 directly binds AU-rich elements in the VDR mRNA 3'-UTR to promote its degradation; mutation of key amino acids in ZFP36 abolishes this mRNA binding; ZFP36-mediated VDR mRNA decay promotes cell death under inflammatory conditions.","method":"RNA affinity chromatography, ZFP36 key amino acid mutagenesis, mRNA decay assay, luciferase reporter (3'UTR ARE assay), Co-immunoprecipitation","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA affinity chromatography and mutagenesis confirm direct binding, multiple methods, single lab","pmids":["34380509"],"is_preprint":false},{"year":2023,"finding":"ZFP36 binds the 3'-UTR of BARX1 mRNA and mediates its destabilization; loss of ZFP36 leads to BARX1 upregulation, which transactivates oncogenes promoting NSCLC proliferation, migration, and invasion.","method":"ZFP36-BARX1 mRNA 3'UTR binding assays, mRNA stability assays, ZFP36/BARX1 knockdown/overexpression, NSCLC xenograft mouse model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'UTR binding and mRNA stability, in vivo tumor model, single lab","pmids":["37587140"],"is_preprint":false},{"year":2024,"finding":"ZFP36 promotes E2F1 mRNA degradation by binding AREs in the E2F1 3'-UTR; loss of this suppression allows E2F1 to transactivate ATF4, collectively promoting malignant progression and suppressing ferroptosis in osteosarcoma.","method":"RIP assay, 3'-UTR ARE binding assay, E2F1/ATF4 promoter transactivation assays, ZFP36/E2F1/ATF4 overexpression/knockdown, in vivo xenograft","journal":"Journal of pharmaceutical analysis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP confirms ARE binding, transcriptional epistasis through E2F1/ATF4, in vivo validation, single lab","pmids":["41050116"],"is_preprint":false},{"year":2024,"finding":"ZFP36 binds to SIK1 mRNA (confirmed by RIP) to promote its degradation; in high-glucose conditions, upregulated ZFP36 suppresses SIK1, promoting gluconeogenesis; DUSP1 overexpression downregulates ZFP36, relieving SIK1 suppression and inhibiting gluconeogenesis.","method":"RNA binding protein immunoprecipitation (RIP), ZFP36 overexpression/knockdown, DUSP1 overexpression, gluconeogenesis assays","journal":"The Kaohsiung journal of medical sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single RIP assay, no mutagenesis of binding sites, single lab","pmids":["36524461"],"is_preprint":false},{"year":2021,"finding":"Macrophage-expressed ZFP36 promotes degradation of IL-27 p28 mRNA (confirmed by siRNA-mediated ZFP36 silencing leading to impaired IL-27 mRNA degradation); macrophage-specific Zfp36 conditional knockout leads to increased IL-27 and CD8+ T cell hyperactivation, exacerbating renal allograft rejection.","method":"siRNA knockdown of Zfp36 in p21high macrophages, mRNA stability assay for IL-27, macrophage-specific Zfp36 conditional KO mouse model, kidney transplantation model, IL-27 neutralizing antibody rescue","journal":"Cell discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA-confirmed mRNA decay, in vivo cKO with antibody rescue epistasis, single lab","pmids":["40234384"],"is_preprint":false},{"year":2022,"finding":"ZFP36 directly binds CDK6 mRNA ARE and reduces CDK6 expression; ZFP36-mediated CDK6 repression blocks cell cycle at G1 in prostate cancer cells, as confirmed by dual-luciferase and RIP assays.","method":"Dual-luciferase reporter assay, RIP, ZFP36 overexpression, cell cycle analysis, xenograft tumor model","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase and RIP confirm direct 3'UTR ARE binding, cell cycle phenotype measured, single lab","pmids":["36111167"],"is_preprint":false}],"current_model":"ZFP36 (TTP/NUP475/TIS11/G0S24) is an RNA-binding protein containing tandem CCCH zinc-finger domains that each coordinate one zinc ion and selectively bind the consensus sequence UUAUUUAUU (and related AU-rich elements) within the 3'-UTRs of target mRNAs; upon binding, ZFP36 promotes mRNA deadenylation and decay through the exosome, thereby post-transcriptionally suppressing a broad set of targets including cytokines (TNF, IL-6, IL-8), signaling mediators (RGS2, NOX4, CREBBP, ATG16L1, PRC1, CDK6, BARX1, Jag1, Eno2, Ythdc2), and others; ZFP36 expression is induced by mitogens, cytokines, growth factors (via EGR-1/Sp1/AP2 promoter elements and intronic Sp1 sites), and by IFNβ through ISGF3, and is activated by the p38-MK2 kinase cascade while being inactivated by MK2-mediated phosphorylation; ZFP36 protein undergoes ubiquitin-independent proteasomal degradation driven by its intrinsically disordered termini (inhibited by phosphorylation), and is also targeted for proteasomal degradation via FBXW7 recognition of a SFSGLPS degron; the protein shuttles between nucleus and cytoplasm via a ZnF-region NLS (CRM1-dependent NES), localizes to cytoplasmic stress granules through its zinc-finger domain, and additionally promotes K63-linked polyubiquitination of RIG-I to enhance antiviral innate immune signaling."},"narrative":{"mechanistic_narrative":"ZFP36 (TTP/TIS11) is a CCCH tandem zinc-finger RNA-binding protein that acts as a master post-transcriptional repressor, binding AU-rich elements in target mRNA 3'-UTRs and coding sequences to drive their decay and translational silencing across immune, metabolic, vascular, and oncogenic programs [PMID:24401661, PMID:12324455, PMID:29848443]. Each of its two Cys3His repeats coordinates a single zinc ion in tetrahedral geometry, and even one zinc-loaded domain confers selective binding to the UUAUUUAUU/UUUAUUU consensus, discriminating against sequences lacking the central adenine or flanking uridines [PMID:8943007, PMID:12705825, PMID:12324455]; iron can substitute for zinc while preserving high-affinity, sequence-selective RNA binding [PMID:17087518]. Originally identified as a primary response gene induced by tumor-promoter and serum stimulation via EGR-1/AP2/Sp1 promoter and intronic Sp1 elements [PMID:2915901, PMID:7559666, PMID:9417109], ZFP36 is wired into stimulus-coupled signaling: it is transcriptionally activated by ISGF3 (IFNβ), AngII/PARP1, and other inputs, and its repressive activity is switched off by p38-MK2-mediated phosphorylation that stabilizes ARE-containing cytokine mRNAs such as TNF, IL-6, and IL-8 [PMID:39117638, PMID:39589932, PMID:39046234]. Genome-wide CLIP defined its in vivo AU-rich binding landscape, overlapping that of ELAVL1, and confirmed it as a direct decay factor for immune and cancer transcripts [PMID:24401661]. Through this activity ZFP36 represses a broad target set—cytokines and inflammasome components (IL-27, NLRP3, TNF), signaling and metabolic regulators (RGS2, NOX4, Eno2, SIK1, RNF128, CREBBP, Jag1), cell-cycle and oncogenic drivers (CDK6, E2F1, PRC1, BARX1, CEMIP), and ferroptosis modulators (Ythdc2, ATG16L1, VDR)—placing it at control points in inflammation resolution, vascular tone, angiogenesis, adipocyte homeostasis, and tumor suppression [PMID:39589932, PMID:38157296, PMID:36111167, PMID:37587140, PMID:39761791, PMID:40000392]. ZFP36 shuttles between nucleus and cytoplasm via a ZnF-region NLS and CRM1-dependent NES, partitions into stress granules through its tandem zinc fingers, and is itself controlled by rapid ubiquitin-independent proteasomal turnover driven by its disordered termini (blocked by phosphorylation) as well as FBXW7-directed degradation of an SFSGLPS degron [PMID:12054509, PMID:15652343, PMID:25246635, PMID:31679460]. Beyond mRNA decay, ZFP36 associates with RIG-I and promotes its K63-linked polyubiquitination to enhance antiviral IFN-β signaling [PMID:37565597].","teleology":[{"year":1991,"claim":"Establishing that ZFP36 belongs to a conserved family defined by tandem CCCH zinc fingers framed it as a putative nucleic-acid-binding protein rather than a featureless immediate-early product.","evidence":"cDNA cloning and cross-family sequence comparison identifying the YKTELC CCCH repeat shared with TIS11b/TIS11d","pmids":["1996120"],"confidence":"Medium","gaps":["Domain identity did not establish a ligand or biochemical activity","No metal coordination or RNA-binding data"]},{"year":1996,"claim":"Determining that each Cys3His repeat coordinates one zinc ion in tetrahedral geometry provided the structural basis for how these fingers fold and function.","evidence":"Co2+ spectroscopy and NMR on synthetic ZFP36 zinc-finger peptides","pmids":["8943007"],"confidence":"High","gaps":["Did not show what the folded finger binds","Used isolated peptides, not full-length protein"]},{"year":2003,"claim":"Defining the RNA target sequence and demonstrating selective high-affinity binding established ZFP36 as a sequence-specific AU-rich element reader.","evidence":"SELEX and RNA EMSA with recombinant protein (UUAUUUAUU consensus) plus quantitative fluorescence binding by a single zinc-loaded domain (UUUAUUU, ~5 µM, discriminating against non-canonical sequences)","pmids":["12324455","12705825"],"confidence":"High","gaps":["In vitro binding did not establish in vivo target repertoire","Did not connect binding to mRNA fate"]},{"year":2006,"claim":"Showing iron can replace zinc in the two-domain protein while retaining nanomolar, sequence-selective RNA binding addressed which metal cofactor supports activity.","evidence":"Metal-ion titration and fluorescence RNA-binding assays with Fe2+/Fe3+-reconstituted recombinant TTP-2D","pmids":["17087518"],"confidence":"Medium","gaps":["Physiological relevance of iron occupancy in cells not demonstrated","Single lab in vitro reconstitution"]},{"year":2004,"claim":"Mapping nucleocytoplasmic shuttling signals and stress-granule recruitment to the zinc-finger region established where ZFP36 acts and how its localization is controlled.","evidence":"GFP fusions, deletion/point mutagenesis, leptomycin B (CRM1 dependence), and heat-shock co-localization with stress-granule markers; later identification of a cryptic Transportin PY-NLS overlapping ZnF2","pmids":["12054509","15652343","23951221"],"confidence":"Medium","gaps":["Functional consequence of nuclear pool not defined","Stress-granule role in target regulation not quantified"]},{"year":2014,"claim":"Genome-wide CLIP coupled to knockout mRNA half-life analysis transformed ZFP36 from a TNF-ARE binder into a defined global decay factor with a measurable in vivo target set.","evidence":"HITS-CLIP in human cells and ZFP36-KO mouse mRNA stability analysis, with comparison to ELAVL1 binding overlap","pmids":["24401661"],"confidence":"High","gaps":["Did not resolve the deadenylase/decay machinery recruited","Binding-decay coupling varied by transcript"]},{"year":2014,"claim":"Defining ZFP36 turnover as ubiquitin-independent proteasomal degradation gated by phosphorylation, alongside FBXW7-directed degron recognition, explained how the repressor's own abundance is dynamically controlled.","evidence":"In vitro and cell-based proteasome/degradation assays with phosphorylation manipulation; FBXW7 SFSGLPS degron identification with in vivo overexpression","pmids":["25246635","31679460"],"confidence":"Medium","gaps":["Relative contribution of ubiquitin-independent vs FBXW7 routes in vivo unclear","Kinases setting the degradation-protective phosphostate not fully mapped"]},{"year":2018,"claim":"Linking ZFP36 binding to both transcript abundance and translation in primary T cells with an in vivo infection phenotype established it as a brake on immune activation kinetics, not solely a decay enzyme.","evidence":"HITS-CLIP plus ribosome profiling and conditional Zfp36 knockout in acute viral infection in mice","pmids":["29848443"],"confidence":"High","gaps":["Mechanism of translational (vs decay) repression not separated","Coding-sequence ARE function not biochemically defined"]},{"year":2024,"claim":"Reconstructing the upstream signaling that drives and inactivates ZFP36 connected its expression and activity to defined kinase and transcription-factor circuits across inflammation and necroptosis.","evidence":"ISGF3/IFNβ and MKK3-p38-MK2 manipulation with cytokine mRNA stability readouts; dsRNA/p38-MK2 phosphorylation linked to ARE-mRNA stabilization and reversed pharmacologically","pmids":["39117638","39046234","26546680"],"confidence":"Medium","gaps":["Phosphosite-resolved mechanism of activity loss not structurally defined here","Feedback via DUSP1 quantified only in select cell types"]},{"year":2025,"claim":"A series of tissue-specific knockout and target-decay studies established ZFP36 as a physiological regulator of vascular tone, angiogenesis, adipocyte homeostasis, and tumor suppression through distinct 3'-UTR targets.","evidence":"Cell-type-specific Zfp36 knockouts with genetic/pharmacological rescue defining RGS2 (VSMC/hypertension), Jag1 (endothelial angiogenesis), RNF128 (adipose obesity), and oncogenic targets CDK6/E2F1/BARX1/PRC1/CEMIP/Ythdc2","pmids":["39589932","38157296","39761791","36111167"],"confidence":"High","gaps":["Target hierarchy within each tissue not fully resolved","Many oncogenic targets rest on single-lab RIP/luciferase evidence"]},{"year":2023,"claim":"Identifying a decay-independent role in which ZFP36 promotes K63-linked polyubiquitination of RIG-I revealed an unexpected positive function in antiviral signaling.","evidence":"Co-IP, RIG-I ubiquitination-site mutagenesis, and ZFP36 zinc-finger mutant (C118S/C162S) in SeV infection","pmids":["37565597"],"confidence":"Medium","gaps":["Whether ZFP36 acts as or recruits the relevant E3 is not defined","Single Co-IP-based mechanism without reconstitution"]},{"year":null,"claim":"How ZFP36 mechanistically recruits the deadenylation/decay machinery and how phosphorylation, localization, and the decay-independent ubiquitin-promoting activity are integrated on a single transcript remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of ZFP36 on the decay machinery in the corpus","Mechanism by which ZFP36 promotes RIG-I ubiquitination undefined","Integration of nuclear pool and stress-granule partitioning with target decay unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[8,10,14,18]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[14,18,19,23]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[9,11]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[9,13]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[14,18,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[18,28,29,37]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[28,29,16]}],"complexes":[],"partners":["RIG-I","FBXW7","ELAVL1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P26651","full_name":"mRNA decay activator protein ZFP36","aliases":["G0/G1 switch regulatory protein 24","Growth factor-inducible nuclear protein NUP475","Tristetraprolin","Zinc finger protein 36","Zfp-36"],"length_aa":326,"mass_kda":34.0,"function":"Zinc-finger RNA-binding protein that destabilizes several cytoplasmic AU-rich element (ARE)-containing mRNA transcripts by promoting their poly(A) tail removal or deadenylation, and hence provide a mechanism for attenuating protein synthesis (PubMed:10330172, PubMed:10751406, PubMed:11279239, PubMed:12115244, PubMed:12748283, PubMed:15187101, PubMed:15634918, PubMed:16702957, PubMed:17030620, PubMed:20221403, PubMed:20702587, PubMed:21775632, PubMed:23644599, PubMed:25815583, PubMed:27193233, PubMed:31439631, PubMed:9703499). Acts as an 3'-untranslated region (UTR) ARE mRNA-binding adapter protein to communicate signaling events to the mRNA decay machinery (PubMed:15687258, PubMed:23644599). Recruits deadenylase CNOT7 (and probably the CCR4-NOT complex) via association with CNOT1, and hence promotes ARE-mediated mRNA deadenylation (PubMed:23644599). Functions also by recruiting components of the cytoplasmic RNA decay machinery to the bound ARE-containing mRNAs (PubMed:11719186, PubMed:12748283, PubMed:15687258, PubMed:16364915). Self regulates by destabilizing its own mRNA (PubMed:15187101). Binds to 3'-UTR ARE of numerous mRNAs and of its own mRNA (PubMed:10330172, PubMed:10751406, PubMed:12115244, PubMed:15187101, PubMed:15634918, PubMed:16702957, PubMed:17030620, PubMed:19188452, PubMed:20221403, PubMed:20702587, PubMed:21775632, PubMed:25815583). Plays a role in anti-inflammatory responses; suppresses tumor necrosis factor (TNF)-alpha production by stimulating ARE-mediated TNF mRNA decay and several other inflammatory ARE-containing mRNAs in interferon (IFN)- and/or lipopolysaccharide (LPS)-induced macrophages (By similarity). Also plays a role in the regulation of dendritic cell maturation at the post-transcriptional level, and hence operates as part of a negative feedback loop to limit the inflammatory response (PubMed:18367721). Promotes ARE-mediated mRNA decay of hypoxia-inducible factor HIF1A mRNA during the response of endothelial cells to hypoxia (PubMed:21775632). Positively regulates early adipogenesis of preadipocytes by promoting ARE-mediated mRNA decay of immediate early genes (IEGs) (By similarity). Negatively regulates hematopoietic/erythroid cell differentiation by promoting ARE-mediated mRNA decay of the transcription factor STAT5B mRNA (PubMed:20702587). Plays a role in maintaining skeletal muscle satellite cell quiescence by promoting ARE-mediated mRNA decay of the myogenic determination factor MYOD1 mRNA (By similarity). Associates also with and regulates the expression of non-ARE-containing target mRNAs at the post-transcriptional level, such as MHC class I mRNAs (PubMed:18367721). Participates in association with argonaute RISC catalytic components in the ARE-mediated mRNA decay mechanism; assists microRNA (miRNA) targeting ARE-containing mRNAs (PubMed:15766526). May also play a role in the regulation of cytoplasmic mRNA decapping; enhances decapping of ARE-containing RNAs, in vitro (PubMed:16364915). Involved in the delivery of target ARE-mRNAs to processing bodies (PBs) (PubMed:17369404). In addition to its cytosolic mRNA-decay function, affects nuclear pre-mRNA processing (By similarity). Negatively regulates nuclear poly(A)-binding protein PABPN1-stimulated polyadenylation activity on ARE-containing pre-mRNA during LPS-stimulated macrophages (By similarity). Also involved in the regulation of stress granule (SG) and P-body (PB) formation and fusion (By similarity). Plays a role in the regulation of keratinocyte proliferation, differentiation and apoptosis (PubMed:27182009). Plays a role as a tumor suppressor by inhibiting cell proliferation in breast cancer cells (PubMed:26926077) (Microbial infection) Negatively regulates HTLV-1 TAX-dependent transactivation of viral long terminal repeat (LTR) promoter","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P26651/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZFP36","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ZFP36","total_profiled":1310},"omim":[{"mim_id":"615001","title":"ZINC FINGER CCCH DOMAIN-CONTAINING PROTEIN 12C; ZC3H12C","url":"https://www.omim.org/entry/615001"},{"mim_id":"612053","title":"ZINC FINGER PROTEIN 36-LIKE 2; ZFP36L2","url":"https://www.omim.org/entry/612053"},{"mim_id":"611296","title":"ANNEXIN A2 RECEPTOR; ANXA2R","url":"https://www.omim.org/entry/611296"},{"mim_id":"611106","title":"ZINC FINGER CCCH DOMAIN-CONTAINING PROTEIN 12D; ZC3H12D","url":"https://www.omim.org/entry/611106"},{"mim_id":"610562","title":"ZINC FINGER CCCH DOMAIN-CONTAINING PROTEIN 12A; ZC3H12A","url":"https://www.omim.org/entry/610562"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Intermediate filaments","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ZFP36"},"hgnc":{"alias_symbol":["TIS11","G0S24","TTP","NUP475"],"prev_symbol":[]},"alphafold":{"accession":"P26651","domains":[{"cath_id":"-","chopping":"102-138","consensus_level":"medium","plddt":93.2895,"start":102,"end":138},{"cath_id":"-","chopping":"139-175","consensus_level":"medium","plddt":84.9849,"start":139,"end":175}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P26651","model_url":"https://alphafold.ebi.ac.uk/files/AF-P26651-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P26651-F1-predicted_aligned_error_v6.png","plddt_mean":62.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZFP36","jax_strain_url":"https://www.jax.org/strain/search?query=ZFP36"},"sequence":{"accession":"P26651","fasta_url":"https://rest.uniprot.org/uniprotkb/P26651.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P26651/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P26651"}},"corpus_meta":[{"pmid":"31679460","id":"PMC_31679460","title":"RNA-binding 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abscisic acid-induced antioxidant defence and oxidative stress tolerance in rice.","date":"2014","source":"Journal of experimental botany","url":"https://pubmed.ncbi.nlm.nih.gov/25071223","citation_count":150,"is_preprint":false},{"pmid":"2915901","id":"PMC_2915901","title":"Nucleotide sequence of a cDNA encoding TIS11, a message induced in Swiss 3T3 cells by the tumor promoter tetradecanoyl phorbol acetate.","date":"1989","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/2915901","citation_count":138,"is_preprint":false},{"pmid":"24401661","id":"PMC_24401661","title":"Global target mRNA specification and regulation by the RNA-binding protein ZFP36.","date":"2014","source":"Genome biology","url":"https://pubmed.ncbi.nlm.nih.gov/24401661","citation_count":135,"is_preprint":false},{"pmid":"25043949","id":"PMC_25043949","title":"ZFP36-FOSB fusion defines a subset of epithelioid hemangioma with atypical features.","date":"2014","source":"Genes, chromosomes & 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/23559629","citation_count":57,"is_preprint":false},{"pmid":"29106954","id":"PMC_29106954","title":"The ascorbate peroxidase APX1 is a direct target of a zinc finger transcription factor ZFP36 and a late embryogenesis abundant protein OsLEA5 interacts with ZFP36 to co-regulate OsAPX1 in seed germination in rice.","date":"2017","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/29106954","citation_count":55,"is_preprint":false},{"pmid":"12705825","id":"PMC_12705825","title":"Selective RNA binding by a single CCCH zinc-binding domain from Nup475 (Tristetraprolin).","date":"2003","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12705825","citation_count":53,"is_preprint":false},{"pmid":"22968342","id":"PMC_22968342","title":"Multiple functions of tristetraprolin/TIS11 RNA-binding proteins in the regulation of mRNA biogenesis and degradation.","date":"2012","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/22968342","citation_count":51,"is_preprint":false},{"pmid":"17546847","id":"PMC_17546847","title":"ZFP36: a promising candidate gene for obesity-related metabolic complications identified by converging genomics.","date":"2007","source":"Obesity surgery","url":"https://pubmed.ncbi.nlm.nih.gov/17546847","citation_count":51,"is_preprint":false},{"pmid":"1861870","id":"PMC_1861870","title":"A corrected sequence for the predicted protein from the mitogen-inducible TIS11 primary response gene.","date":"1991","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/1861870","citation_count":49,"is_preprint":false},{"pmid":"16546352","id":"PMC_16546352","title":"Genetic variations in ZFP36 and their possible relationship to autoimmune diseases.","date":"2006","source":"Journal of autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/16546352","citation_count":46,"is_preprint":false},{"pmid":"27463018","id":"PMC_27463018","title":"Loss of ZFP36 expression in colorectal cancer correlates to wnt/ ß-catenin activity and enhances epithelial-to-mesenchymal transition through upregulation of ZEB1, SOX9 and MACC1.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27463018","citation_count":45,"is_preprint":false},{"pmid":"9417109","id":"PMC_9417109","title":"Characteristics of the intron involvement in the mitogen-induced expression of Zfp-36.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9417109","citation_count":43,"is_preprint":false},{"pmid":"12054509","id":"PMC_12054509","title":"Identification of nuclear import and export signals within the structure of the zinc finger protein TIS11.","date":"2002","source":"Biochemical and biophysical research 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regulators of the TIS11/tristetraprolin family is induced by an intrinsically unstructured region independently of ubiquitination.","date":"2014","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/25246635","citation_count":28,"is_preprint":false},{"pmid":"22544323","id":"PMC_22544323","title":"ZFP36 expression impairs glioblastoma cell lines viability and invasiveness by targeting multiple signal transduction pathways.","date":"2012","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/22544323","citation_count":27,"is_preprint":false},{"pmid":"26546680","id":"PMC_26546680","title":"Negative Feed-forward Control of Tumor Necrosis Factor (TNF) by Tristetraprolin (ZFP36) Is Limited by the Mitogen-activated Protein Kinase Phosphatase, Dual-specificity Phosphatase 1 (DUSP1): IMPLICATIONS FOR REGULATION BY GLUCOCORTICOIDS.","date":"2015","source":"The Journal of biological 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Science. 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J-Protein OsDjC46 Interacts with ZFP36 to Participate in ABA-Mediated Antioxidant Defense in Rice.","date":"2022","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/35204090","citation_count":5,"is_preprint":false},{"pmid":"37744530","id":"PMC_37744530","title":"MiR-934 Exacerbates Malignancy of Gastric Cancer Cells by Targeting ZFP36.","date":"2023","source":"Iranian journal of public health","url":"https://pubmed.ncbi.nlm.nih.gov/37744530","citation_count":5,"is_preprint":false},{"pmid":"36524461","id":"PMC_36524461","title":"FAM3D inhibits gluconeogenesis in high glucose environment via DUSP1/ZFP36/SIK1 axis.","date":"2022","source":"The Kaohsiung journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36524461","citation_count":5,"is_preprint":false},{"pmid":"38337546","id":"PMC_38337546","title":"Endotyping Eosinophilic Inflammation in COPD with ELAVL1, ZfP36 and HNRNPD mRNA Genes.","date":"2024","source":"Journal of clinical 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transiently induced in Swiss 3T3 cells by the tumor promoter TPA; cDNA sequence and deduced amino acid sequence were determined.\",\n      \"method\": \"cDNA cloning and sequencing\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single descriptive cDNA cloning study, no functional mechanistic follow-up in this paper\",\n      \"pmids\": [\"2915901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"TIS11/ZFP36 protein contains two tandemly repeated CCCH-type Cys3His zinc-finger motifs (YKTELC repeat) that are highly conserved across a gene family including TIS11b and TIS11d.\",\n      \"method\": \"cDNA cloning, sequence comparison\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — conserved domain identified across multiple family members and replicated by multiple labs\",\n      \"pmids\": [\"1996120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"IL-6 signal transduction in B-cell hybridoma activates TIS11 gene transcription through a novel protein kinase cascade requiring tyrosine kinase activity and an H7-sensitive kinase, independently of cycloheximide-sensitive protein synthesis.\",\n      \"method\": \"Pharmacological inhibition (cycloheximide, H7), tyrosine phosphorylation assays, primary response gene induction\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological tools used, tyrosine phosphorylation of p160 measured, pathway characterized in single lab\",\n      \"pmids\": [\"1705005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The Zfp-36 promoter requires 77 bp 5' of the transcription start site for full serum inducibility; cis-acting elements for EGR-1, AP2, Sp1, and a novel TPE1 palindrome each contribute to serum-induced transcription.\",\n      \"method\": \"Promoter deletion analysis, gel mobility shift assay (EMSA), reporter gene assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple deletion constructs, EMSA, and heterologous promoter assays in single lab\",\n      \"pmids\": [\"7559666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The Nup475/ZFP36 Cys3His repeats each bind one equivalent of zinc (or cobalt) with tetrahedral coordination; NMR structural data indicate the zinc ion is coordinated by conserved cysteines and histidine, with the conserved YKTEL motif forming a parallel sheet-like structure.\",\n      \"method\": \"Metal-binding titration (Co2+ spectroscopy), NMR spectroscopy, synthetic peptides\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with metal binding quantification, in vitro biochemical characterization, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"8943007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Full serum-induced expression of Zfp-36 requires both promoter elements and an intronic element; a Sp1-binding sequence (bp 618-626) within the intron contributes ~70% of serum-induced expression.\",\n      \"method\": \"Intron replacement/deletion analysis, site-directed mutagenesis of Sp1 binding site, reporter gene assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of specific Sp1 site combined with multiple deletion constructs, single lab\",\n      \"pmids\": [\"9417109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"TIS11/ZFP36 functions as a positive transcriptional activator when fused to a GAL4 DNA-binding domain; the N-terminal 101 amino acid region contains the major transactivation domain, and PMA negatively regulates this activity via protein kinase C/MAP kinase cascade.\",\n      \"method\": \"GAL4 fusion transactivation assay, deletion mutagenesis, pharmacological inhibition (calphostin C, PD98059)\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional transactivation assay with domain mapping and signaling inhibitors, single lab\",\n      \"pmids\": [\"10913371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Continuous expression of TTP/ZFP36 at physiological levels causes apoptotic cell death dependent on the zinc finger domains; TTP but not TIS11b or TIS11d sensitizes cells to TNF-alpha-induced apoptosis.\",\n      \"method\": \"Stable transfection, apoptosis assays, zinc finger domain mutants\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-dependence established by mutagenesis, apoptosis phenotype measured by multiple criteria, single lab\",\n      \"pmids\": [\"10763822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Recombinant Nup475/ZFP36 protein binds the TNF AU-rich element via SELEX-determined optimal sequence UUAUUUAUU; zinc excess inhibits binding; the protein also shows weaker binding to poly(A) sequences.\",\n      \"method\": \"RNA gel shift (EMSA), RNA SELEX, site-directed mutagenesis of TNF ARE, recombinant protein from E. coli\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with recombinant protein, SELEX to define binding consensus, mutagenesis validation, multiple orthogonal methods\",\n      \"pmids\": [\"12324455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TIS11/ZFP36 contains a functional nuclear localization signal (NLS) in the tandem zinc-finger region (requiring Arg127 and Arg131) and a CRM1-dependent Leu-rich nuclear export signal (NES) in the N-terminal region, enabling nucleocytoplasmic shuttling.\",\n      \"method\": \"GFP fusion constructs, leptomycin B treatment, deletion analysis, site-directed mutagenesis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — localization mapped by deletion and mutagenesis with pharmacological validation (leptomycin B), single lab\",\n      \"pmids\": [\"12054509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"A single CCCH zinc-binding domain of Nup475/ZFP36 is sufficient for selective RNA binding; the zinc(II)-complexed first domain binds UUUAUUU with ~5 µM affinity and discriminates against sequences lacking the central A or flanking U residues.\",\n      \"method\": \"Fluorescence-based binding assay with synthetic peptide, metal ion binding characterization\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with defined peptide, quantitative binding assay, sequence selectivity probed, single rigorous study\",\n      \"pmids\": [\"12705825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TIS11/ZFP36 is recruited to stress granules (SGs) upon heat shock; recruitment requires the tandem zinc-finger domain, with specific residues Tyr105/Tyr113, Gly109/Gly114, Phe119 and zinc-chelating Cys residues in both fingers being critical.\",\n      \"method\": \"GFP fusion constructs, deletion analysis, site-directed mutagenesis, heat shock treatment, co-localization with SG markers\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping with mutagenesis and co-localization, single lab\",\n      \"pmids\": [\"15652343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Iron (Fe2+ and Fe3+) can substitute for zinc in the TTP-2D (ZFP36 two-domain) protein; iron-substituted TTP-2D binds the canonical UUUAUUUAUUU RNA sequence with nanomolar affinity and retains selectivity for adenine-containing sequences.\",\n      \"method\": \"Metal ion titration, fluorescence-based RNA binding assay, Fe2+/Fe3+ reconstitution of recombinant protein\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution with quantitative binding, but single lab study\",\n      \"pmids\": [\"17087518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A cryptic Transportin-dependent PY-NLS overlapping the second zinc finger (ZnF2) is conserved across TIS11/ZFP36 family; mutations disrupting ZnF2 zinc coordination unmask this NLS and promote nuclear import; nuclear export in Drosophila dTIS11 is CRM1-dependent via a divergent NES.\",\n      \"method\": \"Deletion mutagenesis, zinc finger mutation, nuclear import/export assays, leptomycin B treatment, Drosophila and mammalian cell systems\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of zinc coordination residues unmasks NLS, validated in two species, single lab\",\n      \"pmids\": [\"23951221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ZFP36 globally binds AU-rich sequences in vivo; CLIP-seq defined in vivo binding preferences in human embryonic kidney cells; ZFP36 degrades target transcripts through specific AU-rich sequences representing a subset of U-rich sequences; targets include immune function and cancer transcripts; ZFP36 and ELAVL1 share overlapping binding sites in 1,313 genes but with differential relative preferences.\",\n      \"method\": \"HITS-CLIP (cross-linking and immunoprecipitation), mRNA half-life analysis in ZFP36 knockout mouse cells, partial correlation analysis\",\n      \"journal\": \"Genome biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide CLIP with orthogonal validation using ZFP36 KO mRNA half-lives, quantitative binding-activity correlation\",\n      \"pmids\": [\"24401661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Rapid proteasomal degradation of ZFP36/TTP is ubiquitin-independent and driven by intrinsically disordered N- and C-terminal domains; phosphorylation inhibits proteasomal degradation of TTP in vitro.\",\n      \"method\": \"Proteasome inhibitor assays, ubiquitin-independent degradation assays, in vitro degradation with phosphorylation manipulation, Drosophila dTIS11 and mammalian TTP\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitin independence demonstrated directly, in vitro degradation assay, conserved mechanism shown in two species, single lab\",\n      \"pmids\": [\"25246635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ZFP36 exerts negative feed-forward control of TNF mRNA expression via ARE-mediated mRNA degradation; DUSP1-dependent negative feedback on MAPKs reduces ZFP36 expression, limiting this feed-forward control; dexamethasone represses TNF independently of ZFP36.\",\n      \"method\": \"siRNA silencing of DUSP1 and ZFP36, DUSP1 overexpression, MAPK inhibition, TNF mRNA stability assays in primary human bronchial epithelial cells and A549 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via dual knockdown with mRNA stability readout, primary cells used, single lab\",\n      \"pmids\": [\"26546680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ZFP36 promotes assembly of the Ripoptosome death complex by depleting XIAP and cIAP2 ubiquitin ligases (via destabilizing their mRNAs), leading to RIP1 stabilization, association of RIP1 with caspase-8 and FADD, and RIP1-dependent cell death/necroptosis.\",\n      \"method\": \"Co-immunoprecipitation, size exclusion chromatography, shRNA lentivectors, cell death assays in glioma neural stem cells\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirmed complex, shRNA depletion with specific phenotypic rescue, single lab\",\n      \"pmids\": [\"25939870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ZFP36 represses mRNA target abundance and translation in T cells, including through novel AU-rich sites in coding sequences; ZFP36 regulates early T-cell activation kinetics by attenuating activation marker expression, limiting expansion, and promoting apoptosis; loss of ZFP36 in vivo accelerates T cell responses to acute viral infection.\",\n      \"method\": \"HITS-CLIP in mouse T cells, ribosome profiling, transcriptome analysis, in vivo viral infection model with ZFP36 conditional knockout\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — HITS-CLIP target identification combined with ribosome profiling and in vivo KO phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"29848443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ZFP36/TTP promotes ATG16L1 mRNA decay by binding AU-rich elements in its 3'-UTR; internal mutation of the ARE region abrogates ZFP36-mediated ATG16L1 mRNA instability; FBXW7 ubiquitin ligase degrades ZFP36 protein by recognizing a SFSGLPS motif, linking ZFP36 to ferroptosis resistance through autophagy inhibition.\",\n      \"method\": \"ARE mutagenesis, mRNA decay assays, plasmid overexpression, FBXW7 recognition motif identification, in vivo HSC-specific Zfp36 overexpression mouse model\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ARE mutagenesis abrogates binding, FBXW7 motif identified, in vivo validation, single lab\",\n      \"pmids\": [\"31679460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZFP36 directly binds AU-rich elements in the NOX4 mRNA 3'-UTR to inhibit NOX4 expression, thereby suppressing NOX4-mediated DRP1 activation and mitochondrial fragmentation in neurons under OGD/R conditions.\",\n      \"method\": \"RNA immunoprecipitation (RIP), 3'-UTR binding assay, siRNA knockdown, ZFP36 overexpression, NOX4 inhibitor experiments\",\n      \"journal\": \"Brain research bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP confirmed direct mRNA binding, epistasis with NOX4 inhibitor, single lab\",\n      \"pmids\": [\"34896479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZFP36 directly binds ARE sequences in the CREBBP mRNA 3'-UTR to promote its degradation, as confirmed by pull-down and RIP assays; ZFP36 deficiency upregulates CREBBP and enhances I/R-induced lung injury via CREBBP/p53/p21/Bax pathway.\",\n      \"method\": \"RIP assay, pull-down assay, in silico prediction, Western blot, in vivo ZFP36 knockdown mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP and pull-down confirm direct mRNA interaction, pathway epistasis, single lab\",\n      \"pmids\": [\"34238924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ZFP36 binds AU-rich elements in the PRC1 mRNA 3'-UTR to downregulate PRC1 expression, suppressing HCC tumor growth and increasing 5-Fu sensitivity, as demonstrated by luciferase reporter and RIP assays.\",\n      \"method\": \"Luciferase reporter assay, RIP assay, ZFP36 overexpression, xenograft mouse model\",\n      \"journal\": \"Frontiers in molecular biosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter and RIP confirm direct 3'UTR binding, in vivo validation, single lab\",\n      \"pmids\": [\"32766276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ZFP36 directly promotes mRNA decay of Enolase 2 (Eno2), altering Eno2 protein expression and enzymatic activity; ZFP36/L1/L2 family proteins are key drivers of metabolic regulation downstream of acute growth factor signaling, with ZFP36 binding catalogued against metabolic enzyme and nutrient transporter mRNAs.\",\n      \"method\": \"CLIP-seq, mRNA stability assays, Eno2 enzymatic activity measurement, VEGF-stimulated retinal angiogenesis model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CLIP-seq with functional mRNA decay validation and enzymatic activity readout, in vivo tissue evidence, single lab\",\n      \"pmids\": [\"37086408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Jag1 mRNA is a direct target of ZFP36-mediated decay; VEGF induces ZFP36 in endothelial cells creating a feedforward loop that suppresses Jag1 to enable adequate Notch signaling; endothelial Zfp36 knockout mice show mispatterned JAG1 and increased tip cell numbers, rescued by Jag1 haploinsufficiency.\",\n      \"method\": \"ZFP36 CLIP, mRNA decay assays, endothelial-specific Zfp36 knockout mice, retinal vascular plexus imaging, Jag1 haploinsufficiency rescue\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct CLIP evidence for Jag1 binding, in vivo KO with specific phenotype and genetic rescue by Jag1 haploinsufficiency\",\n      \"pmids\": [\"38157296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ZFP36 associates with RIG-I and promotes K63-linked polyubiquitination of RIG-I at K154/K164/K172, facilitating RIG-I activation and IFN-β production during viral infection; a ZFP36 zinc-finger mutant (C118S/C162S) fails to promote RIG-I ubiquitination.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis of RIG-I ubiquitination sites, ZFP36 zinc-finger domain mutagenesis, SeV infection model\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirmed association, ubiquitination site mutagenesis, zinc-finger mutant abolishes activity, single lab\",\n      \"pmids\": [\"37565597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZFP36 binds the 3'-UTR of RGS2 mRNA and promotes its degradation, thereby regulating GPCR-mediated intracellular calcium increases in vascular smooth muscle cells; VSMC-specific ZFP36 deletion reduces vessel contractility, blood pressure, and attenuates AngII-induced hypertension in mice; AngII activates ZFP36 transcription via PARP1.\",\n      \"method\": \"mRNA stability assays, VSMC-specific ZFP36 knockout mice, blood pressure measurement, calcium signaling assays, AAV-mediated knockdown in spontaneously hypertensive rats, PARP1 inhibitor experiments\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific KO with defined hemodynamic phenotype, in vivo rat AAV validation, mechanistic pathway through RGS2 mRNA target, multiple orthogonal methods\",\n      \"pmids\": [\"39589932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZFP36 binds to the 3'-UTR of CREBBP/NLRP3 mRNAs to promote their decay; ZFP36 directly targets NLRP3 mRNA for degradation in fibroblasts, reducing inflammasome activation; ZFP36 gene undergoes promoter methylation in psoriatic fibroblasts reducing its expression.\",\n      \"method\": \"RIP assay, mRNA stability assay, ZFP36 restoration experiments, promoter methylation analysis, NLRP3 inflammasome activity assay\",\n      \"journal\": \"Frontiers in medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP confirms direct binding, functional rescue experiment, single lab\",\n      \"pmids\": [\"33585499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IFNβ-induced ISGF3 transcription factor complex drives ZFP36 expression during necroptosis, and ZFP36 then post-transcriptionally degrades mRNAs of inflammatory cytokines (IL-6, IL-8, DUSP1, PTGS2, TNFAIP3) through ARE recognition; the MKK3-p38-MK2 axis regulates ZFP36 expression upstream.\",\n      \"method\": \"Transcriptomics, ISGF3 and MK2/MKK3 overexpression/knockdown, mRNA stability assays, ZFP36 knockdown validation, coronavirus infection models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via multiple kinase KD/OE with mRNA stability readout, multiple cytokine targets validated, single lab\",\n      \"pmids\": [\"39117638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"dsRNA/poly(I:C) activates p38 MAPK-MK2 signaling to phosphorylate ZFP36/TTP, inactivating it and stabilizing AU-rich cytokine mRNAs (TNF, IL-6, COX-2, IL-8); hydroxychloroquine reduces ZFP36 phosphorylation by suppressing p38/MK2, thereby reducing phosphorylated TTP abundance and destabilizing these inflammatory mRNAs.\",\n      \"method\": \"p38/MK2 phosphorylation assays, mRNA stability assays, hydroxychloroquine treatment, THP-1 and primary blood monocytes\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphorylation state linked to mRNA stability outcome with pharmacological manipulation, single lab\",\n      \"pmids\": [\"39046234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Adipose ZFP36 represses RNF128 mRNA stability and translation; loss of ZFP36 in adipose tissue increases RNF128, which negatively regulates Sirt1, promoting adipocyte hypertrophy and obesity; adipose-specific ZFP36 knockout mice show decreased PLIN1, ATGL, and HSL expression and increased susceptibility to diet-induced obesity.\",\n      \"method\": \"Adipose-specific ZFP36 knockout mice, gene array assay, mRNA stability assay, in vivo metabolic phenotyping\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific KO with defined metabolic phenotype, pathway through RNF128/Sirt1 identified, single lab\",\n      \"pmids\": [\"39761791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZFP36 binds to the 3'-UTR of Ythdc2 mRNA to promote its degradation; loss of this suppression allows Ythdc2 to degrade SLC7A11 mRNA, reducing glutathione and promoting ferroptosis and cardiac hypertrophy; Ythdc2 overexpression reverses ZFP36-mediated protection.\",\n      \"method\": \"3'-UTR binding assays, Ythdc2/SLC7A11 mRNA stability measurements, ZFP36 overexpression/knockdown in cardiomyocytes, transverse aortic constriction mouse model, epistasis rescue experiments\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'UTR binding established, pathway epistasis via Ythdc2 rescue, in vivo model, single lab\",\n      \"pmids\": [\"40000392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Smooth muscle ZFP36 binds CEMIP mRNA and promotes its degradation, reducing CEMIP protein and limiting VSMC proliferation and migration; smooth muscle-specific Zfp36 knockout accelerates neointimal hyperplasia; PDGF-BB downregulates ZFP36 in VSMCs via KLF4 binding to the Zfp36 promoter.\",\n      \"method\": \"Smooth muscle-specific ZFP36 knockout mice, carotid artery ligation model, mRNA stability assay for CEMIP, Cemip knockdown rescue, KLF4 promoter binding analysis\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific KO with in vivo vascular phenotype, CEMIP mRNA target validated by rescue, single lab\",\n      \"pmids\": [\"39890944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZFP36 directly binds AU-rich elements in the VDR mRNA 3'-UTR to promote its degradation; mutation of key amino acids in ZFP36 abolishes this mRNA binding; ZFP36-mediated VDR mRNA decay promotes cell death under inflammatory conditions.\",\n      \"method\": \"RNA affinity chromatography, ZFP36 key amino acid mutagenesis, mRNA decay assay, luciferase reporter (3'UTR ARE assay), Co-immunoprecipitation\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA affinity chromatography and mutagenesis confirm direct binding, multiple methods, single lab\",\n      \"pmids\": [\"34380509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ZFP36 binds the 3'-UTR of BARX1 mRNA and mediates its destabilization; loss of ZFP36 leads to BARX1 upregulation, which transactivates oncogenes promoting NSCLC proliferation, migration, and invasion.\",\n      \"method\": \"ZFP36-BARX1 mRNA 3'UTR binding assays, mRNA stability assays, ZFP36/BARX1 knockdown/overexpression, NSCLC xenograft mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'UTR binding and mRNA stability, in vivo tumor model, single lab\",\n      \"pmids\": [\"37587140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZFP36 promotes E2F1 mRNA degradation by binding AREs in the E2F1 3'-UTR; loss of this suppression allows E2F1 to transactivate ATF4, collectively promoting malignant progression and suppressing ferroptosis in osteosarcoma.\",\n      \"method\": \"RIP assay, 3'-UTR ARE binding assay, E2F1/ATF4 promoter transactivation assays, ZFP36/E2F1/ATF4 overexpression/knockdown, in vivo xenograft\",\n      \"journal\": \"Journal of pharmaceutical analysis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP confirms ARE binding, transcriptional epistasis through E2F1/ATF4, in vivo validation, single lab\",\n      \"pmids\": [\"41050116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZFP36 binds to SIK1 mRNA (confirmed by RIP) to promote its degradation; in high-glucose conditions, upregulated ZFP36 suppresses SIK1, promoting gluconeogenesis; DUSP1 overexpression downregulates ZFP36, relieving SIK1 suppression and inhibiting gluconeogenesis.\",\n      \"method\": \"RNA binding protein immunoprecipitation (RIP), ZFP36 overexpression/knockdown, DUSP1 overexpression, gluconeogenesis assays\",\n      \"journal\": \"The Kaohsiung journal of medical sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single RIP assay, no mutagenesis of binding sites, single lab\",\n      \"pmids\": [\"36524461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Macrophage-expressed ZFP36 promotes degradation of IL-27 p28 mRNA (confirmed by siRNA-mediated ZFP36 silencing leading to impaired IL-27 mRNA degradation); macrophage-specific Zfp36 conditional knockout leads to increased IL-27 and CD8+ T cell hyperactivation, exacerbating renal allograft rejection.\",\n      \"method\": \"siRNA knockdown of Zfp36 in p21high macrophages, mRNA stability assay for IL-27, macrophage-specific Zfp36 conditional KO mouse model, kidney transplantation model, IL-27 neutralizing antibody rescue\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA-confirmed mRNA decay, in vivo cKO with antibody rescue epistasis, single lab\",\n      \"pmids\": [\"40234384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ZFP36 directly binds CDK6 mRNA ARE and reduces CDK6 expression; ZFP36-mediated CDK6 repression blocks cell cycle at G1 in prostate cancer cells, as confirmed by dual-luciferase and RIP assays.\",\n      \"method\": \"Dual-luciferase reporter assay, RIP, ZFP36 overexpression, cell cycle analysis, xenograft tumor model\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase and RIP confirm direct 3'UTR ARE binding, cell cycle phenotype measured, single lab\",\n      \"pmids\": [\"36111167\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZFP36 (TTP/NUP475/TIS11/G0S24) is an RNA-binding protein containing tandem CCCH zinc-finger domains that each coordinate one zinc ion and selectively bind the consensus sequence UUAUUUAUU (and related AU-rich elements) within the 3'-UTRs of target mRNAs; upon binding, ZFP36 promotes mRNA deadenylation and decay through the exosome, thereby post-transcriptionally suppressing a broad set of targets including cytokines (TNF, IL-6, IL-8), signaling mediators (RGS2, NOX4, CREBBP, ATG16L1, PRC1, CDK6, BARX1, Jag1, Eno2, Ythdc2), and others; ZFP36 expression is induced by mitogens, cytokines, growth factors (via EGR-1/Sp1/AP2 promoter elements and intronic Sp1 sites), and by IFNβ through ISGF3, and is activated by the p38-MK2 kinase cascade while being inactivated by MK2-mediated phosphorylation; ZFP36 protein undergoes ubiquitin-independent proteasomal degradation driven by its intrinsically disordered termini (inhibited by phosphorylation), and is also targeted for proteasomal degradation via FBXW7 recognition of a SFSGLPS degron; the protein shuttles between nucleus and cytoplasm via a ZnF-region NLS (CRM1-dependent NES), localizes to cytoplasmic stress granules through its zinc-finger domain, and additionally promotes K63-linked polyubiquitination of RIG-I to enhance antiviral innate immune signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ZFP36 (TTP/TIS11) is a CCCH tandem zinc-finger RNA-binding protein that acts as a master post-transcriptional repressor, binding AU-rich elements in target mRNA 3'-UTRs and coding sequences to drive their decay and translational silencing across immune, metabolic, vascular, and oncogenic programs [#14, #8, #18]. Each of its two Cys3His repeats coordinates a single zinc ion in tetrahedral geometry, and even one zinc-loaded domain confers selective binding to the UUAUUUAUU/UUUAUUU consensus, discriminating against sequences lacking the central adenine or flanking uridines [#4, #10, #8]; iron can substitute for zinc while preserving high-affinity, sequence-selective RNA binding [#12]. Originally identified as a primary response gene induced by tumor-promoter and serum stimulation via EGR-1/AP2/Sp1 promoter and intronic Sp1 elements [#0, #3, #5], ZFP36 is wired into stimulus-coupled signaling: it is transcriptionally activated by ISGF3 (IFN\\u03b2), AngII/PARP1, and other inputs, and its repressive activity is switched off by p38-MK2-mediated phosphorylation that stabilizes ARE-containing cytokine mRNAs such as TNF, IL-6, and IL-8 [#28, #26, #29]. Genome-wide CLIP defined its in vivo AU-rich binding landscape, overlapping that of ELAVL1, and confirmed it as a direct decay factor for immune and cancer transcripts [#14]. Through this activity ZFP36 represses a broad target set\\u2014cytokines and inflammasome components (IL-27, NLRP3, TNF), signaling and metabolic regulators (RGS2, NOX4, Eno2, SIK1, RNF128, CREBBP, Jag1), cell-cycle and oncogenic drivers (CDK6, E2F1, PRC1, BARX1, CEMIP), and ferroptosis modulators (Ythdc2, ATG16L1, VDR)\\u2014placing it at control points in inflammation resolution, vascular tone, angiogenesis, adipocyte homeostasis, and tumor suppression [#26, #24, #38, #34, #30, #31]. ZFP36 shuttles between nucleus and cytoplasm via a ZnF-region NLS and CRM1-dependent NES, partitions into stress granules through its tandem zinc fingers, and is itself controlled by rapid ubiquitin-independent proteasomal turnover driven by its disordered termini (blocked by phosphorylation) as well as FBXW7-directed degradation of an SFSGLPS degron [#9, #11, #15, #19]. Beyond mRNA decay, ZFP36 associates with RIG-I and promotes its K63-linked polyubiquitination to enhance antiviral IFN-\\u03b2 signaling [#25].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Establishing that ZFP36 belongs to a conserved family defined by tandem CCCH zinc fingers framed it as a putative nucleic-acid-binding protein rather than a featureless immediate-early product.\",\n      \"evidence\": \"cDNA cloning and cross-family sequence comparison identifying the YKTELC CCCH repeat shared with TIS11b/TIS11d\",\n      \"pmids\": [\"1996120\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Domain identity did not establish a ligand or biochemical activity\", \"No metal coordination or RNA-binding data\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Determining that each Cys3His repeat coordinates one zinc ion in tetrahedral geometry provided the structural basis for how these fingers fold and function.\",\n      \"evidence\": \"Co2+ spectroscopy and NMR on synthetic ZFP36 zinc-finger peptides\",\n      \"pmids\": [\"8943007\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not show what the folded finger binds\", \"Used isolated peptides, not full-length protein\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defining the RNA target sequence and demonstrating selective high-affinity binding established ZFP36 as a sequence-specific AU-rich element reader.\",\n      \"evidence\": \"SELEX and RNA EMSA with recombinant protein (UUAUUUAUU consensus) plus quantitative fluorescence binding by a single zinc-loaded domain (UUUAUUU, ~5 \\u00b5M, discriminating against non-canonical sequences)\",\n      \"pmids\": [\"12324455\", \"12705825\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro binding did not establish in vivo target repertoire\", \"Did not connect binding to mRNA fate\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showing iron can replace zinc in the two-domain protein while retaining nanomolar, sequence-selective RNA binding addressed which metal cofactor supports activity.\",\n      \"evidence\": \"Metal-ion titration and fluorescence RNA-binding assays with Fe2+/Fe3+-reconstituted recombinant TTP-2D\",\n      \"pmids\": [\"17087518\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance of iron occupancy in cells not demonstrated\", \"Single lab in vitro reconstitution\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Mapping nucleocytoplasmic shuttling signals and stress-granule recruitment to the zinc-finger region established where ZFP36 acts and how its localization is controlled.\",\n      \"evidence\": \"GFP fusions, deletion/point mutagenesis, leptomycin B (CRM1 dependence), and heat-shock co-localization with stress-granule markers; later identification of a cryptic Transportin PY-NLS overlapping ZnF2\",\n      \"pmids\": [\"12054509\", \"15652343\", \"23951221\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of nuclear pool not defined\", \"Stress-granule role in target regulation not quantified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Genome-wide CLIP coupled to knockout mRNA half-life analysis transformed ZFP36 from a TNF-ARE binder into a defined global decay factor with a measurable in vivo target set.\",\n      \"evidence\": \"HITS-CLIP in human cells and ZFP36-KO mouse mRNA stability analysis, with comparison to ELAVL1 binding overlap\",\n      \"pmids\": [\"24401661\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the deadenylase/decay machinery recruited\", \"Binding-decay coupling varied by transcript\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defining ZFP36 turnover as ubiquitin-independent proteasomal degradation gated by phosphorylation, alongside FBXW7-directed degron recognition, explained how the repressor's own abundance is dynamically controlled.\",\n      \"evidence\": \"In vitro and cell-based proteasome/degradation assays with phosphorylation manipulation; FBXW7 SFSGLPS degron identification with in vivo overexpression\",\n      \"pmids\": [\"25246635\", \"31679460\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of ubiquitin-independent vs FBXW7 routes in vivo unclear\", \"Kinases setting the degradation-protective phosphostate not fully mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linking ZFP36 binding to both transcript abundance and translation in primary T cells with an in vivo infection phenotype established it as a brake on immune activation kinetics, not solely a decay enzyme.\",\n      \"evidence\": \"HITS-CLIP plus ribosome profiling and conditional Zfp36 knockout in acute viral infection in mice\",\n      \"pmids\": [\"29848443\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of translational (vs decay) repression not separated\", \"Coding-sequence ARE function not biochemically defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Reconstructing the upstream signaling that drives and inactivates ZFP36 connected its expression and activity to defined kinase and transcription-factor circuits across inflammation and necroptosis.\",\n      \"evidence\": \"ISGF3/IFN\\u03b2 and MKK3-p38-MK2 manipulation with cytokine mRNA stability readouts; dsRNA/p38-MK2 phosphorylation linked to ARE-mRNA stabilization and reversed pharmacologically\",\n      \"pmids\": [\"39117638\", \"39046234\", \"26546680\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphosite-resolved mechanism of activity loss not structurally defined here\", \"Feedback via DUSP1 quantified only in select cell types\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A series of tissue-specific knockout and target-decay studies established ZFP36 as a physiological regulator of vascular tone, angiogenesis, adipocyte homeostasis, and tumor suppression through distinct 3'-UTR targets.\",\n      \"evidence\": \"Cell-type-specific Zfp36 knockouts with genetic/pharmacological rescue defining RGS2 (VSMC/hypertension), Jag1 (endothelial angiogenesis), RNF128 (adipose obesity), and oncogenic targets CDK6/E2F1/BARX1/PRC1/CEMIP/Ythdc2\",\n      \"pmids\": [\"39589932\", \"38157296\", \"39761791\", \"36111167\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Target hierarchy within each tissue not fully resolved\", \"Many oncogenic targets rest on single-lab RIP/luciferase evidence\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying a decay-independent role in which ZFP36 promotes K63-linked polyubiquitination of RIG-I revealed an unexpected positive function in antiviral signaling.\",\n      \"evidence\": \"Co-IP, RIG-I ubiquitination-site mutagenesis, and ZFP36 zinc-finger mutant (C118S/C162S) in SeV infection\",\n      \"pmids\": [\"37565597\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ZFP36 acts as or recruits the relevant E3 is not defined\", \"Single Co-IP-based mechanism without reconstitution\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ZFP36 mechanistically recruits the deadenylation/decay machinery and how phosphorylation, localization, and the decay-independent ubiquitin-promoting activity are integrated on a single transcript remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of ZFP36 on the decay machinery in the corpus\", \"Mechanism by which ZFP36 promotes RIG-I ubiquitination undefined\", \"Integration of nuclear pool and stress-granule partitioning with target decay unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [8, 10, 14, 18]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [14, 18, 19, 23]},\n      {\"term_id\": \"GO:0003729\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [9, 11]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [9, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [14, 18, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [18, 28, 29, 37]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [28, 29, 16]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RIG-I\", \"FBXW7\", \"ELAVL1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}