{"gene":"ZFP36L1","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2004,"finding":"ZFP36L1 (TIS11b) binds AU-rich elements in the 3'-UTR of VEGF mRNA and decreases its stability (half-life reduced from 130 to 60 min); RNP immunoprecipitation confirmed interaction in live cells; siRNA knockdown demonstrated TIS11b participates in basal and ACTH-induced VEGF mRNA expression control","method":"mRNA stability assay, RNP immunoprecipitation, siRNA knockdown, reporter assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal RIP, functional stability assay, and siRNA knockdown with defined readout; independently replicated in multiple subsequent papers","pmids":["15467755"],"is_preprint":false},{"year":2004,"finding":"Disruption of Zfp36l1 in mice causes embryonic lethality with chorioallantoic fusion defects and placental atrophy; Zfp36l1 has mRNA destabilization and deadenylation activities similar to TTP in cellular and cell-free assays","method":"Knockout mouse, cell-free RNA binding and deadenylation assays, cellular RNA destabilization assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro biochemical assays plus in vivo knockout with defined phenotype","pmids":["15226444"],"is_preprint":false},{"year":2006,"finding":"Zfp36l1 knockout embryos show elevated VEGF-A protein with enhanced association with polyribosomes (not altered mRNA stability), suggesting ZFP36L1 influences translational repression of VEGF-A in vivo","method":"Polyribosome fractionation, conditional knockout mouse, mRNA stability measurement","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — polyribosome fractionation plus KO, single lab, two orthogonal methods","pmids":["17013884"],"is_preprint":false},{"year":2009,"finding":"ZFP36L1/TIS11b binds UAUUUAUU repeats in the extended 3'-UTR of the 3.5-kb StAR mRNA and promotes its degradation; direct complex formation demonstrated; AURE mutations showed first two UAUUUAUU motifs required for TIS11b-mediated destabilization; siRNA knockdown of TIS11b enhanced 3.5-kb StAR mRNA levels and halved STAR protein induction with decreased cholesterol metabolism","method":"RNA pull-down, co-transfection reporter assay, site-directed mutagenesis of AREs, siRNA knockdown","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding demonstrated, mutagenesis of binding sites, knockdown phenotype with multiple orthogonal methods","pmids":["19179481"],"is_preprint":false},{"year":2010,"finding":"ZFP36L1 and ZFP36L2 bind evolutionarily conserved AU-rich elements in the 3'-UTR of Notch1 mRNA and suppress its expression; their combined deletion during thymopoiesis leads to elevated Notch1 and T-ALL development dependent on Notch1","method":"Conditional double knockout mouse, RIP, reporter assay, genetic epistasis with Notch1","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal RIP, in vivo knockout, genetic epistasis with Notch1, replicated across multiple approaches","pmids":["20622884"],"is_preprint":false},{"year":2010,"finding":"ZFP36L1 binds the 3'-UTR of Stat5b mRNA via AU-rich elements and promotes its degradation, thereby negatively regulating erythroid differentiation of CD34+ hematopoietic progenitors","method":"mRNA binding assay, overexpression/knockdown, erythroid colony formation assay, luciferase reporter","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding demonstrated, gain/loss of function with defined phenotype, single lab","pmids":["20702587"],"is_preprint":false},{"year":2011,"finding":"TIS11b/ZFP36L1 binds to an AUUUA motif in the Dll4 mRNA 3'-UTR and represses Dll4 expression by interfering with mRNA 3'-end polyadenylation/cleavage efficiency, rather than mRNA stability — a novel mechanism for ZFP36L1 in mRNA 3'-end maturation","method":"RIP, reporter assay, poly(A) signal mutagenesis, mRNA cleavage/poly(A) ratio analysis","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP demonstrating direct binding, mutagenesis of binding sites, multiple mechanistic readouts; single lab","pmids":["21832157"],"is_preprint":false},{"year":2012,"finding":"ZFP36L1 binds AU-rich elements in the BLIMP1 mRNA 3'-UTR and promotes its degradation, thereby negatively regulating plasmacytoid differentiation; shRNA knockdown of ZFP36L1 increased BLIMP1 mRNA and protein but not other differentiation factors (xbp1, irf4, bcl6); ZFP36L1 reduced activity of a BLIMP1 3'-UTR luciferase reporter","method":"shRNA knockdown, luciferase reporter assay, mRNA measurement, microarray network reconstruction","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter, knockdown with defined phenotype, network reconstruction; single lab","pmids":["23284928"],"is_preprint":false},{"year":2014,"finding":"ZFP36L1 and ZFP36L2 bind the 3'-UTR of LDLR mRNA and recruit the CCR4-NOT deadenylase complex, causing mRNA destabilization; p90 ribosomal S6 kinase (RSK), downstream of ERK, directly phosphorylates the C-terminal regions of ZFP36L1/L2, causing dissociation of CCR4-NOT and stabilization of LDLR mRNA","method":"Proteomic RNA pull-down, kinase assay, co-IP with CCR4-NOT subunits, phosphorylation site analysis, antisense oligonucleotides","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assay, protein complex disruption demonstrated, multiple orthogonal methods including proteomics and functional rescue","pmids":["25106868"],"is_preprint":false},{"year":2014,"finding":"ZFP36L1 binds AU-rich elements in BCL2 mRNA 3'-UTR and promotes its degradation in B cells; zinc finger mutant ZFP36L1 failed to downregulate BCL2 3'-UTR reporter; removal of ARE core reduced ZFP36L1-mediated effect","method":"EMSA, luciferase 3'-UTR reporter assay, zinc finger mutagenesis, shRNA knockdown with mRNA stability measurement","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA, reporter assay, mutagenesis; single lab","pmids":["25014217"],"is_preprint":false},{"year":2014,"finding":"Hypertonicity increases TIS11b/ZFP36L1 expression which binds a specific ARE motif in the mineralocorticoid receptor (MR) mRNA 3'-UTR, decreasing MR mRNA stability (~50% shorter half-life); RNA immunoprecipitation confirmed endogenous TIS11b physically interacts with MR mRNA; TIS11b knockdown prevented hypertonicity-induced MR repression in vivo","method":"Luciferase reporter with 3'-UTR mutants, site-directed mutagenesis, RNA immunoprecipitation, co-IP, knockdown, in vivo water deprivation model","journal":"Journal of the American Society of Nephrology","confidence":"High","confidence_rationale":"Tier 2 / Strong — RIP, mutagenesis, knockdown, and in vivo validation with multiple orthogonal methods","pmids":["24700863"],"is_preprint":false},{"year":2015,"finding":"ZFP36L1 binds AU-rich elements in the CDK6 mRNA 3'-UTR and negatively regulates CDK6 expression, thereby promoting monocyte/macrophage differentiation","method":"Lentiviral gain/loss of function, RIP/3'-UTR binding assay, differentiation assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding to CDK6 3'-UTR demonstrated, gain/loss of function with differentiation phenotype; single lab","pmids":["26542173"],"is_preprint":false},{"year":2016,"finding":"ZFP36L1 and ZFP36L2 suppress a posttranscriptional regulon of cell-cycle-promoting mRNAs to maintain quiescence in developing B lymphocytes before and after pre-BCR expression, thereby promoting VDJ recombination","method":"Conditional double knockout mouse, genome-wide mRNA analysis, cell cycle analysis, FACS-based quiescence assay","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with genome-wide target identification and defined cellular phenotypes; replicated across multiple developmental checkpoints","pmids":["27102483"],"is_preprint":false},{"year":2016,"finding":"Zfp36l1 and Zfp36l2 regulate DNA damage response and cell cycle transcripts in thymocytes to enforce the beta-selection checkpoint; their targets were identified genome-wide in primary mouse thymocytes; absence of these RBPs allows DN3 thymocytes to acquire a post-selection gene expression profile despite lacking TCRβ","method":"Conditional double knockout mouse, genome-wide mRNA profiling of primary thymocytes, cell cycle analysis","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide target identification in primary cells, conditional KO with defined developmental phenotype","pmids":["27566829"],"is_preprint":false},{"year":2016,"finding":"PKA activation phosphorylates TIS11b/ZFP36L1 at Ser-54 and Ser-334; phosphomimetic mutation at C-terminal S334 increased TIS11b half-life and enhanced mRNA decay activity; mimicking phosphorylation at S334 enhanced interaction with decapping coactivator Dcp1a, while preventing S334 phosphorylation potentiated interaction with CCR4-NOT subunit Cnot1","method":"Site-directed mutagenesis, kinase assay, phosphosite immunodetection, co-IP with mRNA decay machinery components","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assay, mutagenesis, protein-protein interaction studies with multiple mRNA decay factors; single lab but multiple orthogonal methods","pmids":["27708140"],"is_preprint":false},{"year":2017,"finding":"ZFP36L1 is an FXR target gene; gain and loss of ZFP36L1 function reciprocally regulates Cyp7a1 mRNA levels and bile acid levels in vivo; ZFP36L1 promotes Cyp7a1 mRNA decay; mice lacking hepatic ZFP36L1 are protected from diet-induced obesity and steatosis through altered bile acid metabolism","method":"Conditional liver-specific knockout mouse, gain/loss of function, in vivo bile acid measurement, mRNA decay assay","journal":"Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO, gain/loss of function, in vivo metabolic phenotype; multiple orthogonal methods","pmids":["28891815"],"is_preprint":false},{"year":2017,"finding":"ZFP36L1 controls the identity of marginal-zone B cells by limiting expression of transcription factors KLF2 and IRF8 post-transcriptionally via AU-rich element binding, and regulates a gene-expression program related to signaling, cell adhesion and locomotion; ZFP36L1 is specifically required for proper MZ B cell localization and survival","method":"Conditional knockout mouse, transcriptome analysis, flow cytometry, homing assay","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined cellular phenotype, transcriptome-wide target analysis, multiple functional assays","pmids":["28394372"],"is_preprint":false},{"year":2018,"finding":"ZFP36L1 inhibits cell proliferation and arrests the cell cycle at G1 in a cyclin D-dependent and p53-independent manner; TZF domain mutations abolish antiproliferative activity and cyclin D suppression; demonstrated in p53+/+ and p53-/- cells","method":"Overexpression, TZF domain mutagenesis, cell cycle analysis, knockdown in multiple cancer cell lines","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of functional domain, multiple cell lines including isogenic p53 pairs; single lab","pmids":["29426877"],"is_preprint":false},{"year":2018,"finding":"ZFP36L1 phosphorylation is modulated in a cell cycle-dependent manner; the C-terminal region is critical for cell cycle-dependent phosphorylation; phosphorelay-dependent regulation of ZFP36L1 influences mitotic spindle organization","method":"Cell synchronization, subcellular fractionation, phosphorylation analysis, mitotic spindle imaging","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method for spindle organization, partial mechanistic follow-up; single lab","pmids":["29709483"],"is_preprint":false},{"year":2019,"finding":"ZFP36L1 binds the 3'-UTRs of HSP70 family members (HSPA1A) via AU-rich elements and promotes their mRNA decay; ZFP36L1 knockdown increases HSP70 expression and protects against OA; ZFP36L1 silencing abrogates experimental osteoarthritis in mice","method":"Adenovirus-mediated overexpression, genetic ablation, siRNA knockdown, in vivo OA model, mRNA stability assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO, gain/loss of function with defined OA phenotype, direct mRNA target validation; multiple orthogonal methods","pmids":["30622281"],"is_preprint":false},{"year":2019,"finding":"ZFP36L1 binds AU-rich elements in the 3'-UTRs of HIF1A, CCND1, and E2F1 mRNAs and promotes their decay; wild-type but not zinc-finger mutant ZFP36L1 bound HIF1A 3'-UTR in EMSA and luciferase assays; ZFP36L1 suppresses hypoxia signaling and cell-cycle progression","method":"RNA pull-down with WT and mutant ZFP36L1, whole transcriptome sequencing, luciferase reporter, EMSA, in vitro and in vivo tumor models","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — systematic RNA pull-down with mutant controls, EMSA, reporter assay, transcriptome-wide target identification","pmids":["31551365"],"is_preprint":false},{"year":2020,"finding":"ZFP36L1 nuclear accumulation is cell cycle-dependent, prominent at G1/S boundary and reduced in S and G2 phases; the C-terminal serine-rich cluster is critical for regulating nuclear accumulation and cell cycle-dependent fluctuations; forced nuclear targeting led to ZFP36L1 elimination in S and G2 phases","method":"Cell fractionation, cell cycle synchronization, truncation mutant analysis, nuclear targeting constructs","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — fractionation with functional domain analysis; single lab, single study","pmids":["32687160"],"is_preprint":false},{"year":2020,"finding":"ZFP36L1 represses translation directly via AU-rich elements independent of deadenylation; interaction with CNOT1 is required for translational repression; unlike TTP, ZFP36L1 does not efficiently interact with 4E-HP or GIGYF2; ZFP36L1 translation repression is resistant to eIF4A inhibitor silvestrol, suggesting a distinct mechanism from miRISC","method":"In vitro mammalian translation system, IRES reporter assays, mutant protein functional assays, co-immunoprecipitation","journal":"Biochimie","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro reconstitution, mutant analysis, multiple reporter assays; single lab","pmids":["32311426"],"is_preprint":false},{"year":2020,"finding":"ZFP36L1 reduces influenza A virus (IAV) replication via translational repression of HA, M and NS viral RNA transcripts; ZFP36L1 directly binds IAV NS1 mRNA in the cytoplasm; CCCH zinc finger domain mutations abolished antiviral activity and NS1 mRNA binding","method":"Overexpression/knockdown, zinc finger domain mutagenesis, RIP, viral replication assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding to viral mRNA demonstrated with mutagenesis, functional antiviral assay; single lab","pmids":["32556261"],"is_preprint":false},{"year":2021,"finding":"ZFP36L1 destabilizes JEV genome RNA by targeting AU-rich element (AUUUA) motifs in the 3'-UTR and recruits both XRN1 (5'-3') and RNA-exosome (3'-5') decay pathways; zinc finger domain mutations disrupted RNA binding and antiviral activity","method":"Overexpression/knockdown, zinc finger mutagenesis, XRN1/exosome knockdown epistasis, viral RNA stability assay, 3'-UTR mapping","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic dissection of two decay pathways, mutagenesis, epistasis; single lab","pmids":["34643435"],"is_preprint":false},{"year":2021,"finding":"ZFP36L1 directly regulates G protein-coupled receptor kinase 2 (GRK2) and the integrin chains α4 and β1 mRNAs in splenic antibody-secreting cells (ASCs), limiting their abundance and facilitating ASC homing to the bone marrow; ZFP36L1-deficient ASCs accumulate in spleen and liver with diminished bone marrow accumulation","method":"Conditional knockout mouse, RNA-IP, flow cytometry, homing assay","journal":"Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined homing phenotype, RNA-IP for target validation; single lab","pmids":["33306108"],"is_preprint":false},{"year":2021,"finding":"ZFP36L1 directly binds AREs in the Fgf21 mRNA 3'-UTR and promotes its decay; wild-type but not zinc finger mutant ZFP36L1 decreased Fgf21 mRNA levels in luciferase reporter assays; liver-specific ZFP36L1 KO mice are protected from alcohol-induced hepatic steatosis, associated with elevated Fgf21 mRNA","method":"Liver-specific conditional knockout mouse, luciferase reporter, zinc finger mutant, RNA pull-down, in vivo alcohol model","journal":"American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO, reporter assay, mutagenesis, direct RNA binding; multiple orthogonal methods","pmids":["34774847"],"is_preprint":false},{"year":2022,"finding":"ZFP36L1 binds AU-rich elements in the ZEB2 mRNA 3'-UTR and promotes its degradation; ZFP36L1 silencing increases ZEB2 mRNA stability and promotes EMT in liver cancer cells; ZFP36L1 overexpression downregulates ZEB2 and abolishes EMT; ZEB2 3'-UTR is regulated by ZFP36L1 in luciferase reporter assays","method":"siRNA knockdown, overexpression, mRNA stability assay, luciferase 3'-UTR reporter, RNA-seq","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay, mRNA stability, gain/loss of function; single lab","pmids":["36100056"],"is_preprint":false},{"year":2022,"finding":"LSD1 binds and represses ZFP36L1; upon LSD1 inhibition, ZFP36L1 expression is restored and is sufficient to block SCLC neuroendocrine differentiation; ZFP36L1 binds and destabilizes SOX2 and INSM1 mRNAs (required for neuroendocrine differentiation); constitutive ZFP36L1 was required for LSD1 inhibitor sensitivity in a CRISPR screen","method":"Genome-wide CRISPR loss-of-function screen, overexpression, RIP, mRNA stability assay, ChIP for LSD1","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide CRISPR screen identified ZFP36L1, direct mRNA binding demonstrated, multiple orthogonal methods","pmids":["36008402"],"is_preprint":false},{"year":2023,"finding":"ZFP36L1 promotes mRNA decay of SDC4 by binding AU-rich elements in its 3'-UTR, thereby inhibiting TGF-β signaling and suppressing osteosarcoma lung metastasis; SDC4 protects TGFBR3 from MMP-mediated cleavage, forming a positive SDC4-TGF-β feedback loop that ZFP36L1 inhibits","method":"Knockdown/overexpression, luciferase 3'-UTR reporter, RIP, in vivo metastasis model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding demonstrated, reporter assay, in vivo model; single lab","pmids":["37935976"],"is_preprint":false},{"year":2023,"finding":"ZFP36L1 acts as a sensor of TCR affinity within an incoherent feed-forward loop, suppressing negative regulators of cytokine (IL-2) signaling to promote clonal expansion of high-affinity CD8 T cells; ZFP36L1 has a non-redundant role in establishing the dominance of high-affinity T cells through hierarchical IL-2 competition","method":"Conditional knockout mouse, adoptive transfer, in vivo competition assay, transcriptome analysis","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo clonal competition assay, conditional KO; defined functional circuit but molecular targets not fully characterized in this paper","pmids":["38039407"],"is_preprint":false},{"year":2024,"finding":"ZFP36L1, driven by a super-enhancer with SPI1 as the transcription factor, binds AU-rich elements in the HDAC3 mRNA 3'-UTR and promotes its decay, thereby reducing HDAC3-mediated transcriptional repression of PD-L1 and enhancing IFN-γ-induced PD-L1 expression in gastric cancer","method":"H3K27ac CUT&Tag, luciferase reporter, GST/RNA pull-down, ChIP/RIP, ChIP for SPI1, flow cytometry, in vivo functional assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNA pull-down, RIP, ChIP, reporter assay, and in vivo validation with multiple orthogonal methods","pmids":["39373630"],"is_preprint":false},{"year":2024,"finding":"ZFP36L1 directly binds AU-rich elements in the DCLRE1C mRNA 3'-UTR and promotes its degradation; ZFP36L1 overexpression reduces NHEJ DNA repair efficiency via DCLRE1C downregulation; decreased ZFP36L1 expression enables methotrexate resistance in osteosarcoma","method":"3'-UTR binding analysis, overexpression/knockdown, NHEJ efficiency assay, drug sensitivity assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding to 3'-UTR demonstrated, functional NHEJ assay; single lab","pmids":["41285712"],"is_preprint":false},{"year":2024,"finding":"ZFP36L1 and ZFP36L2 restrain CDK1 and cyclin B1 expression in germinal centre B cells while controlling a p21-mediated negative feedback loop; absence of these RBPs causes G2-M arrest, DNA replication fork stalling, ATR/CHK1 activation, and apoptosis — resulting in curtailed germinal centre responses","method":"Conditional double knockout mouse, cell cycle analysis, DNA replication fork analysis, transcriptome profiling of GC B cells","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined cell cycle phenotype and replication stress readouts; preprint not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2025,"finding":"ZFP36L1 expression in CD8+ T cells is regulated by calcineurin/NFAT signaling (cyclosporin A potently inhibits ZFP36L1 but not ZFP36 expression); p38 MAPK, MEK1/2, and PKC contribute to inducing ZFP36L1; the Zfp36l1 promoter is enriched for NFAT binding sites while Zfp36 promoter has ELK-1/4 sites","method":"Pharmacological inhibitors of TCR signaling pathways, promoter analysis, in vitro T cell activation","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple pharmacological inhibitors, promoter analysis; functional promoter binding not directly demonstrated","pmids":["41211771"],"is_preprint":false},{"year":2025,"finding":"ZFP36L1 protein interacts with CNOT1 and components of mRNA decay, deadenylation, decapping, stress granule/P-body formation, and 5'-UTR-mediated translation repression in primary human T cells; the helicase UPF1 both interacts with ZFP36L1 protein and promotes its protein expression; the ZFP36L1 interactome is dynamic and partly RNA-dependent during T cell activation","method":"Proximity labeling (BioID), mass spectrometry, primary human T cells, RNA dependency analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic proximity labeling in primary human T cells with interactome dynamics; preprint, not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2025,"finding":"Anti-CTLA-4 or anti-LAG-3/PD-1 immunotherapy reduces ZFP36L1 expression in tumor-infiltrating CD4+ T cells, relieving post-transcriptional repression of Gzmb mRNA translation; constitutive ZFP36L1 abrogates the effects of anti-CTLA-4; deletion of ZFP36L1 (with ZFP36) triggers GzmB protein production and promotes tumor control","method":"In vivo tumor model with immune checkpoint blockade, conditional knockout, translational reporter assay, CRISPR","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo conditional KO and checkpoint blockade with defined molecular and tumor phenotype; preprint, not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2026,"finding":"ZFP36L1 promotes mRNA decay of CAMK2A by binding to its 3'-UTR AREs; ZFP36L1 knockout in CRS mice restores CAMK2A expression and attenuates ferroptosis and mitochondrial dysfunction; CAMK2A knockdown reverses the protective effects of ZFP36L1 depletion","method":"In vivo CRS mouse model with ZFP36L1 KO, RIP/binding assay, rescue experiments","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'-UTR binding, KO model, epistasis rescue experiment; single lab","pmids":["42051151"],"is_preprint":false},{"year":2026,"finding":"ZFP36L1 promotes mRNA degradation of PRDM1 by binding AU-rich elements in its 3'-UTR in Kupffer cells, thereby suppressing inflammatory activation and ameliorating liver ischemia-reperfusion injury; PRDM1 overexpression reverses the suppressive effect of ZFP36L1","method":"Rat DCD liver transplant model, LPS-stimulated Kupffer cells, overexpression vectors, RIP","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding demonstrated, in vivo model with rescue experiment; single lab","pmids":["41494598"],"is_preprint":false},{"year":2015,"finding":"In LPS-stimulated macrophages, ZFP36L1 is phosphorylated; hyper-phosphorylated ZFP36L1 stabilizes Mkp-1 mRNA by forming a complex with adapter protein 14-3-3 and decreasing interaction with deadenylase Caf1a; knockdown of ZFP36L1 increases basal Mkp-1 mRNA half-life","method":"siRNA knockdown, mRNA half-life assay, co-immunoprecipitation with 14-3-3 and Caf1a, LPS stimulation","journal":"Journal of inflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP demonstrating 14-3-3 and Caf1a interactions, mRNA stability assay; single lab","pmids":["26180518"],"is_preprint":false},{"year":2017,"finding":"ZFP36L1 binds the 3'-UTR of PPARγ2 (Pparγ2) mRNA and promotes its degradation, repressing adipogenic differentiation; ZFP36L1-containing RNP complexes contained less Pparγ2 mRNA; 3'-UTR reporter constructs demonstrated reduced luciferase in ZFP36L1-overexpressing cells","method":"Biotin pull-down, EMSA, luciferase reporter, RNP immunoprecipitation, transcriptional blockade kinetics","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple binding assays and reporter; single lab","pmids":["28206953"],"is_preprint":false}],"current_model":"ZFP36L1 is a CCCH tandem zinc-finger RNA-binding protein that binds AU-rich elements (AREs) in the 3'-UTRs of target mRNAs and promotes their deadenylation (via CCR4-NOT recruitment), mRNA decay (via XRN1 and RNA-exosome pathways), and translational repression (via CNOT1 interaction independent of deadenylation); its activity is regulated by phosphorylation — notably by RSK downstream of ERK (releasing CCR4-NOT) and by PKA (enhancing mRNA decay and shifting interaction from Cnot1 to Dcp1a) — and its nuclear accumulation is cell cycle-dependent, controlled by a C-terminal serine-rich cluster; key validated targets include VEGF, Notch1, LDLR, BCL2, BLIMP1, HIF1A, CCND1, CDK6, StAR, MR, Cyp7a1, Fgf21, ZEB2, SOX2, INSM1, HDAC3, GRK2, SDC4, DCLRE1C, CAMK2A, and PRDM1; through these mechanisms ZFP36L1 controls cell quiescence, lymphocyte development, angiogenesis, steroidogenesis, bile acid metabolism, antiviral defense, and immune cell differentiation."},"narrative":{"mechanistic_narrative":"ZFP36L1 is a CCCH tandem zinc-finger RNA-binding protein that recognizes AU-rich elements (AREs) in target mRNA 3'-UTRs and drives their post-transcriptional silencing, thereby controlling cell quiescence, lymphocyte development, angiogenesis, metabolism, and immune differentiation [PMID:15226444, PMID:27102483, PMID:31551365]. It functions principally by destabilizing bound transcripts: it recruits the CCR4-NOT deadenylase complex to initiate decay, and in the case of viral and host RNAs engages both the XRN1 5'-3' and RNA-exosome 3'-5' degradation pathways [PMID:25106868, PMID:34643435]. Beyond destabilization, ZFP36L1 represses translation directly through a CNOT1-dependent, deadenylation-independent mechanism that is distinct from the miRISC/4E-HP route used by its paralog TTP [PMID:32311426], and can interfere with 3'-end cleavage/polyadenylation of target pre-mRNAs [PMID:21832157]. ARE recognition requires an intact tandem zinc-finger domain, mutation of which abolishes both RNA binding and downstream regulatory and antiproliferative activity [PMID:25014217, PMID:31551365, PMID:32556261]. Its activity is gated by phosphorylation: RSK acting downstream of ERK phosphorylates the C-terminal region to dissociate CCR4-NOT and stabilize targets, while PKA phosphorylation at Ser-334 increases protein half-life and shifts partner engagement from CNOT1 toward the decapping coactivator Dcp1a [PMID:25106868, PMID:27708140]; a C-terminal serine-rich cluster additionally governs cell cycle-dependent nuclear accumulation [PMID:32687160]. Through ARE-mediated control of cell-cycle and signaling regulons, ZFP36L1 enforces quiescence and developmental checkpoints in B and T lymphocytes—including pre-BCR, beta-selection, and germinal-centre transitions—and shapes T-cell responses to TCR affinity and checkpoint blockade [PMID:27102483, PMID:27566829, PMID:28394372, PMID:38039407]. Validated targets spanning these programs include VEGF/Dll4, Notch1, LDLR, BCL2, HIF1A/CCND1/E2F1, CDK6, Cyp7a1, Fgf21, and the neuroendocrine factors SOX2 and INSM1 [PMID:15467755, PMID:20622884, PMID:25106868, PMID:25014217, PMID:28891815, PMID:31551365, PMID:36008402].","teleology":[{"year":2004,"claim":"Establishing that ZFP36L1 is a functional ARE-binding mRNA-destabilizing protein answered whether it acts directly on target transcripts and is biologically essential.","evidence":"ARE binding and stability assay on VEGF mRNA with RNP-IP and siRNA; knockout mouse plus cell-free deadenylation assays","pmids":["15467755","15226444"],"confidence":"High","gaps":["Did not resolve the decay machinery recruited","Phosphorylation control not yet addressed"]},{"year":2006,"claim":"Polyribosome analysis in knockout embryos revealed that ZFP36L1 can act at the translational level, not only by altering mRNA stability.","evidence":"Polyribosome fractionation and mRNA stability measurement in conditional KO mouse embryos","pmids":["17013884"],"confidence":"Medium","gaps":["Molecular basis of translational repression undefined","No interaction partner identified for this activity"]},{"year":2009,"claim":"Mapping ZFP36L1 to specific UAUUUAUU motifs in StAR mRNA defined the sequence determinants of target recognition and linked decay activity to steroidogenic output.","evidence":"RNA pull-down, ARE mutagenesis, reporter assay, and siRNA knockdown with cholesterol metabolism readout","pmids":["19179481"],"confidence":"High","gaps":["Decay machinery recruited not characterized here","In vivo relevance not tested"]},{"year":2010,"claim":"Genetic work in lymphocytes showed ZFP36L1 (with ZFP36L2) suppresses developmental transcription factors, establishing its role in lymphopoiesis and tumor suppression.","evidence":"Conditional double-KO mice with RIP and genetic epistasis (Notch1 in thymopoiesis; Stat5b in erythroid progenitors)","pmids":["20622884","20702587"],"confidence":"High","gaps":["Redundancy between paralogs not fully separated","Mechanism of decay vs translation control not dissected"]},{"year":2011,"claim":"Discovery that ZFP36L1 represses Dll4 by impairing 3'-end cleavage/polyadenylation extended its mechanistic repertoire beyond stability and translation.","evidence":"RIP, poly(A) signal mutagenesis, and mRNA cleavage/poly(A) ratio analysis","pmids":["21832157"],"confidence":"Medium","gaps":["Generality of the 3'-end maturation mechanism across targets unknown","Factors mediating cleavage interference unidentified"]},{"year":2014,"claim":"Identification of CCR4-NOT recruitment and its release by RSK phosphorylation, plus PKA-driven partner switching, established how signaling kinases gate ZFP36L1 decay activity.","evidence":"Proteomic pull-down, in vitro kinase and co-IP assays with CCR4-NOT subunits, Cnot1 and Dcp1a; phosphosite analysis","pmids":["25106868","27708140"],"confidence":"High","gaps":["Stoichiometry and dynamics of partner switching in vivo unresolved","Full set of regulatory kinases not defined"]},{"year":2014,"claim":"Demonstrating zinc-finger-dependent regulation of BCL2 and stress-responsive control of the mineralocorticoid receptor broadened the target landscape and tied ARE binding mechanistically to zinc-finger integrity.","evidence":"EMSA, 3'-UTR reporter, zinc-finger mutagenesis for BCL2; RIP, mutagenesis and in vivo water deprivation for MR","pmids":["25014217","24700863"],"confidence":"High","gaps":["Decay machinery for these targets not mapped","Tissue-specific regulation incompletely defined"]},{"year":2016,"claim":"Genome-wide target identification in primary lymphocytes showed ZFP36L1 enforces quiescence by suppressing a cell-cycle regulon at developmental checkpoints.","evidence":"Conditional double-KO mice with genome-wide mRNA profiling and cell-cycle/quiescence assays in B cells and thymocytes","pmids":["27102483","27566829"],"confidence":"High","gaps":["Direct vs indirect targets not fully separated transcriptome-wide","Contribution of each paralog not resolved"]},{"year":2017,"claim":"In vivo metabolic and B-cell identity studies extended ZFP36L1 function to bile-acid metabolism and marginal-zone B-cell positioning through defined ARE targets.","evidence":"Liver-specific and conditional KO mice; gain/loss of function with Cyp7a1 decay assay and KLF2/IRF8 transcriptome analysis","pmids":["28891815","28394372"],"confidence":"High","gaps":["Upstream signals coupling FXR to ZFP36L1 activity incompletely mapped","Whether translation vs decay dominates per target not resolved"]},{"year":2018,"claim":"Domain mapping established the antiproliferative G1-arrest activity as zinc-finger-dependent and p53-independent, and linked C-terminal phosphorylation to cell-cycle behavior.","evidence":"TZF mutagenesis and cell-cycle analysis in isogenic p53 cell lines; cell synchronization with phosphorylation and spindle imaging","pmids":["29426877","29709483"],"confidence":"Medium","gaps":["Spindle organization link rests on a single low-confidence method","Phosphorelay components not identified"]},{"year":2020,"claim":"Reconstitution showed ZFP36L1 represses translation via CNOT1 independent of deadenylation and through a mechanism distinct from miRISC, and mapped cell-cycle-dependent nuclear accumulation to a C-terminal serine cluster.","evidence":"In vitro mammalian translation system, IRES reporters, co-IP; cell fractionation with truncation and nuclear-targeting constructs","pmids":["32311426","32687160"],"confidence":"Medium","gaps":["Molecular intermediary between ZFP36L1-CNOT1 and ribosome unknown","Trigger for nuclear elimination in S/G2 undefined"]},{"year":2020,"claim":"Antiviral studies demonstrated ZFP36L1 directly targets viral RNAs, repressing influenza transcripts translationally and destabilizing JEV genome RNA via dual XRN1/exosome decay.","evidence":"Zinc-finger mutagenesis, RIP, viral replication and RNA stability assays; XRN1/exosome knockdown epistasis","pmids":["32556261","34643435"],"confidence":"Medium","gaps":["Determinants of decay-vs-translation choice on viral targets unclear","Breadth of antiviral spectrum not established"]},{"year":2019,"claim":"Cancer- and disease-model work expanded validated targets (HIF1A/CCND1/E2F1, HSP70) and tied ARE-mediated decay to hypoxia, proliferation, and osteoarthritis phenotypes.","evidence":"Systematic RNA pull-down with mutant controls, EMSA, transcriptome sequencing, and in vivo tumor/OA models","pmids":["31551365","30622281"],"confidence":"High","gaps":["Context-dependence of target selection across tissues unresolved","Upstream regulators in these settings not fully mapped"]},{"year":2021,"claim":"Studies in plasma cells, T cells, and adipocyte/macrophage systems linked ZFP36L1 to homing, signaling adaptors, and metabolic differentiation through defined targets.","evidence":"Conditional KO with RNA-IP for GRK2/integrins; reporter and KO for Fgf21; co-IP showing 14-3-3/Caf1a-dependent Mkp-1 control; PPARγ2 reporter assays","pmids":["33306108","34774847","26180518","28206953"],"confidence":"Medium","gaps":["Phospho-dependent stabilization mechanism (14-3-3) not generalized","Relative target hierarchy per cell type unclear"]},{"year":2022,"claim":"Epigenetic and EMT studies showed ZFP36L1 is itself transcriptionally controlled (LSD1 repression, SPI1/super-enhancer activation) and represses neuroendocrine and metastatic programs via SOX2/INSM1, ZEB2, and HDAC3.","evidence":"CRISPR screen, ChIP, RIP, mRNA stability and reporter assays in SCLC, gastric and liver cancer models","pmids":["36008402","36100056","39373630"],"confidence":"High","gaps":["How upstream transcriptional inputs are integrated with phospho-regulation unknown","Causality of individual targets in tumor phenotypes incompletely separated"]},{"year":2023,"claim":"T-cell and metastasis studies positioned ZFP36L1 within signaling circuits, acting as a TCR-affinity sensor in an IL-2 feed-forward loop and suppressing TGF-β signaling via SDC4 decay.","evidence":"Conditional KO with in vivo competition assays; RIP, reporter and in vivo metastasis model for SDC4","pmids":["38039407","37935976"],"confidence":"Medium","gaps":["Direct molecular targets of the affinity-sensing circuit not fully defined","Whether SDC4 effect is decay or translational not dissected"]},{"year":2024,"claim":"DNA-repair and proliferation studies linked ZFP36L1 to NHEJ (via DCLRE1C) and germinal-centre cell-cycle control with replication-stress consequences when lost.","evidence":"3'-UTR binding and NHEJ/drug sensitivity assays; conditional double-KO with replication fork and DNA-damage-response analysis (preprint)","pmids":["41285712"],"confidence":"Medium","gaps":["Germinal-centre findings remain a non-peer-reviewed preprint","Direct vs feedback contribution to CDK1/cyclin B1/p21 control not separated"]},{"year":2025,"claim":"Interactome and signaling studies in primary T cells defined the protein partners and upstream calcineurin/NFAT control of ZFP36L1 and its role in immunotherapy responses.","evidence":"BioID/MS interactome (UPF1, CNOT1, decay/P-body factors), pharmacological TCR-pathway dissection, and checkpoint-blockade tumor models (two preprints plus peer-reviewed promoter analysis)","pmids":["41211771"],"confidence":"Medium","gaps":["Interactome and checkpoint findings are non-peer-reviewed preprints","Functional roles of UPF1 and stress-granule factors not mechanistically resolved"]},{"year":2026,"claim":"Recent disease-model work added CAMK2A and PRDM1 as targets linking ZFP36L1 to ferroptosis/mitochondrial dysfunction and Kupffer-cell inflammation.","evidence":"In vivo KO models with RIP and epistasis rescue (CAMK2A, PRDM1)","pmids":["42051151","41494598"],"confidence":"Medium","gaps":["Single-lab target validations without independent replication","Decay vs translational mechanism per target not dissected"]},{"year":null,"claim":"It remains unresolved how ZFP36L1 selects between deadenylation, decapping, exosome/XRN1 decay, translational repression, and 3'-end interference on a given target, and how phospho-state and partner switching dictate that choice in vivo.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of ZFP36L1-machinery complexes","Rules governing decay-vs-translation outcome per transcript undefined","Quantitative map of phospho-states to interactomes in primary cells missing"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,3,4,9,20,23,24]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[1,8,24]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[8,14,22,39]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[2,22,23,36]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[8,14]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[23,21]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[21,18]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,8,20,24]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[12,13,17,20]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,12,16,30]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,4,11]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,15,26,40]}],"complexes":["CCR4-NOT"],"partners":["CNOT1","DCP1A","XRN1","RSK","UPF1","YWHAB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q07352","full_name":"mRNA decay activator protein ZFP36L1","aliases":["Butyrate response factor 1","EGF-response factor 1","ERF-1","TPA-induced sequence 11b","Zinc finger protein 36, C3H1 type-like 1","ZFP36-like 1"],"length_aa":338,"mass_kda":36.3,"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:12198173, PubMed:15467755, PubMed:15538381, PubMed:17030608, PubMed:19179481, PubMed:20702587, PubMed:24700863, PubMed:25014217, PubMed:25106868, PubMed:26542173). Acts as a 3'-untranslated region (UTR) ARE mRNA-binding adapter protein to communicate signaling events to the mRNA decay machinery (PubMed:15687258). Functions by recruiting the CCR4-NOT deadenylase complex and components of the cytoplasmic RNA decay machinery to the bound ARE-containing mRNAs, and hence promotes ARE-mediated mRNA deadenylation and decay processes (PubMed:15687258, PubMed:18326031, PubMed:25106868). Also induces the degradation of ARE-containing mRNAs even in absence of poly(A) tail (By similarity). Binds to 3'-UTR ARE of numerous mRNAs (PubMed:12198173, PubMed:15467755, PubMed:15538381, PubMed:17030608, PubMed:19179481, PubMed:20702587, PubMed:24700863, PubMed:25014217, PubMed:25106868, PubMed:26542173). Positively regulates early adipogenesis by promoting ARE-mediated mRNA decay of immediate early genes (IEGs) (By similarity). Promotes ARE-mediated mRNA decay of mineralocorticoid receptor NR3C2 mRNA in response to hypertonic stress (PubMed:24700863). Negatively regulates hematopoietic/erythroid cell differentiation by promoting ARE-mediated mRNA decay of the transcription factor STAT5B mRNA (PubMed:20702587). Positively regulates monocyte/macrophage cell differentiation by promoting ARE-mediated mRNA decay of the cyclin-dependent kinase CDK6 mRNA (PubMed:26542173). Promotes degradation of ARE-containing pluripotency-associated mRNAs in embryonic stem cells (ESCs), such as NANOG, through a fibroblast growth factor (FGF)-induced MAPK-dependent signaling pathway, and hence attenuates ESC self-renewal and positively regulates mesendoderm differentiation (By similarity). May play a role in mediating pro-apoptotic effects in malignant B-cells by promoting ARE-mediated mRNA decay of BCL2 mRNA (PubMed:25014217). In association with ZFP36L2 maintains quiescence on developing B lymphocytes by promoting ARE-mediated decay of several mRNAs encoding cell cycle regulators that help B cells progress through the cell cycle, and hence ensuring accurate variable-diversity-joining (VDJ) recombination and functional immune cell formation (By similarity). Together with ZFP36L2 is also necessary for thymocyte development and prevention of T-cell acute lymphoblastic leukemia (T-ALL) transformation by promoting ARE-mediated mRNA decay of the oncogenic transcription factor NOTCH1 mRNA (By similarity). Participates in the delivery of target ARE-mRNAs to processing bodies (PBs) (PubMed:17369404). In addition to its cytosolic mRNA-decay function, plays a role in the regulation of nuclear mRNA 3'-end processing; modulates mRNA 3'-end maturation efficiency of the DLL4 mRNA through binding with an ARE embedded in a weak noncanonical polyadenylation (poly(A)) signal in endothelial cells (PubMed:21832157). Also involved in the regulation of stress granule (SG) and P-body (PB) formation and fusion (PubMed:15967811). Plays a role in vasculogenesis and endocardial development (By similarity). Plays a role in the regulation of keratinocyte proliferation, differentiation and apoptosis (PubMed:27182009). Plays a role in myoblast cell differentiation (By similarity)","subcellular_location":"Nucleus; Cytoplasm; Cytoplasmic granule; Cytoplasm, P-body","url":"https://www.uniprot.org/uniprotkb/Q07352/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZFP36L1","classification":"Not Classified","n_dependent_lines":305,"n_total_lines":1208,"dependency_fraction":0.25248344370860926},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"TBP","stoichiometry":10.0},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"POLR1C","stoichiometry":0.2},{"gene":"POLR2F","stoichiometry":0.2},{"gene":"POLR2H","stoichiometry":0.2},{"gene":"POLR2K","stoichiometry":0.2},{"gene":"POLR3B","stoichiometry":0.2},{"gene":"POLR3F","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ZFP36L1","total_profiled":1310},"omim":[{"mim_id":"612053","title":"ZINC FINGER PROTEIN 36-LIKE 2; ZFP36L2","url":"https://www.omim.org/entry/612053"},{"mim_id":"604260","title":"SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 5B; STAT5B","url":"https://www.omim.org/entry/604260"},{"mim_id":"601064","title":"ZINC FINGER PROTEIN 36-LIKE 1; ZFP36L1","url":"https://www.omim.org/entry/601064"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ZFP36L1"},"hgnc":{"alias_symbol":["Berg36","ERF1","TIS11B","cMG1"],"prev_symbol":["BRF1"]},"alphafold":{"accession":"Q07352","domains":[{"cath_id":"-","chopping":"111-148","consensus_level":"medium","plddt":92.5908,"start":111,"end":148},{"cath_id":"-","chopping":"149-191","consensus_level":"medium","plddt":85.2423,"start":149,"end":191}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q07352","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q07352-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q07352-F1-predicted_aligned_error_v6.png","plddt_mean":58.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZFP36L1","jax_strain_url":"https://www.jax.org/strain/search?query=ZFP36L1"},"sequence":{"accession":"Q07352","fasta_url":"https://rest.uniprot.org/uniprotkb/Q07352.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q07352/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q07352"}},"corpus_meta":[{"pmid":"20622884","id":"PMC_20622884","title":"Deletion of the RNA-binding proteins ZFP36L1 and ZFP36L2 leads to perturbed thymic development and T lymphoblastic leukemia.","date":"2010","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20622884","citation_count":177,"is_preprint":false},{"pmid":"15226444","id":"PMC_15226444","title":"Chorioallantoic fusion defects and embryonic lethality resulting from disruption of Zfp36L1, a gene encoding a CCCH tandem zinc finger protein of the Tristetraprolin family.","date":"2004","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15226444","citation_count":147,"is_preprint":false},{"pmid":"27102483","id":"PMC_27102483","title":"RNA-binding proteins ZFP36L1 and ZFP36L2 promote cell quiescence.","date":"2016","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/27102483","citation_count":143,"is_preprint":false},{"pmid":"15467755","id":"PMC_15467755","title":"Destabilization of vascular endothelial growth factor mRNA by the zinc-finger protein TIS11b.","date":"2004","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/15467755","citation_count":102,"is_preprint":false},{"pmid":"17013884","id":"PMC_17013884","title":"The RNA binding protein Zfp36l1 is required for normal vascularisation and post-transcriptionally regulates VEGF expression.","date":"2006","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/17013884","citation_count":83,"is_preprint":false},{"pmid":"25106868","id":"PMC_25106868","title":"ZFP36L1 and ZFP36L2 control LDLR mRNA stability via the ERK-RSK pathway.","date":"2014","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/25106868","citation_count":78,"is_preprint":false},{"pmid":"10887131","id":"PMC_10887131","title":"Analysis of genes under the downstream control of the t(8;21) fusion protein AML1-MTG8: overexpression of the TIS11b (ERF-1, cMG1) gene induces myeloid cell proliferation in response to G-CSF.","date":"2000","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/10887131","citation_count":66,"is_preprint":false},{"pmid":"30622281","id":"PMC_30622281","title":"RNA-binding protein ZFP36L1 regulates osteoarthritis by modulating members of the heat shock protein 70 family.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30622281","citation_count":65,"is_preprint":false},{"pmid":"29426877","id":"PMC_29426877","title":"ZFP36L1 and ZFP36L2 inhibit cell proliferation in a cyclin D-dependent and p53-independent manner.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29426877","citation_count":63,"is_preprint":false},{"pmid":"27566829","id":"PMC_27566829","title":"The RNA-Binding Proteins Zfp36l1 and Zfp36l2 Enforce the Thymic β-Selection Checkpoint by Limiting DNA Damage Response Signaling and Cell Cycle Progression.","date":"2016","source":"Journal of immunology 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immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41211771","citation_count":0,"is_preprint":false},{"pmid":"41840035","id":"PMC_41840035","title":"RNA-binding proteins Zfp36l1 and Zfp36l2 protect against premature thymic involution.","date":"2026","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41840035","citation_count":0,"is_preprint":false},{"pmid":"41285712","id":"PMC_41285712","title":"Downregulation of ZFP36L1 contributes to methotrexate resistance in osteosarcoma through enhanced NHEJ DNA repair mechanisms.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/41285712","citation_count":0,"is_preprint":false},{"pmid":"40749834","id":"PMC_40749834","title":"ZFP36L1 and L2 as novel antiviral factors for Crimean-Congo hemorrhagic fever virus via interaction with viral nucleoprotein.","date":"2025","source":"The Journal of biological 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mian yi xue za zhi = Chinese journal of cellular and molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35851086","citation_count":0,"is_preprint":false},{"pmid":"41906630","id":"PMC_41906630","title":"ZFP36L1 promotes non-small cell lung cancer progression under hypoxia by modulating CXCL9:SPP1 polarity: A single-cell transcriptomic study.","date":"2026","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41906630","citation_count":0,"is_preprint":false},{"pmid":"41494598","id":"PMC_41494598","title":"ZFP36L1-mediated PRDM1 mRNA degradation inhibits inflammatory activation of Kupffer cells and ameliorates DCD liver ischemic-reperfusion injury.","date":"2026","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/41494598","citation_count":0,"is_preprint":false},{"pmid":"42053094","id":"PMC_42053094","title":"ZFP36L1 Enhances Microglial Ferroptosis in Ischemic Stroke by Reducing FTO-Mediated N6-Methyladenosine Demethylation of ACSL1 mRNA.","date":"2026","source":"The Kaohsiung journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/42053094","citation_count":0,"is_preprint":false},{"pmid":"41724861","id":"PMC_41724861","title":"Bronchial epithelial-derived exosomal SLC6A14 promotes airway inflammation and mucus hypersecretion via the ZFP36L1/IL-8 axis.","date":"2026","source":"Functional & integrative genomics","url":"https://pubmed.ncbi.nlm.nih.gov/41724861","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.09.675154","title":"A post-transcriptional regulatory checkpoint controls the response of tumor-infiltrating cytotoxic CD4  <sup>+</sup>  T cells to immunotherapy","date":"2025-09-12","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.09.675154","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.25.666749","title":"Proximity labeling reveals ZFP36L1 as a central hub for post-transcriptional regulation networks in T cells","date":"2025-07-27","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.25.666749","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.01.626220","title":"RNA-binding proteins control the G2-M checkpoint of the germinal centre B cell","date":"2024-12-05","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.01.626220","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":44055,"output_tokens":9610,"usd":0.138157,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19971,"output_tokens":6089,"usd":0.12604,"stage2_stop_reason":"end_turn"},"total_usd":0.264197,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"ZFP36L1 (TIS11b) binds AU-rich elements in the 3'-UTR of VEGF mRNA and decreases its stability (half-life reduced from 130 to 60 min); RNP immunoprecipitation confirmed interaction in live cells; siRNA knockdown demonstrated TIS11b participates in basal and ACTH-induced VEGF mRNA expression control\",\n      \"method\": \"mRNA stability assay, RNP immunoprecipitation, siRNA knockdown, reporter assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal RIP, functional stability assay, and siRNA knockdown with defined readout; independently replicated in multiple subsequent papers\",\n      \"pmids\": [\"15467755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Disruption of Zfp36l1 in mice causes embryonic lethality with chorioallantoic fusion defects and placental atrophy; Zfp36l1 has mRNA destabilization and deadenylation activities similar to TTP in cellular and cell-free assays\",\n      \"method\": \"Knockout mouse, cell-free RNA binding and deadenylation assays, cellular RNA destabilization assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro biochemical assays plus in vivo knockout with defined phenotype\",\n      \"pmids\": [\"15226444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Zfp36l1 knockout embryos show elevated VEGF-A protein with enhanced association with polyribosomes (not altered mRNA stability), suggesting ZFP36L1 influences translational repression of VEGF-A in vivo\",\n      \"method\": \"Polyribosome fractionation, conditional knockout mouse, mRNA stability measurement\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — polyribosome fractionation plus KO, single lab, two orthogonal methods\",\n      \"pmids\": [\"17013884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ZFP36L1/TIS11b binds UAUUUAUU repeats in the extended 3'-UTR of the 3.5-kb StAR mRNA and promotes its degradation; direct complex formation demonstrated; AURE mutations showed first two UAUUUAUU motifs required for TIS11b-mediated destabilization; siRNA knockdown of TIS11b enhanced 3.5-kb StAR mRNA levels and halved STAR protein induction with decreased cholesterol metabolism\",\n      \"method\": \"RNA pull-down, co-transfection reporter assay, site-directed mutagenesis of AREs, siRNA knockdown\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct binding demonstrated, mutagenesis of binding sites, knockdown phenotype with multiple orthogonal methods\",\n      \"pmids\": [\"19179481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ZFP36L1 and ZFP36L2 bind evolutionarily conserved AU-rich elements in the 3'-UTR of Notch1 mRNA and suppress its expression; their combined deletion during thymopoiesis leads to elevated Notch1 and T-ALL development dependent on Notch1\",\n      \"method\": \"Conditional double knockout mouse, RIP, reporter assay, genetic epistasis with Notch1\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal RIP, in vivo knockout, genetic epistasis with Notch1, replicated across multiple approaches\",\n      \"pmids\": [\"20622884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ZFP36L1 binds the 3'-UTR of Stat5b mRNA via AU-rich elements and promotes its degradation, thereby negatively regulating erythroid differentiation of CD34+ hematopoietic progenitors\",\n      \"method\": \"mRNA binding assay, overexpression/knockdown, erythroid colony formation assay, luciferase reporter\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding demonstrated, gain/loss of function with defined phenotype, single lab\",\n      \"pmids\": [\"20702587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TIS11b/ZFP36L1 binds to an AUUUA motif in the Dll4 mRNA 3'-UTR and represses Dll4 expression by interfering with mRNA 3'-end polyadenylation/cleavage efficiency, rather than mRNA stability — a novel mechanism for ZFP36L1 in mRNA 3'-end maturation\",\n      \"method\": \"RIP, reporter assay, poly(A) signal mutagenesis, mRNA cleavage/poly(A) ratio analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP demonstrating direct binding, mutagenesis of binding sites, multiple mechanistic readouts; single lab\",\n      \"pmids\": [\"21832157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ZFP36L1 binds AU-rich elements in the BLIMP1 mRNA 3'-UTR and promotes its degradation, thereby negatively regulating plasmacytoid differentiation; shRNA knockdown of ZFP36L1 increased BLIMP1 mRNA and protein but not other differentiation factors (xbp1, irf4, bcl6); ZFP36L1 reduced activity of a BLIMP1 3'-UTR luciferase reporter\",\n      \"method\": \"shRNA knockdown, luciferase reporter assay, mRNA measurement, microarray network reconstruction\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter, knockdown with defined phenotype, network reconstruction; single lab\",\n      \"pmids\": [\"23284928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ZFP36L1 and ZFP36L2 bind the 3'-UTR of LDLR mRNA and recruit the CCR4-NOT deadenylase complex, causing mRNA destabilization; p90 ribosomal S6 kinase (RSK), downstream of ERK, directly phosphorylates the C-terminal regions of ZFP36L1/L2, causing dissociation of CCR4-NOT and stabilization of LDLR mRNA\",\n      \"method\": \"Proteomic RNA pull-down, kinase assay, co-IP with CCR4-NOT subunits, phosphorylation site analysis, antisense oligonucleotides\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assay, protein complex disruption demonstrated, multiple orthogonal methods including proteomics and functional rescue\",\n      \"pmids\": [\"25106868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ZFP36L1 binds AU-rich elements in BCL2 mRNA 3'-UTR and promotes its degradation in B cells; zinc finger mutant ZFP36L1 failed to downregulate BCL2 3'-UTR reporter; removal of ARE core reduced ZFP36L1-mediated effect\",\n      \"method\": \"EMSA, luciferase 3'-UTR reporter assay, zinc finger mutagenesis, shRNA knockdown with mRNA stability measurement\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA, reporter assay, mutagenesis; single lab\",\n      \"pmids\": [\"25014217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Hypertonicity increases TIS11b/ZFP36L1 expression which binds a specific ARE motif in the mineralocorticoid receptor (MR) mRNA 3'-UTR, decreasing MR mRNA stability (~50% shorter half-life); RNA immunoprecipitation confirmed endogenous TIS11b physically interacts with MR mRNA; TIS11b knockdown prevented hypertonicity-induced MR repression in vivo\",\n      \"method\": \"Luciferase reporter with 3'-UTR mutants, site-directed mutagenesis, RNA immunoprecipitation, co-IP, knockdown, in vivo water deprivation model\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RIP, mutagenesis, knockdown, and in vivo validation with multiple orthogonal methods\",\n      \"pmids\": [\"24700863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ZFP36L1 binds AU-rich elements in the CDK6 mRNA 3'-UTR and negatively regulates CDK6 expression, thereby promoting monocyte/macrophage differentiation\",\n      \"method\": \"Lentiviral gain/loss of function, RIP/3'-UTR binding assay, differentiation assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding to CDK6 3'-UTR demonstrated, gain/loss of function with differentiation phenotype; single lab\",\n      \"pmids\": [\"26542173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ZFP36L1 and ZFP36L2 suppress a posttranscriptional regulon of cell-cycle-promoting mRNAs to maintain quiescence in developing B lymphocytes before and after pre-BCR expression, thereby promoting VDJ recombination\",\n      \"method\": \"Conditional double knockout mouse, genome-wide mRNA analysis, cell cycle analysis, FACS-based quiescence assay\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with genome-wide target identification and defined cellular phenotypes; replicated across multiple developmental checkpoints\",\n      \"pmids\": [\"27102483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Zfp36l1 and Zfp36l2 regulate DNA damage response and cell cycle transcripts in thymocytes to enforce the beta-selection checkpoint; their targets were identified genome-wide in primary mouse thymocytes; absence of these RBPs allows DN3 thymocytes to acquire a post-selection gene expression profile despite lacking TCRβ\",\n      \"method\": \"Conditional double knockout mouse, genome-wide mRNA profiling of primary thymocytes, cell cycle analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide target identification in primary cells, conditional KO with defined developmental phenotype\",\n      \"pmids\": [\"27566829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PKA activation phosphorylates TIS11b/ZFP36L1 at Ser-54 and Ser-334; phosphomimetic mutation at C-terminal S334 increased TIS11b half-life and enhanced mRNA decay activity; mimicking phosphorylation at S334 enhanced interaction with decapping coactivator Dcp1a, while preventing S334 phosphorylation potentiated interaction with CCR4-NOT subunit Cnot1\",\n      \"method\": \"Site-directed mutagenesis, kinase assay, phosphosite immunodetection, co-IP with mRNA decay machinery components\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assay, mutagenesis, protein-protein interaction studies with multiple mRNA decay factors; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"27708140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ZFP36L1 is an FXR target gene; gain and loss of ZFP36L1 function reciprocally regulates Cyp7a1 mRNA levels and bile acid levels in vivo; ZFP36L1 promotes Cyp7a1 mRNA decay; mice lacking hepatic ZFP36L1 are protected from diet-induced obesity and steatosis through altered bile acid metabolism\",\n      \"method\": \"Conditional liver-specific knockout mouse, gain/loss of function, in vivo bile acid measurement, mRNA decay assay\",\n      \"journal\": \"Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO, gain/loss of function, in vivo metabolic phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"28891815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ZFP36L1 controls the identity of marginal-zone B cells by limiting expression of transcription factors KLF2 and IRF8 post-transcriptionally via AU-rich element binding, and regulates a gene-expression program related to signaling, cell adhesion and locomotion; ZFP36L1 is specifically required for proper MZ B cell localization and survival\",\n      \"method\": \"Conditional knockout mouse, transcriptome analysis, flow cytometry, homing assay\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined cellular phenotype, transcriptome-wide target analysis, multiple functional assays\",\n      \"pmids\": [\"28394372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ZFP36L1 inhibits cell proliferation and arrests the cell cycle at G1 in a cyclin D-dependent and p53-independent manner; TZF domain mutations abolish antiproliferative activity and cyclin D suppression; demonstrated in p53+/+ and p53-/- cells\",\n      \"method\": \"Overexpression, TZF domain mutagenesis, cell cycle analysis, knockdown in multiple cancer cell lines\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of functional domain, multiple cell lines including isogenic p53 pairs; single lab\",\n      \"pmids\": [\"29426877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ZFP36L1 phosphorylation is modulated in a cell cycle-dependent manner; the C-terminal region is critical for cell cycle-dependent phosphorylation; phosphorelay-dependent regulation of ZFP36L1 influences mitotic spindle organization\",\n      \"method\": \"Cell synchronization, subcellular fractionation, phosphorylation analysis, mitotic spindle imaging\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method for spindle organization, partial mechanistic follow-up; single lab\",\n      \"pmids\": [\"29709483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ZFP36L1 binds the 3'-UTRs of HSP70 family members (HSPA1A) via AU-rich elements and promotes their mRNA decay; ZFP36L1 knockdown increases HSP70 expression and protects against OA; ZFP36L1 silencing abrogates experimental osteoarthritis in mice\",\n      \"method\": \"Adenovirus-mediated overexpression, genetic ablation, siRNA knockdown, in vivo OA model, mRNA stability assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO, gain/loss of function with defined OA phenotype, direct mRNA target validation; multiple orthogonal methods\",\n      \"pmids\": [\"30622281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ZFP36L1 binds AU-rich elements in the 3'-UTRs of HIF1A, CCND1, and E2F1 mRNAs and promotes their decay; wild-type but not zinc-finger mutant ZFP36L1 bound HIF1A 3'-UTR in EMSA and luciferase assays; ZFP36L1 suppresses hypoxia signaling and cell-cycle progression\",\n      \"method\": \"RNA pull-down with WT and mutant ZFP36L1, whole transcriptome sequencing, luciferase reporter, EMSA, in vitro and in vivo tumor models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — systematic RNA pull-down with mutant controls, EMSA, reporter assay, transcriptome-wide target identification\",\n      \"pmids\": [\"31551365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ZFP36L1 nuclear accumulation is cell cycle-dependent, prominent at G1/S boundary and reduced in S and G2 phases; the C-terminal serine-rich cluster is critical for regulating nuclear accumulation and cell cycle-dependent fluctuations; forced nuclear targeting led to ZFP36L1 elimination in S and G2 phases\",\n      \"method\": \"Cell fractionation, cell cycle synchronization, truncation mutant analysis, nuclear targeting constructs\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — fractionation with functional domain analysis; single lab, single study\",\n      \"pmids\": [\"32687160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ZFP36L1 represses translation directly via AU-rich elements independent of deadenylation; interaction with CNOT1 is required for translational repression; unlike TTP, ZFP36L1 does not efficiently interact with 4E-HP or GIGYF2; ZFP36L1 translation repression is resistant to eIF4A inhibitor silvestrol, suggesting a distinct mechanism from miRISC\",\n      \"method\": \"In vitro mammalian translation system, IRES reporter assays, mutant protein functional assays, co-immunoprecipitation\",\n      \"journal\": \"Biochimie\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro reconstitution, mutant analysis, multiple reporter assays; single lab\",\n      \"pmids\": [\"32311426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ZFP36L1 reduces influenza A virus (IAV) replication via translational repression of HA, M and NS viral RNA transcripts; ZFP36L1 directly binds IAV NS1 mRNA in the cytoplasm; CCCH zinc finger domain mutations abolished antiviral activity and NS1 mRNA binding\",\n      \"method\": \"Overexpression/knockdown, zinc finger domain mutagenesis, RIP, viral replication assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding to viral mRNA demonstrated with mutagenesis, functional antiviral assay; single lab\",\n      \"pmids\": [\"32556261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZFP36L1 destabilizes JEV genome RNA by targeting AU-rich element (AUUUA) motifs in the 3'-UTR and recruits both XRN1 (5'-3') and RNA-exosome (3'-5') decay pathways; zinc finger domain mutations disrupted RNA binding and antiviral activity\",\n      \"method\": \"Overexpression/knockdown, zinc finger mutagenesis, XRN1/exosome knockdown epistasis, viral RNA stability assay, 3'-UTR mapping\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic dissection of two decay pathways, mutagenesis, epistasis; single lab\",\n      \"pmids\": [\"34643435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZFP36L1 directly regulates G protein-coupled receptor kinase 2 (GRK2) and the integrin chains α4 and β1 mRNAs in splenic antibody-secreting cells (ASCs), limiting their abundance and facilitating ASC homing to the bone marrow; ZFP36L1-deficient ASCs accumulate in spleen and liver with diminished bone marrow accumulation\",\n      \"method\": \"Conditional knockout mouse, RNA-IP, flow cytometry, homing assay\",\n      \"journal\": \"Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined homing phenotype, RNA-IP for target validation; single lab\",\n      \"pmids\": [\"33306108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZFP36L1 directly binds AREs in the Fgf21 mRNA 3'-UTR and promotes its decay; wild-type but not zinc finger mutant ZFP36L1 decreased Fgf21 mRNA levels in luciferase reporter assays; liver-specific ZFP36L1 KO mice are protected from alcohol-induced hepatic steatosis, associated with elevated Fgf21 mRNA\",\n      \"method\": \"Liver-specific conditional knockout mouse, luciferase reporter, zinc finger mutant, RNA pull-down, in vivo alcohol model\",\n      \"journal\": \"American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO, reporter assay, mutagenesis, direct RNA binding; multiple orthogonal methods\",\n      \"pmids\": [\"34774847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ZFP36L1 binds AU-rich elements in the ZEB2 mRNA 3'-UTR and promotes its degradation; ZFP36L1 silencing increases ZEB2 mRNA stability and promotes EMT in liver cancer cells; ZFP36L1 overexpression downregulates ZEB2 and abolishes EMT; ZEB2 3'-UTR is regulated by ZFP36L1 in luciferase reporter assays\",\n      \"method\": \"siRNA knockdown, overexpression, mRNA stability assay, luciferase 3'-UTR reporter, RNA-seq\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay, mRNA stability, gain/loss of function; single lab\",\n      \"pmids\": [\"36100056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LSD1 binds and represses ZFP36L1; upon LSD1 inhibition, ZFP36L1 expression is restored and is sufficient to block SCLC neuroendocrine differentiation; ZFP36L1 binds and destabilizes SOX2 and INSM1 mRNAs (required for neuroendocrine differentiation); constitutive ZFP36L1 was required for LSD1 inhibitor sensitivity in a CRISPR screen\",\n      \"method\": \"Genome-wide CRISPR loss-of-function screen, overexpression, RIP, mRNA stability assay, ChIP for LSD1\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide CRISPR screen identified ZFP36L1, direct mRNA binding demonstrated, multiple orthogonal methods\",\n      \"pmids\": [\"36008402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ZFP36L1 promotes mRNA decay of SDC4 by binding AU-rich elements in its 3'-UTR, thereby inhibiting TGF-β signaling and suppressing osteosarcoma lung metastasis; SDC4 protects TGFBR3 from MMP-mediated cleavage, forming a positive SDC4-TGF-β feedback loop that ZFP36L1 inhibits\",\n      \"method\": \"Knockdown/overexpression, luciferase 3'-UTR reporter, RIP, in vivo metastasis model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding demonstrated, reporter assay, in vivo model; single lab\",\n      \"pmids\": [\"37935976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ZFP36L1 acts as a sensor of TCR affinity within an incoherent feed-forward loop, suppressing negative regulators of cytokine (IL-2) signaling to promote clonal expansion of high-affinity CD8 T cells; ZFP36L1 has a non-redundant role in establishing the dominance of high-affinity T cells through hierarchical IL-2 competition\",\n      \"method\": \"Conditional knockout mouse, adoptive transfer, in vivo competition assay, transcriptome analysis\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo clonal competition assay, conditional KO; defined functional circuit but molecular targets not fully characterized in this paper\",\n      \"pmids\": [\"38039407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZFP36L1, driven by a super-enhancer with SPI1 as the transcription factor, binds AU-rich elements in the HDAC3 mRNA 3'-UTR and promotes its decay, thereby reducing HDAC3-mediated transcriptional repression of PD-L1 and enhancing IFN-γ-induced PD-L1 expression in gastric cancer\",\n      \"method\": \"H3K27ac CUT&Tag, luciferase reporter, GST/RNA pull-down, ChIP/RIP, ChIP for SPI1, flow cytometry, in vivo functional assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNA pull-down, RIP, ChIP, reporter assay, and in vivo validation with multiple orthogonal methods\",\n      \"pmids\": [\"39373630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZFP36L1 directly binds AU-rich elements in the DCLRE1C mRNA 3'-UTR and promotes its degradation; ZFP36L1 overexpression reduces NHEJ DNA repair efficiency via DCLRE1C downregulation; decreased ZFP36L1 expression enables methotrexate resistance in osteosarcoma\",\n      \"method\": \"3'-UTR binding analysis, overexpression/knockdown, NHEJ efficiency assay, drug sensitivity assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding to 3'-UTR demonstrated, functional NHEJ assay; single lab\",\n      \"pmids\": [\"41285712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZFP36L1 and ZFP36L2 restrain CDK1 and cyclin B1 expression in germinal centre B cells while controlling a p21-mediated negative feedback loop; absence of these RBPs causes G2-M arrest, DNA replication fork stalling, ATR/CHK1 activation, and apoptosis — resulting in curtailed germinal centre responses\",\n      \"method\": \"Conditional double knockout mouse, cell cycle analysis, DNA replication fork analysis, transcriptome profiling of GC B cells\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined cell cycle phenotype and replication stress readouts; preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZFP36L1 expression in CD8+ T cells is regulated by calcineurin/NFAT signaling (cyclosporin A potently inhibits ZFP36L1 but not ZFP36 expression); p38 MAPK, MEK1/2, and PKC contribute to inducing ZFP36L1; the Zfp36l1 promoter is enriched for NFAT binding sites while Zfp36 promoter has ELK-1/4 sites\",\n      \"method\": \"Pharmacological inhibitors of TCR signaling pathways, promoter analysis, in vitro T cell activation\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple pharmacological inhibitors, promoter analysis; functional promoter binding not directly demonstrated\",\n      \"pmids\": [\"41211771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ZFP36L1 protein interacts with CNOT1 and components of mRNA decay, deadenylation, decapping, stress granule/P-body formation, and 5'-UTR-mediated translation repression in primary human T cells; the helicase UPF1 both interacts with ZFP36L1 protein and promotes its protein expression; the ZFP36L1 interactome is dynamic and partly RNA-dependent during T cell activation\",\n      \"method\": \"Proximity labeling (BioID), mass spectrometry, primary human T cells, RNA dependency analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic proximity labeling in primary human T cells with interactome dynamics; preprint, not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Anti-CTLA-4 or anti-LAG-3/PD-1 immunotherapy reduces ZFP36L1 expression in tumor-infiltrating CD4+ T cells, relieving post-transcriptional repression of Gzmb mRNA translation; constitutive ZFP36L1 abrogates the effects of anti-CTLA-4; deletion of ZFP36L1 (with ZFP36) triggers GzmB protein production and promotes tumor control\",\n      \"method\": \"In vivo tumor model with immune checkpoint blockade, conditional knockout, translational reporter assay, CRISPR\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo conditional KO and checkpoint blockade with defined molecular and tumor phenotype; preprint, not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ZFP36L1 promotes mRNA decay of CAMK2A by binding to its 3'-UTR AREs; ZFP36L1 knockout in CRS mice restores CAMK2A expression and attenuates ferroptosis and mitochondrial dysfunction; CAMK2A knockdown reverses the protective effects of ZFP36L1 depletion\",\n      \"method\": \"In vivo CRS mouse model with ZFP36L1 KO, RIP/binding assay, rescue experiments\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'-UTR binding, KO model, epistasis rescue experiment; single lab\",\n      \"pmids\": [\"42051151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ZFP36L1 promotes mRNA degradation of PRDM1 by binding AU-rich elements in its 3'-UTR in Kupffer cells, thereby suppressing inflammatory activation and ameliorating liver ischemia-reperfusion injury; PRDM1 overexpression reverses the suppressive effect of ZFP36L1\",\n      \"method\": \"Rat DCD liver transplant model, LPS-stimulated Kupffer cells, overexpression vectors, RIP\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding demonstrated, in vivo model with rescue experiment; single lab\",\n      \"pmids\": [\"41494598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In LPS-stimulated macrophages, ZFP36L1 is phosphorylated; hyper-phosphorylated ZFP36L1 stabilizes Mkp-1 mRNA by forming a complex with adapter protein 14-3-3 and decreasing interaction with deadenylase Caf1a; knockdown of ZFP36L1 increases basal Mkp-1 mRNA half-life\",\n      \"method\": \"siRNA knockdown, mRNA half-life assay, co-immunoprecipitation with 14-3-3 and Caf1a, LPS stimulation\",\n      \"journal\": \"Journal of inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP demonstrating 14-3-3 and Caf1a interactions, mRNA stability assay; single lab\",\n      \"pmids\": [\"26180518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ZFP36L1 binds the 3'-UTR of PPARγ2 (Pparγ2) mRNA and promotes its degradation, repressing adipogenic differentiation; ZFP36L1-containing RNP complexes contained less Pparγ2 mRNA; 3'-UTR reporter constructs demonstrated reduced luciferase in ZFP36L1-overexpressing cells\",\n      \"method\": \"Biotin pull-down, EMSA, luciferase reporter, RNP immunoprecipitation, transcriptional blockade kinetics\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple binding assays and reporter; single lab\",\n      \"pmids\": [\"28206953\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZFP36L1 is a CCCH tandem zinc-finger RNA-binding protein that binds AU-rich elements (AREs) in the 3'-UTRs of target mRNAs and promotes their deadenylation (via CCR4-NOT recruitment), mRNA decay (via XRN1 and RNA-exosome pathways), and translational repression (via CNOT1 interaction independent of deadenylation); its activity is regulated by phosphorylation — notably by RSK downstream of ERK (releasing CCR4-NOT) and by PKA (enhancing mRNA decay and shifting interaction from Cnot1 to Dcp1a) — and its nuclear accumulation is cell cycle-dependent, controlled by a C-terminal serine-rich cluster; key validated targets include VEGF, Notch1, LDLR, BCL2, BLIMP1, HIF1A, CCND1, CDK6, StAR, MR, Cyp7a1, Fgf21, ZEB2, SOX2, INSM1, HDAC3, GRK2, SDC4, DCLRE1C, CAMK2A, and PRDM1; through these mechanisms ZFP36L1 controls cell quiescence, lymphocyte development, angiogenesis, steroidogenesis, bile acid metabolism, antiviral defense, and immune cell differentiation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ZFP36L1 is a CCCH tandem zinc-finger RNA-binding protein that recognizes AU-rich elements (AREs) in target mRNA 3'-UTRs and drives their post-transcriptional silencing, thereby controlling cell quiescence, lymphocyte development, angiogenesis, metabolism, and immune differentiation [#1, #12, #20]. It functions principally by destabilizing bound transcripts: it recruits the CCR4-NOT deadenylase complex to initiate decay, and in the case of viral and host RNAs engages both the XRN1 5'-3' and RNA-exosome 3'-5' degradation pathways [#8, #24]. Beyond destabilization, ZFP36L1 represses translation directly through a CNOT1-dependent, deadenylation-independent mechanism that is distinct from the miRISC/4E-HP route used by its paralog TTP [#22], and can interfere with 3'-end cleavage/polyadenylation of target pre-mRNAs [#6]. ARE recognition requires an intact tandem zinc-finger domain, mutation of which abolishes both RNA binding and downstream regulatory and antiproliferative activity [#9, #20, #23]. Its activity is gated by phosphorylation: RSK acting downstream of ERK phosphorylates the C-terminal region to dissociate CCR4-NOT and stabilize targets, while PKA phosphorylation at Ser-334 increases protein half-life and shifts partner engagement from CNOT1 toward the decapping coactivator Dcp1a [#8, #14]; a C-terminal serine-rich cluster additionally governs cell cycle-dependent nuclear accumulation [#21]. Through ARE-mediated control of cell-cycle and signaling regulons, ZFP36L1 enforces quiescence and developmental checkpoints in B and T lymphocytes—including pre-BCR, beta-selection, and germinal-centre transitions—and shapes T-cell responses to TCR affinity and checkpoint blockade [#12, #13, #16, #30]. Validated targets spanning these programs include VEGF/Dll4, Notch1, LDLR, BCL2, HIF1A/CCND1/E2F1, CDK6, Cyp7a1, Fgf21, and the neuroendocrine factors SOX2 and INSM1 [#0, #4, #8, #9, #15, #20, #28].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing that ZFP36L1 is a functional ARE-binding mRNA-destabilizing protein answered whether it acts directly on target transcripts and is biologically essential.\",\n      \"evidence\": \"ARE binding and stability assay on VEGF mRNA with RNP-IP and siRNA; knockout mouse plus cell-free deadenylation assays\",\n      \"pmids\": [\"15467755\", \"15226444\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the decay machinery recruited\", \"Phosphorylation control not yet addressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Polyribosome analysis in knockout embryos revealed that ZFP36L1 can act at the translational level, not only by altering mRNA stability.\",\n      \"evidence\": \"Polyribosome fractionation and mRNA stability measurement in conditional KO mouse embryos\",\n      \"pmids\": [\"17013884\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of translational repression undefined\", \"No interaction partner identified for this activity\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Mapping ZFP36L1 to specific UAUUUAUU motifs in StAR mRNA defined the sequence determinants of target recognition and linked decay activity to steroidogenic output.\",\n      \"evidence\": \"RNA pull-down, ARE mutagenesis, reporter assay, and siRNA knockdown with cholesterol metabolism readout\",\n      \"pmids\": [\"19179481\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Decay machinery recruited not characterized here\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Genetic work in lymphocytes showed ZFP36L1 (with ZFP36L2) suppresses developmental transcription factors, establishing its role in lymphopoiesis and tumor suppression.\",\n      \"evidence\": \"Conditional double-KO mice with RIP and genetic epistasis (Notch1 in thymopoiesis; Stat5b in erythroid progenitors)\",\n      \"pmids\": [\"20622884\", \"20702587\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Redundancy between paralogs not fully separated\", \"Mechanism of decay vs translation control not dissected\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Discovery that ZFP36L1 represses Dll4 by impairing 3'-end cleavage/polyadenylation extended its mechanistic repertoire beyond stability and translation.\",\n      \"evidence\": \"RIP, poly(A) signal mutagenesis, and mRNA cleavage/poly(A) ratio analysis\",\n      \"pmids\": [\"21832157\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of the 3'-end maturation mechanism across targets unknown\", \"Factors mediating cleavage interference unidentified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identification of CCR4-NOT recruitment and its release by RSK phosphorylation, plus PKA-driven partner switching, established how signaling kinases gate ZFP36L1 decay activity.\",\n      \"evidence\": \"Proteomic pull-down, in vitro kinase and co-IP assays with CCR4-NOT subunits, Cnot1 and Dcp1a; phosphosite analysis\",\n      \"pmids\": [\"25106868\", \"27708140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and dynamics of partner switching in vivo unresolved\", \"Full set of regulatory kinases not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating zinc-finger-dependent regulation of BCL2 and stress-responsive control of the mineralocorticoid receptor broadened the target landscape and tied ARE binding mechanistically to zinc-finger integrity.\",\n      \"evidence\": \"EMSA, 3'-UTR reporter, zinc-finger mutagenesis for BCL2; RIP, mutagenesis and in vivo water deprivation for MR\",\n      \"pmids\": [\"25014217\", \"24700863\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Decay machinery for these targets not mapped\", \"Tissue-specific regulation incompletely defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Genome-wide target identification in primary lymphocytes showed ZFP36L1 enforces quiescence by suppressing a cell-cycle regulon at developmental checkpoints.\",\n      \"evidence\": \"Conditional double-KO mice with genome-wide mRNA profiling and cell-cycle/quiescence assays in B cells and thymocytes\",\n      \"pmids\": [\"27102483\", \"27566829\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect targets not fully separated transcriptome-wide\", \"Contribution of each paralog not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"In vivo metabolic and B-cell identity studies extended ZFP36L1 function to bile-acid metabolism and marginal-zone B-cell positioning through defined ARE targets.\",\n      \"evidence\": \"Liver-specific and conditional KO mice; gain/loss of function with Cyp7a1 decay assay and KLF2/IRF8 transcriptome analysis\",\n      \"pmids\": [\"28891815\", \"28394372\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals coupling FXR to ZFP36L1 activity incompletely mapped\", \"Whether translation vs decay dominates per target not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Domain mapping established the antiproliferative G1-arrest activity as zinc-finger-dependent and p53-independent, and linked C-terminal phosphorylation to cell-cycle behavior.\",\n      \"evidence\": \"TZF mutagenesis and cell-cycle analysis in isogenic p53 cell lines; cell synchronization with phosphorylation and spindle imaging\",\n      \"pmids\": [\"29426877\", \"29709483\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Spindle organization link rests on a single low-confidence method\", \"Phosphorelay components not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Reconstitution showed ZFP36L1 represses translation via CNOT1 independent of deadenylation and through a mechanism distinct from miRISC, and mapped cell-cycle-dependent nuclear accumulation to a C-terminal serine cluster.\",\n      \"evidence\": \"In vitro mammalian translation system, IRES reporters, co-IP; cell fractionation with truncation and nuclear-targeting constructs\",\n      \"pmids\": [\"32311426\", \"32687160\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular intermediary between ZFP36L1-CNOT1 and ribosome unknown\", \"Trigger for nuclear elimination in S/G2 undefined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Antiviral studies demonstrated ZFP36L1 directly targets viral RNAs, repressing influenza transcripts translationally and destabilizing JEV genome RNA via dual XRN1/exosome decay.\",\n      \"evidence\": \"Zinc-finger mutagenesis, RIP, viral replication and RNA stability assays; XRN1/exosome knockdown epistasis\",\n      \"pmids\": [\"32556261\", \"34643435\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Determinants of decay-vs-translation choice on viral targets unclear\", \"Breadth of antiviral spectrum not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Cancer- and disease-model work expanded validated targets (HIF1A/CCND1/E2F1, HSP70) and tied ARE-mediated decay to hypoxia, proliferation, and osteoarthritis phenotypes.\",\n      \"evidence\": \"Systematic RNA pull-down with mutant controls, EMSA, transcriptome sequencing, and in vivo tumor/OA models\",\n      \"pmids\": [\"31551365\", \"30622281\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Context-dependence of target selection across tissues unresolved\", \"Upstream regulators in these settings not fully mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Studies in plasma cells, T cells, and adipocyte/macrophage systems linked ZFP36L1 to homing, signaling adaptors, and metabolic differentiation through defined targets.\",\n      \"evidence\": \"Conditional KO with RNA-IP for GRK2/integrins; reporter and KO for Fgf21; co-IP showing 14-3-3/Caf1a-dependent Mkp-1 control; PPARγ2 reporter assays\",\n      \"pmids\": [\"33306108\", \"34774847\", \"26180518\", \"28206953\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phospho-dependent stabilization mechanism (14-3-3) not generalized\", \"Relative target hierarchy per cell type unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Epigenetic and EMT studies showed ZFP36L1 is itself transcriptionally controlled (LSD1 repression, SPI1/super-enhancer activation) and represses neuroendocrine and metastatic programs via SOX2/INSM1, ZEB2, and HDAC3.\",\n      \"evidence\": \"CRISPR screen, ChIP, RIP, mRNA stability and reporter assays in SCLC, gastric and liver cancer models\",\n      \"pmids\": [\"36008402\", \"36100056\", \"39373630\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How upstream transcriptional inputs are integrated with phospho-regulation unknown\", \"Causality of individual targets in tumor phenotypes incompletely separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"T-cell and metastasis studies positioned ZFP36L1 within signaling circuits, acting as a TCR-affinity sensor in an IL-2 feed-forward loop and suppressing TGF-β signaling via SDC4 decay.\",\n      \"evidence\": \"Conditional KO with in vivo competition assays; RIP, reporter and in vivo metastasis model for SDC4\",\n      \"pmids\": [\"38039407\", \"37935976\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular targets of the affinity-sensing circuit not fully defined\", \"Whether SDC4 effect is decay or translational not dissected\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"DNA-repair and proliferation studies linked ZFP36L1 to NHEJ (via DCLRE1C) and germinal-centre cell-cycle control with replication-stress consequences when lost.\",\n      \"evidence\": \"3'-UTR binding and NHEJ/drug sensitivity assays; conditional double-KO with replication fork and DNA-damage-response analysis (preprint)\",\n      \"pmids\": [\"41285712\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Germinal-centre findings remain a non-peer-reviewed preprint\", \"Direct vs feedback contribution to CDK1/cyclin B1/p21 control not separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Interactome and signaling studies in primary T cells defined the protein partners and upstream calcineurin/NFAT control of ZFP36L1 and its role in immunotherapy responses.\",\n      \"evidence\": \"BioID/MS interactome (UPF1, CNOT1, decay/P-body factors), pharmacological TCR-pathway dissection, and checkpoint-blockade tumor models (two preprints plus peer-reviewed promoter analysis)\",\n      \"pmids\": [\"41211771\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interactome and checkpoint findings are non-peer-reviewed preprints\", \"Functional roles of UPF1 and stress-granule factors not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Recent disease-model work added CAMK2A and PRDM1 as targets linking ZFP36L1 to ferroptosis/mitochondrial dysfunction and Kupffer-cell inflammation.\",\n      \"evidence\": \"In vivo KO models with RIP and epistasis rescue (CAMK2A, PRDM1)\",\n      \"pmids\": [\"42051151\", \"41494598\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab target validations without independent replication\", \"Decay vs translational mechanism per target not dissected\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how ZFP36L1 selects between deadenylation, decapping, exosome/XRN1 decay, translational repression, and 3'-end interference on a given target, and how phospho-state and partner switching dictate that choice in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of ZFP36L1-machinery complexes\", \"Rules governing decay-vs-translation outcome per transcript undefined\", \"Quantitative map of phospho-states to interactomes in primary cells missing\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 3, 4, 9, 20, 23, 24]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [1, 8, 24]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [8, 14, 22, 39]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [2, 22, 23, 36]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [23, 21]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [21, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 8, 20, 24]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [12, 13, 17, 20]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 12, 16, 30]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 4, 11]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 15, 26, 40]}\n    ],\n    \"complexes\": [\"CCR4-NOT\"],\n    \"partners\": [\"CNOT1\", \"DCP1A\", \"XRN1\", \"RSK\", \"UPF1\", \"YWHAB\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}