Atlas of Genetics and Cytogenetics in Oncology and Haematology


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ZFP36L1 (Zinc finger protein 36, C3H type-like 1)

Written2007-11Deborah J Stumpo, Perry J Blackshear
Laboratory of Neurobiology, NIEHS MD A2-05, 111 Alexander Drive, Research Triangle Park, NC 27709, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_namesBRF1
zinc finger protein, C3H type, 36-like 1
zinc finger protein 36, C3H type-like 1
Alias_symbol (synonym)RNF162B
Berg36
ERF1
TIS11B
cMG1
Other alias
HGNC (Hugo) ZFP36L1
LocusID (NCBI) 677
Atlas_Id 42866
Location 14q24.1  [Link to chromosome band 14q24]
Location_base_pair Starts at 68787655 and ends at 68793914 bp from pter ( according to hg19-Feb_2009)  [Mapping ZFP36L1.png]
Fusion genes
(updated 2016)
CRIPT (2p21) / ZFP36L1 (14q24.1)TTC26 (7q34) / ZFP36L1 (14q24.1)ZFP36L1 (14q24.1) / EHD1 (11q13.1)
ZFP36L1 (14q24.1) / FGB (4q31.3)ZFP36L1 (14q24.1) / IGHA2 (14q32.33)ZFP36L1 (14q24.1) / LARGE (22q12.3)
ZFP36L1 (14q24.1) / SMG6 (17p13.3)ZFP36L1 (14q24.1) / TMED9 (5q35.3)
Note The rat clone of ZFP36L1, cMG1, was the first cloned member of the tristetraprolin (TTP, TIS11, NUP475, GOS24) family of CCCH tandem zinc finger proteins. There are 4 mammalian members of this family, TTP, ZFP36L1, ZFP36L2 (TIS11D, ERF2, BRF2), and ZFP36L3. ZFP36L3 is the only family member that is rodent-specific. These proteins have been shown to bind (via their conserved tandem zinc finger domain) directly to class II AU-rich elements (ARE) in the 3'-untranslated region (UTR) of mRNA leading to deadenylation and destabilization of the mRNA.

DNA/RNA

 
  Diagram of the human ZFP36L1 gene. Exons are represented by gray boxes; intron by the hatched box. The translation start site is indicated by the arrow and the translation stop site by the double line. The dark box represents the CCCH tandem zinc finger domain.
Description The human ZFP36L1 has 2 exons spanning 5411 bp on chromosome 14 (NC_000014.7; NT_026437.11). The first exon, which is small (186 bp), is separated from the larger second exon (2834 bp) by a 2388 bp intron.
Transcription 3022 bp human transcript (NM_004926.2) with 1014 bp (338 amino acids) of coding region.
Pseudogene None known.

Protein

Description Human ZFP36L1 is a 338 amino acid protein with a predicted molecular weight of 36.3 kDa.
Expression In the adult mouse, expression appears to be ubiquitous. Based on northern blots, mRNA expression is highest in mouse kidney, spleen, ovary and lung, with lower levels of expression in thymus and heart, and still lower levels in brain, liver and testis. In the embryonic mouse, mRNA was barely detectable at embryonic day 7.5 (E7.5), but increased dramatically by E9.5 and E10.5. In situ hybridization histochemistry demonstrated that there was high level expression in the allantois at E8.0, immediately before fusion with the chorion. Expression is also seen in mouse embryonic stem cells.
Localisation Transfection studies using a GFP-tagged protein have shown diffuse cytoplasmic expression. There is good evidence that the protein can shuttle between the nucleus and the cytoplasm in a CRM1 (nuclear export receptor)-dependent, leptomycin B-inhibitable manner.
Function ZFP36L1 is a member of the TTP (ZFP36) family of CCCH tandem zinc finger proteins. These proteins have been shown to bind to target mRNAs through their AU-rich elements present in the 3'-untranslated regions of the mRNA.
The binding of these proteins to mRNA leads to deadenylation and destabilization of the mRNA. All four family members have been shown to bind directly to single stranded RNA probes (RNA gel shift assays), destabilize target mRNA (co-transfection assays), and deadenylate ARE-containing RNA probes (cell-free deadenylation assays). Physiological target mRNAs have been identified for TTP which include tumor necrosis factor alpha (TNF), granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-2b (IL-2), and immediate early response gene 3 (IER3, IEX-1, gly96).
To date, one physiological target mRNA has been identified for ZFP36L1; however, this target mRNA is not destabilized by ZFP36L1 (see below).
Two reports of ZFP36L1 knockout mice have been published. In one report, knockout embryos died around embryonic day 11 mainly due to failure of chorioallantoic fusion. When fusion did occur, there was increased apoptosis throughout the neural tube, as well as placental failure due to atrophy of the trophoblast layers. In a second report, knockout embryos also died at mid-gestation and exhibited extraembryonic and intraembryonic vascular abnormalities and heart defects. In the developing placenta, the extraembryonic mesoderm failed to invaginate the trophoblast layer. This phenotype was associated with an elevated expression of vascular endothelial growth factor (VEGF)-A (in the embryo and in mouse embryonic fibroblasts). This elevated level of expression was not due to increased stability of the VEGF-A mRNA, but rather due to enhanced association with polyribosomes.
This is in contrast to a prior report using co-transfection studies showing that ZFP36L1 was able to bind to two AU-rich motifs in the 3' UTR of VEGF mRNA that led to destabilization of the mRNA. Mouse ZFP36L1 has been shown to interact with 14-3-3 proteins in a phosphorylation-dependent manner. This interaction causes ZFP36L1 to be sequestered in the cytoplasm preventing it from regulating mRNA decay. Several studies have suggested that ZFP36L1 may function as a pro-apoptotic protein.
Homology Four members of the TTP family of CCCH tandem zinc finger proteins, TTP (ZFP36), ZFP36L1, ZFP36L2 and the rodent-specific ZFP36L3, have been identified. They all share a highly conserved tandem zinc finger domain.

Mutations

Note Eight polymorphisms have been identified. The functional significance of these polymorphisms has not been determined.
1) G change into T at base 644 in the 5' UTR
2) AG change into GC at base 706 in the first coding region
3) G change into A at base 729 in the intron
4) C change into CC at base 772 in the intron
5) A change into G at base 804 in the intron
6) G change into C at base 845 in the intron
7) G change into A at base 3685 in the second coding region
8) C change into A at base 3915 in the second coding region

Implicated in

Note
  
Entity Cisplatin sensitivity in head and neck squamous cell carcinoma (HNSCC).
Note A common feature in HNSCC is cisplatin sensitivity. Microarray analysis identified mouse ZFP36L1 to be differentially expressed by cisplatin treatment. Cisplatin-sensitive HNSCC cell lines expressed elevated levels of ZFP36L1 compared to cisplatin-resistant HNSCC cell lines. Downregulation of ZFP36L1 (using antisense oligonucleotides) in cisplatin-sensitive cell lines made the cells cisplatin-resistant. Conversely, overexpression of ZFP36L1 reverted cisplatin-resistant cells to cisplatin-sensitive cells. There was an inverse correlation between the expression levels of ZFP36L1 and the human inhibitor of apoptosis protein-2, cIAP2 (Birc3, baculoviral IAP repeat-containing 3). Increased expression of ZFP36L1 also correlated with increased caspase-3 activity and increased cisplatin-induced apoptosis. These results suggested that expression of ZFP36L1 enhanced cisplatin sensitivity in HNSCC cells by reducing cIAP2 mRNA levels.
  
  
Entity t(8;21) translocation
Note The AML1-MTG8 fusion transcription factor generated by t(8;21) translocation is thought to affect the normal regulation of genes that are needed for differentiation and proliferation of hematopoietic progenitors leading to acute myelogenous leukemia (AML). ZFP36L1 was identified as an up-regulated gene in t(8;21) leukemic cells suggesting that it may be important to AML1-MTG8-mediated leukemogenesis.
  
  
Entity Human T-lymphotropic virus 1(HTLV-1)
Note ZFP36L1 expression is also up-regulated in human T-lymphotropic virus 1(HTLV-1)-infected cells. HTLV-1 is associated with adult T-cell leukemia/lymphoma and the Tax oncoprotein encoded by the 3' region of HTLV-1 has been proposed to dysregulate the expression of many genes that are important for cell proliferation. The Tax transactivator was shown to bind to two ZFP36L1 upstream elements (a novel transcription factor-binding site labeled BRF1 Tax-responsive site or BTRS and a second consensus cAMP-responsive site or CRE).
  
  
Entity Various cancers.
Note Increased expression of ZFP36L1 has been seen in several cancers including lymph node (+) primary breast tumors and hepatocellular carcinomas. Increased expression has also been demonstrated in a number of the NCI 60 panel of human cancer cell lines. These include the mammary gland cancer cell lines BT549, MDA-MB-231, and NCI/ADR-RES; ovarian cell lines OVCAR-5, OVCAR-8 and SK-OV-3; lung cell line NCI-H226; skin cell lines LOXMVI, M14, MALME-3M, and SK-MEL-2; brain cell lines SF268 and SF295; prostate cell line PC-3; kidney cell lines A498, ACHN, CAKI-1, SN12C, TK10, and UO31; and colon cell line HT29.
  

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The RNA binding protein Zfp36l1 is required for normal vascularisation and post-transcriptionally regulates VEGF expression.
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Zfp36l3, a rodent X chromosome gene encoding a placenta-specific member of the Tristetraprolin family of CCCH tandem zinc finger proteins.
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PMID 15814898
 
The product of the primary response gene BRF1 inhibits the interaction between 14-3-3 proteins and cRaf-1 in the yeast trihybrid system.
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PMID 10463061
 
Cloning and characterization of ERF-1, a human member of the Tis11 family of early-response genes.
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Evidence that tristetraprolin is a physiological regulator of granulocyte-macrophage colony-stimulating factor messenger RNA deadenylation and stability.
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Comparative expression of tristetraprolin (TTP) family member transcripts in normal human tissues and cancer cell lines.
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Destabilization of vascular endothelial growth factor mRNA by the zinc-finger protein TIS11b.
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PMID 15467755
 
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Cytoplasmic localization of tristetraprolin involves 14-3-3-dependent and -independent mechanisms.
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PMID 11886850
 
Interactions of CCCH zinc finger proteins with mRNA. Binding of tristetraprolin-related zinc finger proteins to Au-rich elements and destabilization of mRNA.
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Novel mRNA targets for tristetraprolin (TTP) identified by global analysis of stabilized transcripts in TTP-deficient fibroblasts.
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Butyrate response factor 1 enhances cisplatin sensitivity in human head and neck squamous cell carcinoma cell lines.
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Tristetraprolin down-regulates IL-2 gene expression through AU-rich element-mediated mRNA decay.
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Members of the tristetraprolin family of tandem CCCH zinc finger proteins exhibit CRM1-dependent nucleocytoplasmic shuttling.
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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.
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Chorioallantoic fusion defects and embryonic lethality resulting from disruption of Zfp36L1, a gene encoding a CCCH tandem zinc finger protein of the Tristetraprolin family.
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PMID 15226444
 
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Citation

This paper should be referenced as such :
Stumpo, DJ ; Blackshear, PJ
ZFP36L1 (zinc finger protein 36, C3H type-like 1)
Atlas Genet Cytogenet Oncol Haematol. 2008;12(4):296-298.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/ZFP36L1ID42866ch14q22.html


External links

Nomenclature
HGNC (Hugo)ZFP36L1   1107
Cards
AtlasZFP36L1ID42866ch14q22
Entrez_Gene (NCBI)ZFP36L1  677  ZFP36 ring finger protein like 1
AliasesBRF1; Berg36; ERF-1; ERF1; 
RNF162B; TIS11B; cMG1
GeneCards (Weizmann)ZFP36L1
Ensembl hg19 (Hinxton)ENSG00000185650 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000185650 [Gene_View]  chr14:68787655-68793914 [Contig_View]  ZFP36L1 [Vega]
ICGC DataPortalENSG00000185650
TCGA cBioPortalZFP36L1
AceView (NCBI)ZFP36L1
Genatlas (Paris)ZFP36L1
WikiGenes677
SOURCE (Princeton)ZFP36L1
Genetics Home Reference (NIH)ZFP36L1
Genomic and cartography
GoldenPath hg38 (UCSC)ZFP36L1  -     chr14:68787655-68793914 -  14q24.1   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)ZFP36L1  -     14q24.1   [Description]    (hg19-Feb_2009)
EnsemblZFP36L1 - 14q24.1 [CytoView hg19]  ZFP36L1 - 14q24.1 [CytoView hg38]
Mapping of homologs : NCBIZFP36L1 [Mapview hg19]  ZFP36L1 [Mapview hg38]
OMIM601064   
Gene and transcription
Genbank (Entrez)AI809725 AK024202 AK294363 AK303917 BC018340
RefSeq transcript (Entrez)NM_001244698 NM_001244701 NM_004926
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)ZFP36L1
Cluster EST : UnigeneHs.707091 [ NCBI ]
CGAP (NCI)Hs.707091
Alternative Splicing GalleryENSG00000185650
Gene ExpressionZFP36L1 [ NCBI-GEO ]   ZFP36L1 [ EBI - ARRAY_EXPRESS ]   ZFP36L1 [ SEEK ]   ZFP36L1 [ MEM ]
Gene Expression Viewer (FireBrowse)ZFP36L1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)677
GTEX Portal (Tissue expression)ZFP36L1
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ07352   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ07352  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ07352
Splice isoforms : SwissVarQ07352
PhosPhoSitePlusQ07352
Domaine pattern : Prosite (Expaxy)ZF_C3H1 (PS50103)   
Domains : Interpro (EBI)Tis11B_N    Znf_CCCH   
Domain families : Pfam (Sanger)Tis11B_N (PF04553)    zf-CCCH (PF00642)   
Domain families : Pfam (NCBI)pfam04553    pfam00642   
Domain families : Smart (EMBL)ZnF_C3H1 (SM00356)  
Conserved Domain (NCBI)ZFP36L1
DMDM Disease mutations677
Blocks (Seattle)ZFP36L1
PDB (SRS)1W0V    1W0W   
PDB (PDBSum)1W0V    1W0W   
PDB (IMB)1W0V    1W0W   
PDB (RSDB)1W0V    1W0W   
Structural Biology KnowledgeBase1W0V    1W0W   
SCOP (Structural Classification of Proteins)1W0V    1W0W   
CATH (Classification of proteins structures)1W0V    1W0W   
SuperfamilyQ07352
Human Protein AtlasENSG00000185650
Peptide AtlasQ07352
HPRD03041
IPIIPI00016635   IPI00909768   IPI01012628   IPI01025692   IPI01025809   IPI01025913   IPI01025016   IPI00298099   
Protein Interaction databases
DIP (DOE-UCLA)Q07352
IntAct (EBI)Q07352
FunCoupENSG00000185650
BioGRIDZFP36L1
STRING (EMBL)ZFP36L1
ZODIACZFP36L1
Ontologies - Pathways
QuickGOQ07352
Ontology : AmiGOMAPK cascade  nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay  P-body  vasculogenesis  proepicardium development  DNA binding  transcription factor activity, sequence-specific DNA binding  RNA binding  mRNA binding  protein binding  nucleus  cytoplasm  cytosol  cytosol  regulation of transcription, DNA-templated  mRNA processing  apoptotic process  heart development  cell proliferation  response to wounding  regulation of gene expression  regulation of keratinocyte proliferation  phosphatidylinositol 3-kinase signaling  neural tube development  intracellular ribonucleoprotein complex  nuclear-transcribed mRNA catabolic process, deadenylation-independent decay  regulation of mRNA 3'-end processing  cellular response to insulin stimulus  T cell differentiation in thymus  multicellular organism growth  mRNA 3'-UTR AU-rich region binding  p38MAPK cascade  regulation of mRNA stability  regulation of mRNA stability  regulation of mRNA stability  protein kinase B signaling  cellular response to fibroblast growth factor stimulus  regulation of B cell differentiation  positive regulation of fat cell differentiation  regulation of keratinocyte differentiation  negative regulation of erythrocyte differentiation  positive regulation of monocyte differentiation  regulation of myoblast differentiation  metal ion binding  mesendoderm development  mRNA transport  chorio-allantoic fusion  spongiotrophoblast layer development  3'-UTR-mediated mRNA destabilization  3'-UTR-mediated mRNA destabilization  ERK1 and ERK2 cascade  cellular response to cAMP  cellular response to tumor necrosis factor  cellular response to epidermal growth factor stimulus  cellular response to peptide hormone stimulus  cellular response to glucocorticoid stimulus  cellular response to hypoxia  cellular response to salt stress  cellular response to transforming growth factor beta stimulus  14-3-3 protein binding  regulation of stem cell proliferation  cellular response to raffinose  positive regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay  negative regulation of mitotic cell cycle phase transition  regulation of keratinocyte apoptotic process  positive regulation of intracellular mRNA localization  cellular response to phorbol 13-acetate 12-myristate  
Ontology : EGO-EBIMAPK cascade  nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay  P-body  vasculogenesis  proepicardium development  DNA binding  transcription factor activity, sequence-specific DNA binding  RNA binding  mRNA binding  protein binding  nucleus  cytoplasm  cytosol  cytosol  regulation of transcription, DNA-templated  mRNA processing  apoptotic process  heart development  cell proliferation  response to wounding  regulation of gene expression  regulation of keratinocyte proliferation  phosphatidylinositol 3-kinase signaling  neural tube development  intracellular ribonucleoprotein complex  nuclear-transcribed mRNA catabolic process, deadenylation-independent decay  regulation of mRNA 3'-end processing  cellular response to insulin stimulus  T cell differentiation in thymus  multicellular organism growth  mRNA 3'-UTR AU-rich region binding  p38MAPK cascade  regulation of mRNA stability  regulation of mRNA stability  regulation of mRNA stability  protein kinase B signaling  cellular response to fibroblast growth factor stimulus  regulation of B cell differentiation  positive regulation of fat cell differentiation  regulation of keratinocyte differentiation  negative regulation of erythrocyte differentiation  positive regulation of monocyte differentiation  regulation of myoblast differentiation  metal ion binding  mesendoderm development  mRNA transport  chorio-allantoic fusion  spongiotrophoblast layer development  3'-UTR-mediated mRNA destabilization  3'-UTR-mediated mRNA destabilization  ERK1 and ERK2 cascade  cellular response to cAMP  cellular response to tumor necrosis factor  cellular response to epidermal growth factor stimulus  cellular response to peptide hormone stimulus  cellular response to glucocorticoid stimulus  cellular response to hypoxia  cellular response to salt stress  cellular response to transforming growth factor beta stimulus  14-3-3 protein binding  regulation of stem cell proliferation  cellular response to raffinose  positive regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay  negative regulation of mitotic cell cycle phase transition  regulation of keratinocyte apoptotic process  positive regulation of intracellular mRNA localization  cellular response to phorbol 13-acetate 12-myristate  
REACTOMEQ07352 [protein]
REACTOME PathwaysR-HSA-450385 [pathway]   
NDEx NetworkZFP36L1
Atlas of Cancer Signalling NetworkZFP36L1
Wikipedia pathwaysZFP36L1
Orthology - Evolution
OrthoDB677
GeneTree (enSembl)ENSG00000185650
Phylogenetic Trees/Animal Genes : TreeFamZFP36L1
HOVERGENQ07352
HOGENOMQ07352
Homologs : HomoloGeneZFP36L1
Homology/Alignments : Family Browser (UCSC)ZFP36L1
Gene fusions - Rearrangements
Fusion : MitelmanZFP36L1/EHD1 [14q24.1/11q13.1]  
Fusion : MitelmanZFP36L1/IGHA2 [14q24.1/14q32.33]  [del(14)(q24)]  [del(14)(q24q32)]  
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerZFP36L1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)ZFP36L1
dbVarZFP36L1
ClinVarZFP36L1
1000_GenomesZFP36L1 
Exome Variant ServerZFP36L1
ExAC (Exome Aggregation Consortium)ZFP36L1 (select the gene name)
Genetic variants : HAPMAP677
Genomic Variants (DGV)ZFP36L1 [DGVbeta]
DECIPHERZFP36L1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisZFP36L1 
Mutations
ICGC Data PortalZFP36L1 
TCGA Data PortalZFP36L1 
Broad Tumor PortalZFP36L1
OASIS PortalZFP36L1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICZFP36L1  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDZFP36L1
intOGen PortalZFP36L1
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch ZFP36L1
DgiDB (Drug Gene Interaction Database)ZFP36L1
DoCM (Curated mutations)ZFP36L1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)ZFP36L1 (select a term)
intoGenZFP36L1
NCG5 (London)ZFP36L1
Cancer3DZFP36L1(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM601064   
Orphanet
MedgenZFP36L1
Genetic Testing Registry ZFP36L1
NextProtQ07352 [Medical]
TSGene677
GENETestsZFP36L1
Target ValidationZFP36L1
Huge Navigator ZFP36L1 [HugePedia]
snp3D : Map Gene to Disease677
BioCentury BCIQZFP36L1
ClinGenZFP36L1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD677
Chemical/Pharm GKB GenePA35027
Clinical trialZFP36L1
Miscellaneous
canSAR (ICR)ZFP36L1 (select the gene name)
Probes
Litterature
PubMed49 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineZFP36L1
EVEXZFP36L1
GoPubMedZFP36L1
iHOPZFP36L1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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