ZFP36

Summary

ZFP36 (ZFP36 zinc finger CCCH-type, HGNC:12862) is a protein-coding gene on chromosome 19q13.2, encoding mRNA decay activator protein ZFP36 (P26651). 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.

Enables several functions, including 14-3-3 protein binding activity; mRNA 3’-UTR AU-rich region binding activity; and protein-RNA sequence-specific adaptor activity. Involved in several processes, including cellular response to cytokine stimulus; cellular response to epidermal growth factor stimulus; and regulation of gene expression. Acts upstream of or within mRNA catabolic process. Located in cytoplasmic ribonucleoprotein granule; cytosol; and nucleus. Part of ribonucleoprotein complex. Biomarker of breast cancer.

Source: NCBI Gene 7538 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 42 total
• MANE Select transcript: NM_003407

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12862
Approved symbol	ZFP36
Name	ZFP36 zinc finger CCCH-type
Location	19q13.2
Locus type	gene with protein product
Status	Approved
Aliases	TIS11, G0S24, TTP, NUP475
Ensembl gene	ENSG00000128016
Ensembl biotype	protein_coding
OMIM	190700
Entrez	7538

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000594045, ENST00000597629, ENST00000600033, ENST00000652583, ENST00000918416

RefSeq mRNA: 1 — MANE Select: NM_003407 NM_003407

CCDS: CCDS12534

Canonical transcript exons

ENST00000597629 — 2 exons

Exon	Start	End
ENSE00004023568	39407743	39409407
ENSE00004023569	39406847	39406928

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.98.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 564.7047 / max 31487.9066, expressed in 1825 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
175722	550.1476	1825
175730	3.0501	694
175748	2.5630	677
175728	2.3563	580
175725	2.2935	488
175723	2.0852	473
175747	0.5235	214
175727	0.4957	166
175726	0.4306	172
175729	0.2435	100

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
vena cava	UBERON:0004087	99.98	gold quality
mucosa of stomach	UBERON:0001199	99.88	gold quality
left uterine tube	UBERON:0001303	99.83	gold quality
trachea	UBERON:0003126	99.76	gold quality
saphenous vein	UBERON:0007318	99.72	gold quality
cardia of stomach	UBERON:0001162	99.70	gold quality
omental fat pad	UBERON:0010414	99.70	gold quality
nipple	UBERON:0002030	99.68	gold quality
peritoneum	UBERON:0002358	99.67	gold quality
gall bladder	UBERON:0002110	99.66	gold quality
upper lobe of left lung	UBERON:0008952	99.63	gold quality
lower esophagus mucosa	UBERON:0035834	99.61	gold quality
right lung	UBERON:0002167	99.60	gold quality
tibial nerve	UBERON:0001323	99.54	gold quality
pericardium	UBERON:0002407	99.51	gold quality
pharyngeal mucosa	UBERON:0000355	99.50	gold quality
monocyte	CL:0000576	99.45	gold quality
upper leg skin	UBERON:0004262	99.45	gold quality
skin of abdomen	UBERON:0001416	99.44	gold quality
granulocyte	CL:0000094	99.40	gold quality
urethra	UBERON:0000057	99.39	gold quality
upper lobe of lung	UBERON:0008948	99.39	gold quality
leukocyte	CL:0000738	99.38	gold quality
right ovary	UBERON:0002118	99.38	gold quality
olfactory bulb	UBERON:0002264	99.38	gold quality
ectocervix	UBERON:0012249	99.38	gold quality
mononuclear cell	CL:0000842	99.37	gold quality
ascending aorta	UBERON:0001496	99.36	gold quality
thoracic aorta	UBERON:0001515	99.35	gold quality
tibial artery	UBERON:0007610	99.35	gold quality

Single-cell (SCXA)

Detected in 41 experiment(s), a significant marker in 33.

Experiment	Marker?	Max mean expression
E-MTAB-9543	yes	10188.83
E-GEOD-135922	yes	5725.15
E-MTAB-6308	yes	5216.99
E-HCAD-24	yes	4911.33
E-ANND-2	yes	4716.48
E-GEOD-139324	yes	4541.63
E-CURD-122	yes	3780.15
E-GEOD-149689	yes	3019.45
E-GEOD-134144	yes	2765.14
E-GEOD-106540	yes	2758.58
E-MTAB-7052	yes	1185.17
E-GEOD-89232	yes	317.75
E-MTAB-6701	yes	101.58
E-MTAB-10287	yes	63.24
E-HCAD-4	yes	46.28

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

8 targets.

Target	Regulation
CXCL8	Repression
ELAVL1	Activation
HIF1A	Activation
IL2	Repression
IL6	Repression
LATS2	Repression
SERPINB2	Unknown
VEGFA	Repression

Upstream regulators (CollecTRI, top): CEBPB, CREB1, ELK1, IRF6, JUN, JUNB, MYC, NR1I2, RNF141, SMAD3, SMAD4, STAT1, STAT3, TBXT, TCF3, ZNF91

miRNA regulators (miRDB)

76 targeting ZFP36, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-145-5P	99.92	71.13	1836

Literature-anchored findings (GeneRIF, showing 40)

• TTP and the related proteins bind specifically to 14-3-3 proteins and 14-3-3 isoforms preferentially bind to different phosphorylated TTP species. 14-3-3 binding is one of multiple mechanisms that localize TTP to the cytoplasm. (PMID:11886850)
• is likely to function in the posttranscriptional regulation of TNFalpha. (PMID:12115244)
• TTP can accomplish accelerated mRNA degradation [review] (PMID:12440952)
• The three-dimensional solution structure of the first domain of Nup475 has been determined by multidimensional nuclear magnetic resonance spectroscopy, revealing a novel fold around a central zinc ion. (PMID:12515557)
• TTP is a functional PAI-2 ARE-binding protein that modulates the post-transcriptional regulation of the PAI-2 gene (PMID:12578825)
• Tristetraprolin binds to the 3’-untranslated region of cyclooxygenase-2 mRNA (PMID:12578839)
• characteristics of interaction of tandem zinc finger peptide with AU-rich element-containing RNA substrates (PMID:12639954)
• TTP can be phosphorylated by JNK as well as by the other members of the greater MAP kinase family (PMID:12646273)
• Results show that tristetraprolin can promote the deadenylation of AU-rich element (ARE)-containing, polyadenylated substrates by poly(A) RNase. (PMID:12748283)
• TTP binds to COX-2 3’UTR between nucleotides 3125 and 3432 and is expressed in HCA-7 tumor cell line (PMID:12751757)
• tristetraprolin is transcriptionally regulated by transforming growth factor-beta in human T cells (PMID:12754205)
• Regulation and localization of tristetraprolin in leukocytes. (PMID:12823857)
• polymorphisms sequenced in genomic DNA encoding the TTP protein (ZFP36) and those of its two known mammalian relatives, ZFP36L1 and ZFP36L2, from 72 to 92 anonymous human subjects from various geographical and ethnic backgrounds (PMID:14604009)
• TTP localization is regulated by interaction with Nup214 (PMID:14766228)
• mechanism by which the p38-MAPK/MAPKAP kinase-2 kinase cascade inhibits TTP-mediated degradation of AU-rich element-containing transcripts (PMID:15014438)
• Altered mRNA expression is associated with prostate cancer recurrence. (PMID:15067324)
• the zinc finger domain of tristetraprolin requires specific RNA sequence elements for high affinity binding (PMID:15117938)
• Inappropriate TTP production may be one factor that contributes to higher rheumatoid arthritis disease activity. (PMID:15170914)
• stability of tristetraprolin mRNA is regulated by mitogen-activated protein kinase p38 and by tristetraprolin itself (PMID:15187092)
• TTP regulates its own expression in a manner identical to that seen with the TNF-alpha 3’ untranslated region, indicating that this autoregulation is mediated at the level of mRNA stability. (PMID:15187101)
• HSV-1 virion host shutoff protein dependent degradation of AU-rich element-containing RNAs correlates with the transactivation, cytoplasmic accumulation, and persistence of tristetraprolin in infected cells. (PMID:15280467)
• A model is supported in which each subunit of the tristetraprolin (TTP) tetramer binds to one of the five overlapping UUAUUUAUU sequences of the AU-rich element (ARE), resulting in a stable TTP-ARE complex. (PMID:15504035)
• Review. The structure, genetic variants, and role of TTP (especially in TNF-alpha and Gm-CSF mRNA degradation) are discussed. (PMID:15535838)
• tristetraprolin positively regulates human inducible nitric oxide synthetase (iNOS) expression by enhancing the stability of human iNOS mRNA. (PMID:15778452)
• The identification of multiple phosphorylation sites in TTP in mammalian cells is reported; this should provide the molecular basis for further studies on the function and regulation of TTP in controlling pro-inflammatory cytokines. (PMID:16262601)
• Data suggest that multiple proteins involved in human decapping are important subunits of processing bodies and are activated on ARE-mRNAs by the protein TTP. (PMID:16364915)
• Results suggest that TTP may be a potential target for new therapies against Rheumatoid Arthritis. (PMID:16596264)
• Knockdown of TTP increased both cognate macrophage gene mRNAs and inflammatory tumor necrosis factor protein release. Overexpression of TTP resulted in decreased levels of the same genes supporting its role in regulating macrophage gene expression. (PMID:16614304)
• Results describe the gene expression of tristetraprolin, T-cell intracellular antigen and Hu antigen R in synovial tissues from rheumatoid arthritis and osteoarthritis patients. (PMID:16820934)
• These results suggest that tristetraprolin is a regulator of HIV-1 replication and enhances splicing by direct binding to AU-rich sequence of HIV-1 RNAs. (PMID:16935542)
• depletion of endogenous TTP and BRF-1 proteins, or overexpression of dominant-negative mutant TTP proteins, impairs the localization of reporter AU-rich element mRNAs (PMID:17369404)
• the present study, we developed a real-time PCR assay for all three human family members that allowed for comparative measurements of all three family members in the same tissues and cells. (PMID:17517366)
• ZFP36 is a promising cadidate gene for obesity-associated metabolic complications. (PMID:17546847)
• Positive correlations between tristetraprolin gene expression in patients with rheumatoid and healthy persons. (PMID:17599736)
• These data establish that TTP mediated TNF-alpha mRNA decay is inhibited by the combined activation of ERK and p38 and not by p38 activation alone (PMID:17606294)
• Tristetraprolin might represent a novel antiangiogenic and antitumor agent acting through its destabilizing activity on vascular endothelial growth factor mRNA (PMID:17855506)
• ZFP36 gene expression in omental adipose tissue, but not in abdominal s.c. fat, may offer partial protection against the development of insulin resistance and diabetes. (PMID:17893259)
• Tristetraprolin predominantly regulates CXCL1/KC chemokine mRNA decay in mononuclear phagocytes, acting via multiple 3’-untranslated region-localized adenine-uridine-rich elements. (PMID:18250465)
• identified six MHC Class I alleles, five MHC Class II alleles, seven chemokine and chemokine receptor genes, indoleamine 2,3 dioxygenase, and CD86 as putative TTP ligands in dendritic cells (PMID:18367721)
• the disease duration in Rheuamtoid arthritis patients with Tristetraprolin (TTP) genotype GG was shorter than that of patients with genotypes AA/AG (PMID:18536977)

Cross-species orthologs

23 orthologs

Organism	Symbol	Gene ID
danio_rerio	cth1	ENSDARG00000057328
mus_musculus	Zfp36	ENSMUSG00000044786
rattus_norvegicus	Zfp36	ENSRNOG00000058388
drosophila_melanogaster	Tis11	FBGN0011837
caenorhabditis_elegans		WBGENE00003230
caenorhabditis_elegans		WBGENE00003231
caenorhabditis_elegans		WBGENE00003388
caenorhabditis_elegans		WBGENE00003864
caenorhabditis_elegans		WBGENE00003865
caenorhabditis_elegans		WBGENE00004078
caenorhabditis_elegans		WBGENE00007961
caenorhabditis_elegans		WBGENE00009532
caenorhabditis_elegans		WBGENE00009537
caenorhabditis_elegans		WBGENE00009539
caenorhabditis_elegans	gla-3	WBGENE00011376
caenorhabditis_elegans		WBGENE00013319
caenorhabditis_elegans		WBGENE00013370
caenorhabditis_elegans		WBGENE00013794
caenorhabditis_elegans		WBGENE00013796
caenorhabditis_elegans		WBGENE00013797
caenorhabditis_elegans		WBGENE00017182
caenorhabditis_elegans		WBGENE00022438
caenorhabditis_elegans		WBGENE00022446

Paralogs (2): ZFP36L2 (ENSG00000152518), ZFP36L1 (ENSG00000185650)

Protein

Protein identifiers

mRNA decay activator protein ZFP36 — P26651 (reviewed: P26651)

Alternative names: G0/G1 switch regulatory protein 24, Growth factor-inducible nuclear protein NUP475, Tristetraprolin, Zinc finger protein 36

All UniProt accessions (2): P26651, M0R252

UniProt curated annotations — full annotation on UniProt →

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. Acts as an 3’-untranslated region (UTR) ARE mRNA-binding adapter protein to communicate signaling events to the mRNA decay machinery. Recruits deadenylase CNOT7 (and probably the CCR4-NOT complex) via association with CNOT1, and hence promotes ARE-mediated mRNA deadenylation. Functions also by recruiting components of the cytoplasmic RNA decay machinery to the bound ARE-containing mRNAs. Self regulates by destabilizing its own mRNA. Binds to 3’-UTR ARE of numerous mRNAs and of its own mRNA. Plays a role in anti-inflammatory responses; suppresses tumor necrosis factor (TNF)-alpha production by stimulating ARE-mediated TNF mRNA decay and several other inflammatory ARE-containing mRNAs in interferon (IFN)- and/or lipopolysaccharide (LPS)-induced macrophages. Also plays a role in the regulation of dendritic cell maturation at the post-transcriptional level, and hence operates as part of a negative feedback loop to limit the inflammatory response. Promotes ARE-mediated mRNA decay of hypoxia-inducible factor HIF1A mRNA during the response of endothelial cells to hypoxia. Positively regulates early adipogenesis of preadipocytes by promoting ARE-mediated mRNA decay of immediate early genes (IEGs). Negatively regulates hematopoietic/erythroid cell differentiation by promoting ARE-mediated mRNA decay of the transcription factor STAT5B mRNA. Plays a role in maintaining skeletal muscle satellite cell quiescence by promoting ARE-mediated mRNA decay of the myogenic determination factor MYOD1 mRNA. Associates also with and regulates the expression of non-ARE-containing target mRNAs at the post-transcriptional level, such as MHC class I mRNAs. Participates in association with argonaute RISC catalytic components in the ARE-mediated mRNA decay mechanism; assists microRNA (miRNA) targeting ARE-containing mRNAs. May also play a role in the regulation of cytoplasmic mRNA decapping; enhances decapping of ARE-containing RNAs, in vitro. Involved in the delivery of target ARE-mRNAs to processing bodies (PBs). In addition to its cytosolic mRNA-decay function, affects nuclear pre-mRNA processing. Negatively regulates nuclear poly(A)-binding protein PABPN1-stimulated polyadenylation activity on ARE-containing pre-mRNA during LPS-stimulated macrophages. Also involved in the regulation of stress granule (SG) and P-body (PB) formation and fusion. Plays a role in the regulation of keratinocyte proliferation, differentiation and apoptosis. Plays a role as a tumor suppressor by inhibiting cell proliferation in breast cancer cells. (Microbial infection) Negatively regulates HTLV-1 TAX-dependent transactivation of viral long terminal repeat (LTR) promoter.

Subunit / interactions. Associates with cytoplasmic CCR4-NOT and PAN2-PAN3 deadenylase complexes to trigger ARE-containing mRNA deadenylation and decay processes. Part of a mRNA decay activation complex at least composed of poly(A)-specific exoribonucleases CNOT6, EXOSC2 and XRN1 and mRNA-decapping enzymes DCP1A and DCP2. Associates with the RNA exosome complex. Interacts (via phosphorylated form) with 14-3-3 proteins; these interactions promote exclusion of ZFP36 from cytoplasmic stress granules in response to arsenite treatment in a MAPKAPK2-dependent manner and does not prevent CCR4-NOT deadenylase complex recruitment or ZFP36-induced ARE-containing mRNA deadenylation and decay processes. Interacts with 14-3-3 proteins; these interactions occur in response to rapamycin in an Akt-dependent manner. Interacts with AGO2 and AGO4. Interacts (via C-terminus) with CNOT1; this interaction occurs in a RNA-independent manner and induces mRNA deadenylation. Interacts (via N-terminus) with CNOT6. Interacts with CNOT6L. Interacts (via C-terminus) with CNOT7; this interaction occurs in a RNA-independent manner, induces mRNA deadenylation and is inhibited in a phosphorylation MAPKAPK2-dependent manner. Interacts (via unphosphorylated form) with CNOT8; this interaction occurs in a RNA-independent manner and is inhibited in a phosphorylation MAPKAPK2-dependent manner. Interacts with DCP1A. Interacts (via N-terminus) with DCP2. Interacts with EDC3. Interacts (via N-terminus) with EXOSC2. Interacts with heat shock 70 kDa proteins. Interacts with KHSRP; this interaction increases upon cytokine-induced treatment. Interacts with MAP3K4; this interaction enhances the association with SH3KBP1/CIN85. Interacts with MAPKAPK2; this interaction occurs upon skeletal muscle satellite cell activation. Interacts with NCL. Interacts with NUP214; this interaction increases upon lipopolysaccharide (LPS) stimulation. Interacts with PABPC1; this interaction occurs in a RNA-dependent manner. Interacts (via hypophosphorylated form) with PABPN1 (via RRM domain and C-terminal arginine-rich region); this interaction occurs in the nucleus in a RNA-independent manner, decreases in presence of single-stranded poly(A) RNA-oligomer and in a p38 MAPK-dependent-manner and inhibits nuclear poly(A) tail synthesis. Interacts with PAN2. Interacts (via C3H1-type zinc finger domains) with PKM. Interacts (via C3H1-type zinc finger domains) with nuclear RNA poly(A) polymerase. Interacts with PPP2CA; this interaction occurs in LPS-stimulated cells and induces ZFP36 dephosphorylation, and hence may promote ARE-containing mRNAs decay. Interacts (via C-terminus) with PRR5L (via C-terminus); this interaction may accelerate ZFP36-mediated mRNA decay during stress. Interacts (via C-terminus) with SFN; this interaction occurs in a phosphorylation-dependent manner. Interacts (via extreme C-terminal region) with SH3KBP1/CIN85 (via SH3 domains); this interaction enhances MAP3K4-induced phosphorylation of ZFP36 at Ser-66 and Ser-93 and does not alter neither ZFP36 binding to ARE-containing transcripts nor TNF mRNA decay. Interacts with XRN1. Interacts (via C-terminus and Ser-186 phosphorylated form) with YWHAB; this interaction occurs in a p38/MAPKAPK2-dependent manner, increases cytoplasmic localization of ZFP36 and protects ZFP36 from Ser-186 dephosphorylation by serine/threonine phosphatase 2A, and hence may be crucial for stabilizing ARE-containing mRNAs. Interacts (via phosphorylated form) with YWHAE. Interacts (via C-terminus) with YWHAG; this interaction occurs in a phosphorylation-dependent manner. Interacts with YWHAH; this interaction occurs in a phosphorylation-dependent manner. Interacts with YWHAQ; this interaction occurs in a phosphorylation-dependent manner. Interacts with (via C-terminus) YWHAZ; this interaction occurs in a phosphorylation-dependent manner. Interacts (via P-P-P-P-G repeats) with GIGYF2; the interaction is direct. (Microbial infection) Interacts (via C-terminus) with HTLV-1 TAX (via C-terminus); this interaction inhibits HTLV-1 TAX to transactivate viral long terminal repeat (LTR) promoter.

Subcellular location. Nucleus. Cytoplasm. Cytoplasmic granule. P-body Nucleus.

Tissue specificity. Expressed in both basal and suprabasal epidermal layers. Expressed in epidermal keratinocytes. Expressed strongly in mature dendritic cells. Expressed in immature dendritic cells (at protein level).

Post-translational modifications. Phosphorylated. Phosphorylation at serine and/or threonine residues occurs in a p38 MAPK- and MAPKAPK2-dependent manner. Phosphorylated by MAPKAPK2 at Ser-60 and Ser-186; phosphorylation increases its stability and cytoplasmic localization, promotes binding to 14-3-3 adapter proteins and inhibits the recruitment of cytoplasmic CCR4-NOT and PAN2-PAN3 deadenylase complexes to the mRNA decay machinery, thereby inhibiting ZFP36-induced ARE-containing mRNA deadenylation and decay processes. Phosphorylation by MAPKAPK2 does not impair ARE-containing RNA-binding. Phosphorylated in a MAPKAPK2- and p38 MAPK-dependent manner upon skeletal muscle satellite cell activation; this phosphorylation inhibits ZFP36-mediated mRNA decay activity, and hence stabilizes MYOD1 mRNA. Phosphorylated by MAPK1 upon mitogen stimulation. Phosphorylated at Ser-66 and Ser-93; these phosphorylations increase in a SH3KBP1-dependent manner. Phosphorylated at serine and threonine residues in a pyruvate kinase PKM- and p38 MAPK-dependent manner. Phosphorylation at Ser-60 may participate in the PKM-mediated degradation of ZFP36 in a p38 MAPK-dependent manner. Dephosphorylated by serine/threonine phosphatase 2A at Ser-186. Ubiquitinated; pyruvate kinase (PKM)-dependent ubiquitination leads to proteasomal degradation through a p38 MAPK signaling pathway.

Domain organisation. The C3H1-type zinc finger domains are necessary for ARE-binding activity.

Induction. Up-regulated by T cell activation. Up-regulated in keratinocytes in response to wounding. Up-regulated by lipopolysaccharide (LPS) in a p38 MAPK- and ERK-dependent manner (at protein level). Up-regulated strongly during epidermal repair after wounding in keratinocytes. Up-regulated strongly by epidermal growth factor (EGF) and tumor necrosis factor (TNF) in keratinocytes. Up-regulated moderately by granulocyte macrophage colony-stimulating factor (GM-CSF) and fibroblast growth factor (FGF1) in keratinocytes. Up-regulated also by glucocorticoid dexamethasone in keratinocytes. Up-regulated by LPS in a p38 MAPK-dependent manner.

RefSeq proteins (1): NP_003398* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000571	Znf_CCCH	Domain
IPR036855	Znf_CCCH_sf	Homologous_superfamily
IPR045877	ZFP36-like	Family

Pfam: PF00642

UniProt features (47 total): modified residue 14, region of interest 13, mutagenesis site 7, sequence variant 4, repeat 3, compositionally biased region 2, zinc finger region 2, chain 1, helix 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4J8S	X-RAY DIFFRACTION	1.55

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P26651-F1	63.34	0.19

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (14): 60, 66, 88, 90, 92, 93, 169, 186, 197, 218, 228, 276, 296, 323

Mutagenesis-validated functional residues (7):

Position	Phenotype
60	inhibits pkm-induced zfp36 degradation through a p38 mapk signaling pathway.
124	inhibits binding to are-containing transcripts. inhibits binding to and deadenylation activities of are-containing mrnas
126	inhibits are-containing rna-binding, deadenylation and rna decapping activities.
147	inhibits both are-binding and mrna deadenylation activities.
309	inhibits interaction with sh3kbp1.
315	abolishes interaction with cnot1.
319	abolishes interaction with cnot1 and impairs tnf mrna deadenylation.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-450513	Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA

MSigDB gene sets: 576 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GSE45365_NK_CELL_VS_CD11B_DC_DN, GSE45365_NK_CELL_VS_BCELL_UP, TAKEDA_TARGETS_OF_NUP98_HOXA9_FUSION_6HR_DN, TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_EPITHELIAL_CELL_APOPTOTIC_PROCESS, GOBP_MYELOID_CELL_HOMEOSTASIS, AMIT_DELAYED_EARLY_GENES, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_REGULATION_OF_EPIDERMIS_DEVELOPMENT

GO Biological Process (37): negative regulation of transcription by RNA polymerase II (GO:0000122), MAPK cascade (GO:0000165), nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay (GO:0000288), nuclear-transcribed mRNA poly(A) tail shortening (GO:0000289), mRNA catabolic process (GO:0006402), response to wounding (GO:0009611), regulation of keratinocyte proliferation (GO:0010837), nuclear-transcribed mRNA catabolic process, deadenylation-independent decay (GO:0031086), regulation of tumor necrosis factor production (GO:0032680), negative regulation of interleukin-2 production (GO:0032703), negative regulation of viral transcription (GO:0032897), miRNA-mediated gene silencing by inhibition of translation (GO:0035278), p38MAPK cascade (GO:0038066), response to starvation (GO:0042594), regulation of mRNA stability (GO:0043488), cellular response to fibroblast growth factor stimulus (GO:0044344), positive regulation of fat cell differentiation (GO:0045600), regulation of keratinocyte differentiation (GO:0045616), negative regulation of erythrocyte differentiation (GO:0045647), mRNA transport (GO:0051028), positive regulation of nuclear-transcribed mRNA poly(A) tail shortening (GO:0060213), 3’-UTR-mediated mRNA destabilization (GO:0061158), 3’-UTR-mediated mRNA stabilization (GO:0070935), cellular response to lipopolysaccharide (GO:0071222), cellular response to tumor necrosis factor (GO:0071356), cellular response to epidermal growth factor stimulus (GO:0071364), cellular response to glucocorticoid stimulus (GO:0071385), cellular response to granulocyte macrophage colony-stimulating factor stimulus (GO:0097011), negative regulation of cytokine production involved in inflammatory response (GO:1900016), positive regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay (GO:1900153), positive regulation of deadenylation-independent decapping of nuclear-transcribed mRNA (GO:1901835), regulation of keratinocyte apoptotic process (GO:1902172), negative regulation of polynucleotide adenylyltransferase activity (GO:1904246), positive regulation of intracellular mRNA localization (GO:1904582), negative regulation of 3’-UTR-mediated mRNA stabilization (GO:1905869), positive regulation of miRNA-mediated gene silencing (GO:2000637), regulatory ncRNA-mediated gene silencing (GO:0031047)

GO Molecular Function (16): DNA binding (GO:0003677), RNA binding (GO:0003723), mRNA binding (GO:0003729), zinc ion binding (GO:0008270), enzyme binding (GO:0019899), protein kinase binding (GO:0019901), C-C chemokine binding (GO:0019957), heat shock protein binding (GO:0031072), mRNA 3’-UTR AU-rich region binding (GO:0035925), protein-containing complex binding (GO:0044877), RNA polymerase binding (GO:0070063), 14-3-3 protein binding (GO:0071889), protein-RNA sequence-specific adaptor activity (GO:0160134), mRNA 3’-UTR binding (GO:0003730), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (7): P-body (GO:0000932), nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), cytoplasmic stress granule (GO:0010494), ribonucleoprotein complex (GO:1990904), CCR4-NOT complex (GO:0030014)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Regulation of mRNA stability by proteins that bind AU-rich elements	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
nuclear-transcribed mRNA catabolic process	3
protein binding	3
response to stress	2
nucleic acid binding	2
binding	2
cytoplasmic ribonucleoprotein granule	2
cellular anatomical structure	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
intracellular signaling cassette	1
mRNA destabilization	1
nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay	1
RNA catabolic process	1
negative regulation of gene expression	1
mRNA metabolic process	1
keratinocyte proliferation	1
regulation of epithelial cell proliferation	1
tumor necrosis factor production	1
regulation of tumor necrosis factor superfamily cytokine production	1
negative regulation of cytokine production	1
interleukin-2 production	1
regulation of interleukin-2 production	1
viral transcription	1
regulation of viral transcription	1
negative regulation of viral process	1
negative regulation of translation	1
miRNA-mediated post-transcriptional gene silencing	1
MAPK cascade	1
response to nutrient levels	1
regulation of RNA stability	1
regulation of mRNA catabolic process	1
cellular response to growth factor stimulus	1
response to fibroblast growth factor	1
fat cell differentiation	1
positive regulation of cell differentiation	1
regulation of fat cell differentiation	1
keratinocyte differentiation	1
regulation of epidermal cell differentiation	1
erythrocyte differentiation	1

Protein interactions and networks

STRING

2002 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZFP36	AGO2	Q9UKV8	895
ZFP36	CNOT1	A5YKK6	879
ZFP36	TIA1	P31483	854
ZFP36	ELAVL1	Q15717	837
ZFP36	TNF	P01375	808
ZFP36	KHSRP	Q92945	793
ZFP36	HNRNPD	P07029	784
ZFP36	XRN1	Q8IZH2	735
ZFP36	DCP2	Q8IU60	714
ZFP36	DUSP1	P28562	707
ZFP36	AGO1	Q9UL18	688
ZFP36	EDC3	Q96F86	683
ZFP36	DICER1	Q9UPY3	675
ZFP36	TIAL1	Q01085	651
ZFP36	EIF4E	P06730	649

IntAct

47 interactions, top by confidence:

A	B	Type	Score
CNOT1	ZFP36	psi-mi:“MI:0407”(direct interaction)	0.620
ZFP36	RUNX1T1	psi-mi:“MI:0915”(physical association)	0.560
ZFP36	PECAM1	psi-mi:“MI:0915”(physical association)	0.560
ZFP36	VIM	psi-mi:“MI:0915”(physical association)	0.560
ZFP36	JPH3	psi-mi:“MI:0915”(physical association)	0.560
Zfp36	CNOT1	psi-mi:“MI:0914”(association)	0.560
DCP1A	ZFP36	psi-mi:“MI:0915”(physical association)	0.500
ZFP36	EDC3	psi-mi:“MI:0915”(physical association)	0.500
FHL3	ZFP36	psi-mi:“MI:0915”(physical association)	0.490
ZFP36	DCP2	psi-mi:“MI:0915”(physical association)	0.400
DDX17	ZFP36	psi-mi:“MI:0915”(physical association)	0.400
HOXC9	ZFP36	psi-mi:“MI:0915”(physical association)	0.370
ZFP36	CCDC85B	psi-mi:“MI:0915”(physical association)	0.370
ZFP36	ZDHHC17	psi-mi:“MI:0915”(physical association)	0.370
ZFP36	EDC4	psi-mi:“MI:0914”(association)	0.350
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
CUL4B	GGTLC3	psi-mi:“MI:0914”(association)	0.350
SF1	ZFP36	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (214): ZFP36 (Biochemical Activity), ZFP36 (Reconstituted Complex), ZFP36 (Affinity Capture-Western), PPP2CA (Affinity Capture-Western), YWHAB (Affinity Capture-Western), PRR5L (Two-hybrid), DNAJB1 (Two-hybrid), DCP1B (Two-hybrid), XRN1 (Two-hybrid), DHX36 (Two-hybrid), PRR5L (Affinity Capture-Western), ZFP36 (Affinity Capture-Western), CCL3 (Affinity Capture-RNA), DUSP2 (Affinity Capture-RNA), ZEB2 (Affinity Capture-RNA)

ESM2 similar proteins: A1A5P0, A1XSY8, A1YF15, A1YG91, A2AFE9, A2D4Z7, A2T762, A5PJK7, A8WFF7, C0LZJ1, O36399, O43474, O75956, P03413, P08651, P09414, P17923, P21999, P22893, P26633, P26651, P41162, P46153, P47973, P97489, Q01196, Q02780, Q03347, Q08427, Q08775, Q12857, Q13761, Q13950, Q2HRB6, Q58CN7, Q60793, Q61169, Q63046, Q64131, Q76IQ7

Diamond homologs: A2ZVY5, A4IIN5, G5EC86, G5EF15, P17431, P22893, P23949, P23950, P26651, P47973, P47974, P47976, P47977, P47979, P47980, P53781, Q07352, Q10MN8, Q23359, Q5ISE2, Q5PP65, Q6L5G1, Q6S9E0, Q7ZXW9, Q805B4, Q84UQ3, Q9C7C3, Q9C9F5, Q9C9N3, Q9FG30, Q9LQM3, Q9LT81, Q9XV46, Q57W26, Q69XQ3, Q7F8R0, Q7XPK1, Q94131, Q8L7S3, Q5VR07

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
ZFP36	“up-regulates activity”	“EIF4E2/GIGYF1 complex”	relocalization
ZFP36	“up-regulates activity”	“EIF4E2/GIGYF2 complex”	relocalization
MAPK1	unknown	ZFP36	phosphorylation
MAPKAPK2	“down-regulates activity”	ZFP36	phosphorylation
MAPK14	“down-regulates activity”	ZFP36	phosphorylation
ZFP36	“down-regulates quantity by destabilization”	MYOD1	“post transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

42 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	37
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

371 predictions. Top by Δscore:

Variant	Effect	Δscore
19:39406926:GAG:G	donor_gain	0.9900
19:39406927:AGG:A	donor_loss	0.9900
19:39406928:GGTG:G	donor_loss	0.9900
19:39406929:G:C	donor_loss	0.9900
19:39406930:T:G	donor_loss	0.9900
19:39406929:G:GG	donor_gain	0.9800
19:39406931:GAG:G	donor_loss	0.9600
19:39407741:A:AG	acceptor_gain	0.9500
19:39407742:G:GG	acceptor_gain	0.9500
19:39407742:GA:G	acceptor_gain	0.9400
19:39407563:G:GA	donor_gain	0.9300
19:39407479:GTG:G	donor_gain	0.9200
19:39407523:G:T	donor_gain	0.9000
19:39407548:GGA:G	donor_gain	0.9000
19:39407523:G:GT	donor_gain	0.8900
19:39407549:GA:G	donor_gain	0.8900
19:39407737:CCGCA:C	acceptor_loss	0.8900
19:39407739:GCAGA:G	acceptor_loss	0.8900
19:39407741:AG:A	acceptor_loss	0.8900
19:39407742:G:C	acceptor_loss	0.8900
19:39407742:GAGC:G	acceptor_gain	0.8900
19:39407331:A:AG	acceptor_gain	0.8600
19:39407332:G:GG	acceptor_gain	0.8600
19:39407740:CAG:C	acceptor_gain	0.8500
19:39407741:AGA:A	acceptor_gain	0.8500
19:39407742:GAG:G	acceptor_gain	0.8500
19:39407441:A:AG	donor_gain	0.8400
19:39407481:G:GA	donor_gain	0.8400
19:39407218:G:GT	donor_gain	0.8300
19:39407733:ATTTC:A	acceptor_loss	0.8300

AlphaMissense

2044 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:39408031:A:G	K105E	1.000
19:39408033:G:C	K105N	1.000
19:39408033:G:T	K105N	1.000
19:39408043:T:A	C109S	1.000
19:39408043:T:C	C109R	1.000
19:39408044:G:A	C109Y	1.000
19:39408044:G:C	C109S	1.000
19:39408044:G:T	C109F	1.000
19:39408045:T:G	C109W	1.000
19:39408070:T:A	C118S	1.000
19:39408070:T:C	C118R	1.000
19:39408071:G:C	C118S	1.000
19:39408077:A:G	Y120C	1.000
19:39408088:T:A	C124S	1.000
19:39408088:T:C	C124R	1.000
19:39408089:G:A	C124Y	1.000
19:39408089:G:C	C124S	1.000
19:39408089:G:T	C124F	1.000
19:39408090:C:G	C124W	1.000
19:39408094:T:A	F126I	1.000
19:39408094:T:C	F126L	1.000
19:39408094:T:G	F126V	1.000
19:39408095:T:C	F126S	1.000
19:39408095:T:G	F126C	1.000
19:39408096:T:A	F126L	1.000
19:39408096:T:G	F126L	1.000
19:39408098:C:A	A127D	1.000
19:39408145:A:G	K143E	1.000
19:39408147:G:C	K143N	1.000
19:39408147:G:T	K143N	1.000

dbSNP variants (sampled 300 via entrez): RS1000958798 (19:39405932 T>C), RS1001299622 (19:39404951 G>A), RS1001372786 (19:39409597 G>C), RS1001448193 (19:39409767 G>A), RS1002350747 (19:39406743 C>A,G), RS1002873963 (19:39406493 C>G), RS1003375232 (19:39404913 C>G,T), RS1003666206 (19:39406292 T>C), RS1004981093 (19:39407970 C>T), RS1005339574 (19:39405765 G>A), RS1005915403 (19:39409772 C>A,G,T), RS1006047671 (19:39407491 G>A,T), RS1007021279 (19:39407129 C>A,T), RS1007718211 (19:39408927 C>T), RS1009554514 (19:39407231 T>A,C,G)

Disease associations

OMIM: gene MIM:190700 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

125 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases abundance, increases expression, affects localization, decreases expression	5
(+)-JQ1 compound	increases expression, decreases expression	5
Estradiol	affects expression, increases reaction, increases expression	3
Tetrachlorodibenzodioxin	increases expression	3
Cadmium Chloride	decreases expression, increases abundance, increases expression	3
hydroquinone	decreases expression, decreases reaction, increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
Resveratrol	affects cotreatment, decreases expression, increases expression	2
Arsenic Trioxide	affects expression, decreases expression	2
Air Pollutants	affects expression, increases abundance, increases expression	2
Benzo(a)pyrene	increases expression	2
Cadmium	decreases expression, increases abundance	2
Calcitriol	increases expression, affects cotreatment	2
Cisplatin	increases expression, affects response to substance	2
Copper	affects binding, decreases expression, increases expression	2
Dexamethasone	increases expression, affects cotreatment	2
Doxorubicin	increases expression, decreases expression	2
Hydrogen Peroxide	affects expression, increases expression	2
Nickel	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Silicon Dioxide	decreases expression, increases expression	2
Valproic Acid	affects expression, decreases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
GSK-J4	increases expression	1
Glupearl 19S	increases expression	1
bisphenol F	affects cotreatment, increases expression	1
dicrotophos	increases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	decreases expression	1

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D9W0	Ubigene HEK293 ZFP36 KO	Transformed cell line	Female
CVCL_TZ13	HAP1 ZFP36 (-) 1	Cancer cell line	Male
CVCL_TZ14	HAP1 ZFP36 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.