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Protein

mRNA decay activator protein ZFP36L1

Gene

Zfp36l1

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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:22701344, PubMed:24700863, PubMed:24733888, PubMed:27102483). Acts as a 3'-untranslated region (UTR) ARE mRNA-binding adapter protein to communicate signaling events to the mRNA decay machinery (By similarity). Functions by recruiting the CCR4-NOT deadenylating 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 (By similarity). Induces also the degradation of ARE-containing mRNAs even in absence of poly(A) tail (By similarity). Binds to 3'-UTR ARE of numerous mRNAs (PubMed:22701344, PubMed:24700863, PubMed:24733888). Positively regulates early adipogenesis by promoting ARE-mediated mRNA decay of immediate early genes (IEGs) (PubMed:22701344). 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 (By similarity). Positively regulates monocyte/macrophage cell differentiation by promoting ARE-mediated mRNA decay of the cyclin-dependent kinase CDK6 mRNA (By similarity). 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 (PubMed:24733888). May play a role in mediating pro-apoptotic effects in malignant B-cells by promoting ARE-mediated mRNA decay of BCL2 mRNA (By similarity). 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 (PubMed:27102483). 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 (PubMed:20622884). Involved in the delivery of target ARE-mRNAs to processing bodies (PBs) (By similarity). 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 (By similarity). Also involved in the regulation of stress granule (SG) and P-body (PB) formation and fusion (By similarity). Plays a role in vasculogenesis and endocardial development (PubMed:15226444, PubMed:17013884). Involved in the regulation of keratinocyte proliferation, differentiation and apoptosis (By similarity). Plays a role in myoblast cell differentiation (PubMed:17889962).By similarity8 Publications

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri114 – 142C3H1-type 1PROSITE-ProRule annotationAdd BLAST29
Zinc fingeri152 – 180C3H1-type 2PROSITE-ProRule annotationAdd BLAST29

GO - Molecular functioni

  • 14-3-3 protein binding Source: UniProtKB
  • DNA binding Source: UniProtKB-KW
  • metal ion binding Source: UniProtKB-KW
  • mRNA 3'-UTR AU-rich region binding Source: UniProtKB
  • mRNA 3'-UTR binding Source: GO_Central
  • mRNA binding Source: UniProtKB
  • poly(A) RNA binding Source: MGI

GO - Biological processi

  • 3'-UTR-mediated mRNA destabilization Source: UniProtKB
  • apoptotic process Source: MGI
  • cell proliferation Source: MGI
  • cellular response to cAMP Source: UniProtKB
  • cellular response to epidermal growth factor stimulus Source: UniProtKB
  • cellular response to fibroblast growth factor stimulus Source: UniProtKB
  • cellular response to glucocorticoid stimulus Source: UniProtKB
  • cellular response to hypoxia Source: UniProtKB
  • cellular response to insulin stimulus Source: UniProtKB
  • cellular response to peptide hormone stimulus Source: UniProtKB
  • cellular response to phorbol 13-acetate 12-myristate Source: UniProtKB
  • cellular response to raffinose Source: UniProtKB
  • cellular response to salt stress Source: UniProtKB
  • cellular response to transforming growth factor beta stimulus Source: UniProtKB
  • cellular response to tumor necrosis factor Source: UniProtKB
  • chorio-allantoic fusion Source: MGI
  • embryonic organ development Source: MGI
  • ERK1 and ERK2 cascade Source: UniProtKB
  • heart development Source: MGI
  • MAPK cascade Source: UniProtKB
  • mesendoderm development Source: UniProtKB
  • mRNA catabolic process Source: MGI
  • mRNA processing Source: UniProtKB-KW
  • mRNA transport Source: UniProtKB
  • multicellular organism growth Source: MGI
  • negative regulation of erythrocyte differentiation Source: UniProtKB
  • negative regulation of mitotic cell cycle phase transition Source: UniProtKB
  • neural tube development Source: MGI
  • nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay Source: MGI
  • nuclear-transcribed mRNA catabolic process, deadenylation-independent decay Source: UniProtKB
  • p38MAPK cascade Source: UniProtKB
  • phosphatidylinositol 3-kinase signaling Source: UniProtKB
  • positive regulation of fat cell differentiation Source: UniProtKB
  • positive regulation of intracellular mRNA localization Source: UniProtKB
  • positive regulation of monocyte differentiation Source: UniProtKB
  • positive regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay Source: UniProtKB
  • proepicardium development Source: MGI
  • protein kinase B signaling Source: UniProtKB
  • regulation of B cell differentiation Source: UniProtKB
  • regulation of gene expression Source: UniProtKB
  • regulation of keratinocyte apoptotic process Source: UniProtKB
  • regulation of keratinocyte differentiation Source: UniProtKB
  • regulation of keratinocyte proliferation Source: UniProtKB
  • regulation of mRNA 3'-end processing Source: MGI
  • regulation of mRNA stability Source: UniProtKB
  • regulation of myoblast differentiation Source: UniProtKB
  • regulation of stem cell proliferation Source: UniProtKB
  • regulation of translation Source: MGI
  • response to wounding Source: UniProtKB
  • spongiotrophoblast layer development Source: MGI
  • T cell differentiation in thymus Source: UniProtKB
  • vasculogenesis Source: MGI
Complete GO annotation...

Keywords - Molecular functioni

Developmental protein, Ribonucleoprotein

Keywords - Biological processi

mRNA processing, mRNA transport, Transport

Keywords - Ligandi

DNA-binding, Metal-binding, RNA-binding, Zinc

Enzyme and pathway databases

ReactomeiR-MMU-450385. Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA.

Names & Taxonomyi

Protein namesi
Recommended name:
mRNA decay activator protein ZFP36L1Curated
Alternative name(s):
Butyrate response factor 1By similarity
TPA-induced sequence 11b1 Publication
Zinc finger protein 36, C3H1 type-like 1Imported
Short name:
ZFP36-like 1Imported
Gene namesi
Name:Zfp36l1Imported
Synonyms:Brf1By similarity, Tis11b1 Publication
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 12

Organism-specific databases

MGIiMGI:107946. Zfp36l1.

Subcellular locationi

GO - Cellular componenti

  • cytoplasm Source: UniProtKB
  • cytoplasmic mRNA processing body Source: UniProtKB
  • cytosol Source: MGI
  • intracellular ribonucleoprotein complex Source: UniProtKB
  • nucleus Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Disruption phenotypei

Embryos die in utero at 11 dpc (PubMed:15226444, PubMed:17013884). Exhibit extraembryonic, intraembryonic, vascular and neural tube defects and cardiac abnormalities at 9.5 dpc (PubMed:17013884). Show a reduced number of circulating blood cells (PubMed:17013884). Show failure of chorioallantoic fusion (PubMed:15226444). Exhibited increased level of VEGFA protein level in embryonic fibroblasts under both normoxic and hypoxic conditions (PubMed:17013884). Knockout mice lacking both ZFP36L1 and ZFP36L2 during thymopoiesis lead to aberrant T cell development and subsequently develop a T-cell acute lymphoblastic leukemia (T-ALL) (PubMed:20622884). Show also higher levels of NOTCH1 protein and mRNA in thymocytes (PubMed:20622884). Conditional knockout mice of both ZFP36L1 and ZFP36L2 in pro-B cells display reduced B lymphocyte number and delayed variable-diversity-joining (VDJ) recombination (PubMed:27102483). Exhibit also increased protein and ARE-containing mRNA expressions of several factors implicated in cell cycle progression in late pre-B cells (PubMed:27102483).4 Publications

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000891681 – 338mRNA decay activator protein ZFP36L1Add BLAST338

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei54Phosphoserine; by MAPKAPK2By similarity1
Modified residuei90Phosphoserine; by PKB/AKT1By similarity1
Modified residuei92Phosphoserine; by PKB/AKT1 and MAPKAPK2By similarity1
Modified residuei203Phosphoserine; by PKB/AKT1 and MAPKAPK2By similarity1
Modified residuei318PhosphoserineBy similarity1
Modified residuei334Phosphoserine; by RPS6KA1By similarity1

Post-translational modificationi

Phosphorylated (PubMed:19179481). Phosphorylated by RPS6KA1 at Ser-334 upon phorbol 12-myristate 13-acetate (PMA) treatment; this phosphorylation results in dissociation of the CCR4-NOT deadenylase complex and induces p38 MAPK-mediated stabilization of the low-density lipoprotein receptor LDLR mRNA. Phosphorylated by protein kinase AKT1 at Ser-92 and Ser-203 in response to insulin; these phosphorylations stabilize ZFP36L1, increase the association with 14-3-3 proteins and mediate ARE-containing mRNA stabilization. AKT1-mediated phosphorylation at Ser-92 does not impair ARE-containing RNA-binding. Phosphorylated at Ser-54, Ser-92 and Ser-203 by MAPKAPK2; these phosphorylations increase the association with 14-3-3 proteins and mediate ARE-containing mRNA stabilization in a protein kinase AKT1-independent manner. MAPKAPK2-mediated phosphorylations at Ser-54, Ser-92 and Ser-203 do not impair ARE-containing RNA-binding (By similarity). Phosphorylations increase the association with 14-3-3 proteins and mediate ARE-containing mRNA stabilization during early adipogenesis in a p38 MAPK- and AKT-dependent manner (PubMed:22701344).By similarity2 Publications
Ubiquitinated. Ubiquitination leads to proteasomal degradation, a process inhibited by phosphorylations at Ser-90, Ser-92 and Ser-203.By similarity

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiP23950.
PeptideAtlasiP23950.
PRIDEiP23950.

PTM databases

iPTMnetiP23950.
PhosphoSitePlusiP23950.

Expressioni

Tissue specificityi

Expressed in preadipocytes and adipocytes (PubMed:22701344). Expressed in the proximal and distal tubules in the renal cortex (at protein level) (PubMed:24700863). Expressed in ovary, heart, kidney, lung, spleen and thymus (PubMed:15226444). Weakly expressed in brain, liver and testis (PubMed:15226444). Expressed in osteoblasts (PubMed:15465005). Expressed in embryonic stem cells (ESCs) (PubMed:24733888). Expressed through B lymphocyte development (PubMed:27102483).6 Publications

Developmental stagei

Expressed in embryos at 8 dpc, onward (PubMed:15226444). Expressed in the allantois and throughout the neuroectoderm and paraxial mesoderm at 8 dpc (PubMed:15226444). Expressed in the chorion and blood vessels at 8.5 dpc (PubMed:17013884). Expressed in the neural tube, paraxial mesoderm, heart, brain, otic vesicle and yolk sac at 9.5 dpc (PubMed:17013884). Expressed in embryonic stem cells (ESC) (PubMed:15226444).2 Publications

Inductioni

Up-regulated during myogenic differentiation in a p38 MAPK-dependent manner (PubMed:17889962). Up-regulated in response to fibroblast growth factor FGF4 in embryonic stem cells (ESCs) in a p38 MAPK-dependent manner (PubMed:24733888). Up-regulated during high sodium diet-fed in the renal tubules (PubMed:24700863). Up-regulated upon hypertonic stress condition with raffinose (at protein level) (PubMed:24700863). Up-regulated by parathyroid hormone (PTH) in calvarial osteoblasts (PubMed:15465005). Up-regulated in response to adrenocorticotropic hormone (ACTH) (PubMed:19179481). Up-regulated in response to cAMP (PubMed:19179481). Down-regulated by bone morphogenetic protein BMP2 treatment in calvarial osteoblasts (PubMed:15465005). Down-regulated during the conversion from quiescence to activated satellite cells upon muscle injury (PubMed:23046558, PubMed:25815583).7 Publications

Gene expression databases

BgeeiENSMUSG00000021127.
CleanExiMM_ZFP36L1.
ExpressionAtlasiP23950. baseline and differential.
GenevisibleiP23950. MM.

Interactioni

Subunit structurei

Associates with the cytoplasmic CCR4-NOT deadenylase and RNA exosome complexes to trigger ARE-containing mRNA deadenylation and decay processes. Interacts with CNOT1. Interacts (via N-terminus) with CNOT6. Interacts with CNOT7; this interaction is inhibited in response to phorbol 12-myristate 13-acetate (PMA) treatment in a p38 MAPK-dependent manner. Interacts with DCP1A. Interacts (via N-terminus) with DCP2. Interacts (via N-terminus) with EXOSC2. Interacts with XRN1. Interacts (via phosphorylated form) with YWHAB; this interaction occurs in a protein kinase AKT1-dependent manner (By similarity). Interacts (via phosphorylated form) with YWHAZ; this interaction occurs in a p38 MAPK- and AKT-signaling pathways (PubMed:22701344).By similarity1 Publication

GO - Molecular functioni

Protein-protein interaction databases

BioGridi198385. 1 interactor.
IntActiP23950. 1 interactor.
STRINGi10090.ENSMUSP00000021552.

Structurei

3D structure databases

ProteinModelPortaliP23950.
SMRiP23950.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 111Necessary and sufficient for the association with mRNA decay enzymes and mRNA decay activationBy similarityAdd BLAST111
Regioni185 – 338Necessary for mRNA decay activationBy similarityAdd BLAST154

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi307 – 316Poly-Ser10

Sequence similaritiesi

Contains 2 C3H1-type zinc fingers.PROSITE-ProRule annotation

Zinc finger

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri114 – 142C3H1-type 1PROSITE-ProRule annotationAdd BLAST29
Zinc fingeri152 – 180C3H1-type 2PROSITE-ProRule annotationAdd BLAST29

Keywords - Domaini

Repeat, Zinc-finger

Phylogenomic databases

eggNOGiKOG1677. Eukaryota.
COG5063. LUCA.
GeneTreeiENSGT00530000063262.
HOGENOMiHOG000233479.
HOVERGENiHBG008483.
InParanoidiP23950.
KOiK18753.
OMAiLQHSYSF.
OrthoDBiEOG091G0957.
PhylomeDBiP23950.
TreeFamiTF315463.

Family and domain databases

Gene3Di4.10.1000.10. 2 hits.
InterProiIPR007635. Tis11B_N.
IPR000571. Znf_CCCH.
[Graphical view]
PfamiPF04553. Tis11B_N. 1 hit.
PF00642. zf-CCCH. 2 hits.
[Graphical view]
SMARTiSM00356. ZnF_C3H1. 2 hits.
[Graphical view]
SUPFAMiSSF90229. SSF90229. 2 hits.
PROSITEiPS50103. ZF_C3H1. 2 hits.
[Graphical view]

Sequencei

Sequence statusi: Complete.

P23950-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MTTTLVSATI FDLSEVLCKG NKMLNYSTPS AGGCLLDRKA VGTPAGGGFP
60 70 80 90 100
RRHSVTLPSS KFHQNQLLSS LKGEPAPSLS SRDSRFRDRS FSEGGERLLP
110 120 130 140 150
TQKQPGSGQV NSSRYKTELC RPFEENGACK YGDKCQFAHG IHELRSLTRH
160 170 180 190 200
PKYKTELCRT FHTIGFCPYG PRCHFIHNAE ERRALAGGRD LSADRPRLQH
210 220 230 240 250
SFSFAGFPSA AATAAATGLL DSPTSITPPP ILSADDLLGS PTLPDGTNNP
260 270 280 290 300
FAFSSQELAS LFAPSMGLPG GGSPTTFLFR PMSESPHMFD SPPSPQDSLS
310 320 330
DHEGYLSSSS SSHSGSDSPT LDNSRRLPIF SRLSISDD
Length:338
Mass (Da):36,385
Last modified:March 1, 1992 - v1
Checksum:iA28F2C8BF476496C
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M58566 mRNA. Translation: AAA72948.1.
CCDSiCCDS26010.1.
PIRiB39590.
RefSeqiNP_031590.1. NM_007564.5.
UniGeneiMm.235132.

Genome annotation databases

EnsembliENSMUST00000021552; ENSMUSP00000021552; ENSMUSG00000021127.
ENSMUST00000165114; ENSMUSP00000127522; ENSMUSG00000021127.
GeneIDi12192.
KEGGimmu:12192.
UCSCiuc007oal.1. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M58566 mRNA. Translation: AAA72948.1.
CCDSiCCDS26010.1.
PIRiB39590.
RefSeqiNP_031590.1. NM_007564.5.
UniGeneiMm.235132.

3D structure databases

ProteinModelPortaliP23950.
SMRiP23950.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi198385. 1 interactor.
IntActiP23950. 1 interactor.
STRINGi10090.ENSMUSP00000021552.

PTM databases

iPTMnetiP23950.
PhosphoSitePlusiP23950.

Proteomic databases

PaxDbiP23950.
PeptideAtlasiP23950.
PRIDEiP23950.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000021552; ENSMUSP00000021552; ENSMUSG00000021127.
ENSMUST00000165114; ENSMUSP00000127522; ENSMUSG00000021127.
GeneIDi12192.
KEGGimmu:12192.
UCSCiuc007oal.1. mouse.

Organism-specific databases

CTDi677.
MGIiMGI:107946. Zfp36l1.

Phylogenomic databases

eggNOGiKOG1677. Eukaryota.
COG5063. LUCA.
GeneTreeiENSGT00530000063262.
HOGENOMiHOG000233479.
HOVERGENiHBG008483.
InParanoidiP23950.
KOiK18753.
OMAiLQHSYSF.
OrthoDBiEOG091G0957.
PhylomeDBiP23950.
TreeFamiTF315463.

Enzyme and pathway databases

ReactomeiR-MMU-450385. Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA.

Miscellaneous databases

ChiTaRSiZfp36l1. mouse.
PROiP23950.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000021127.
CleanExiMM_ZFP36L1.
ExpressionAtlasiP23950. baseline and differential.
GenevisibleiP23950. MM.

Family and domain databases

Gene3Di4.10.1000.10. 2 hits.
InterProiIPR007635. Tis11B_N.
IPR000571. Znf_CCCH.
[Graphical view]
PfamiPF04553. Tis11B_N. 1 hit.
PF00642. zf-CCCH. 2 hits.
[Graphical view]
SMARTiSM00356. ZnF_C3H1. 2 hits.
[Graphical view]
SUPFAMiSSF90229. SSF90229. 2 hits.
PROSITEiPS50103. ZF_C3H1. 2 hits.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiTISB_MOUSE
AccessioniPrimary (citable) accession number: P23950
Entry historyi
Integrated into UniProtKB/Swiss-Prot: March 1, 1992
Last sequence update: March 1, 1992
Last modified: November 30, 2016
This is version 127 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.