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PIAS1 (protein inhibitor of activated STAT, 1)

Written2013-07Andrea Rabellino, Pier Paolo Scaglioni
Division of Hematology, Oncology, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_namesMIZ-type containing 3
DDXBP1
Alias_symbol (synonym)GBP
GU/RH-II
ZMIZ3
Other alias
HGNC (Hugo) PIAS1
LocusID (NCBI) 8554
Atlas_Id 45688
Location 15q23  [Link to chromosome band 15q23]
Location_base_pair Starts at 68054576 and ends at 68191466 bp from pter ( according to hg19-Feb_2009)  [Mapping PIAS1.png]
 
  Chromosomal mapping of PIAS1. Modified from Weiskirchen et al., 2001.
Fusion genes
(updated 2016)
PIAS1 (15q23) / PIAS1 (15q23)PIAS1 (15q23) / ZNF609 (15q22.31)
Note PIAS1 gene was initially located at 15q22 (Weiskirchen et al., 2001).

DNA/RNA

 
  Structural organization of PIAS1 human gene.
Description PIAS1 gene is composed of 14 exons and spans approximately 134,8 kb of genomic DNA.
Transcription PIAS1 gene encodes a 2309 bp mRNA transcript.
Pseudogene No pseudogenes have been reported.

Protein

 
  Schematic representation of PIAS1 protein. The different domains are illustrated. A purple square represents the SUMO binding domain (SBD).
Description The human PIAS1 protein is composed of 651 amino acids, with a predicted molecular weight of 71,85 kDa. PIAS1 has five distinct functional domains, with different functions: the SAP (scaffold attachment factor-A/B, Acinus and PIAS), the PINIT motif, the RING-type zinc-binding domain, the SBD (SUMO binding domain, also indicated as SIM, SUMO interacting motif) and a C-terminal serine/threonine rich region. The SAP domain contains a LXXLL motif which is involved in direct-DNA binding or in physical interaction with other proteins involved in DNA-binding, such as transcription factors, co-regulators and nuclear receptors (Aravind and Koonin, 2000). The PINIT motif is involved in the sub-cellular organization of PIAS1 (Duval et al., 2003). The RING domain is essential for the E3 SUMO-ligase activity of PIAS1 and also mediates protein-protein interactions (Hochstrasser, 2001). The SBD domain interact in a non-covalently way with SUMO proteins (Rytinki et al., 2009). The C-terminal portion of PIAS1 is a serine/threonine rich region: this is the most variable region within the PIAS proteins family. PIAS1 undergoes several post-translational modifications, including phosphorylation, acetylation, methylation, SUMOylation and ubiquitination (Liu et al., 2005; Depaux et al., 2007; Rytinki et al., 2009; Stehmeier and Muller, 2009; Weber et al., 2009).
Expression PIAS1 is ubiquitously expressed.
Localisation Nuclear.
Function PIAS1 has been implicated in several cellular functions and most of them have been associated to its SUMO E3-ligase activity (Schimdt and Müller, 2003; Shuai and Liu, 2005; Rytinki et al., 2009).
Transcriptional regulation: PIAS1 is a negative regulator of several transcription factors. PIAS1 was initially described as a negative regulator of the STAT1 signal by blocking the DNA-binding activity of STAT1 (Liu et al., 1998). PIAS1 SUMOylates the TP53 tumor suppressor, inhibiting its activity (Kahyo et al., 2001; Schmidt and Müller, 2002). PIAS1 SUMOylates the androgen receptor (AR) repressing the AR-dependent transcription (Nishida and Yasuda, 2002). PIAS1 also regulates the homeoprotein Msx1 by regulating its subnuclear localization and its DNA-binding specificity in a SUMO E3-ligase independent manner (Lee et al., 2006). PIAS1 SUMOylates the progesterone receptor (PR), and cAMP attenuates ligand-dependent SUMOylation of PR (Jones et al., 2006).
Inflammation and immunity: upon various inflammatory stimuli, IKKa phosphorylates PIAS1 associating it with the promoter of NF-κB target genes (Liu et al., 2007). PIAS1 regulates the natural T regulatory cells by restricting their differentiation through the recruitment of the protein DNA-methyltransferase and CBX5 at the FOXP3 promoter (Liu et al., 2010).
DNA damage: PIAS1 co-operates with PIAS4 promoting double-strand DNA breaks repair (Galanty et al., 2009).
Cancer: PIAS1 SUMOylates the promyelocytic leukemia (PML) gene and promotes its ubiquitin/proteasome-dependent degradation, inhibiting its tumor suppressor functions. PIAS1 also SUMOylates the PML-RARA oncoprotein of acute promyelocytic leukemia (APL); in this case, PIAS1-dependent SUMOylation is required for the degradation of PML-RARA in APL cells treated with arsenic trioxide (Rabellino et al., 2012).
Homology PIAS1 belongs to the PIAS proteins family and is evolutionary conserved from yeast to man. PIAS1 can be found in Saccharomyces cerevisiae, in plants (Arabidopis thaliana and Oryza sativa), Caernorhabditis elegans, Drosophila melanogaster, Danio renio, Xenopus laevis, Gallus gallus and mammals. All PIAS1 orthologues share a high degree of homology. The human PIAS family consists of at least 5 different members: PIAS1, PIAS2 (with two variants called PIASxα and PIASxβ), PIAS3 and PIAS4 (also known as PIASy). All family members share high protein homology, except for the C-terminus (Shuai and Liu, 2005; Rytinki et al., 2009).

Mutations

Note No translocations involving PIAS1 gene have been reported so far.
 
  Schematic representation of the mutations of human PIAS1 protein found in tumor samples. Notably, most of the mutations reside in the PINIT domain.
Germinal No germinal mutations of PIAS1 have been reported.
Somatic At least 25 different somatic mutations have been described in different tumor types. All the informations in this regard can be found at the COSMIC website.

Implicated in

Note
  
Entity Prostate cancer
Note High expression of PIAS1 is found in malignant areas of prostate cancer as compared to benign areas. Immunohistochemistry staining positively correlates with positive staining for the PCNA and Ki-67 proliferative markers suggesting a pro-proliferative role of PIAS1 in prostate cancer (Hoefer, 2012).
  
  
Entity Colon cancer
Note Activated STAT3 signaling has been involved in colon cancer. PIAS1 is a negative regulator of the STAT signaling. Accordingly, PIAS1 expression is high in colonic non-tumor cells and adenomas, and lower in colon cancer cells (Coppola et al., 2009).
  
  
Entity Gastric cancer
Prognosis One study shows that 70% of the gastric tumors specimens analyzed show a low level of PIAS1 expression. Moreover, the low expression of PIAS1 significantly correlates with tumor staging (Chen et al., 2012).
  
  
Entity Non-small cell lung cancer (NSCLC)
Note PIAS1-dependent SUMOylation of PML leads to its degradation, blocking the tumor suppression activity of PML. Accordingly with this observation obtained with in vitro experiments, a correlation between high level of PIAS1 protein expression and low level of PML was reported in NSCLC specimens. Furthermore, high expression of mRNA levels of PIAS1 in NSCLC specimens correlates with PIAS1 gene amplification (Rabellino et al., 2012).
  

Breakpoints

Note None.

Bibliography

SAP - a putative DNA-binding motif involved in chromosomal organization.
Aravind L, Koonin EV.
Trends Biochem Sci. 2000 Mar;25(3):112-4.
PMID 10694879
 
Protein inhibitor of activated STAT-1 is downregulated in gastric cancer tissue and involved in cell metastasis.
Chen P, Zhao D, Sun Y, Huang L, Zhang S, Yuan Y.
Oncol Rep. 2012 Dec;28(6):2149-55. doi: 10.3892/or.2012.2030. Epub 2012 Sep 12.
PMID 22972521
 
Substantially reduced expression of PIAS1 is associated with colon cancer development.
Coppola D, Parikh V, Boulware D, Blanck G.
J Cancer Res Clin Oncol. 2009 Sep;135(9):1287-91. doi: 10.1007/s00432-009-0570-z. Epub 2009 Mar 15.
PMID 19288270
 
A crosstalk between hSiah2 and Pias E3-ligases modulates Pias-dependent activation.
Depaux A, Regnier-Ricard F, Germani A, Varin-Blank N.
Oncogene. 2007 Oct 11;26(46):6665-76. Epub 2007 May 28.
PMID 17533377
 
The 'PINIT' motif, of a newly identified conserved domain of the PIAS protein family, is essential for nuclear retention of PIAS3L.
Duval D, Duval G, Kedinger C, Poch O, Boeuf H.
FEBS Lett. 2003 Nov 6;554(1-2):111-8.
PMID 14596924
 
Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks.
Galanty Y, Belotserkovskaya R, Coates J, Polo S, Miller KM, Jackson SP.
Nature. 2009 Dec 17;462(7275):935-9. doi: 10.1038/nature08657.
PMID 20016603
 
SP-RING for SUMO: new functions bloom for a ubiquitin-like protein.
Hochstrasser M.
Cell. 2001 Oct 5;107(1):5-8. (REVIEW)
PMID 11595179
 
PIAS1 is increased in human prostate cancer and enhances proliferation through inhibition of p21.
Hoefer J, Schafer G, Klocker H, Erb HH, Mills IG, Hengst L, Puhr M, Culig Z.
Am J Pathol. 2012 May;180(5):2097-107. doi: 10.1016/j.ajpath.2012.01.026. Epub 2012 Mar 23.
PMID 22449952
 
Regulation of the SUMO pathway sensitizes differentiating human endometrial stromal cells to progesterone.
Jones MC, Fusi L, Higham JH, Abdel-Hafiz H, Horwitz KB, Lam EW, Brosens JJ.
Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16272-7. Epub 2006 Oct 19.
PMID 17053081
 
Involvement of PIAS1 in the sumoylation of tumor suppressor p53.
Kahyo T, Nishida T, Yasuda H.
Mol Cell. 2001 Sep;8(3):713-8.
PMID 11583632
 
PIAS1 confers DNA-binding specificity on the Msx1 homeoprotein.
Lee H, Quinn JC, Prasanth KV, Swiss VA, Economides KD, Camacho MM, Spector DL, Abate-Shen C.
Genes Dev. 2006 Apr 1;20(7):784-94.
PMID 16600910
 
Inhibition of Stat1-mediated gene activation by PIAS1.
Liu B, Liao J, Rao X, Kushner SA, Chung CD, Chang DD, Shuai K.
Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10626-31.
PMID 9724754
 
The ligase PIAS1 restricts natural regulatory T cell differentiation by epigenetic repression.
Liu B, Tahk S, Yee KM, Fan G, Shuai K.
Science. 2010 Oct 22;330(6003):521-5. doi: 10.1126/science.1193787.
PMID 20966256
 
Proinflammatory stimuli induce IKKalpha-mediated phosphorylation of PIAS1 to restrict inflammation and immunity.
Liu B, Yang Y, Chernishof V, Loo RR, Jang H, Tahk S, Yang R, Mink S, Shultz D, Bellone CJ, Loo JA, Shuai K.
Cell. 2007 Jun 1;129(5):903-14.
PMID 17540171
 
PIAS1 and PIASxalpha function as SUMO-E3 ligases toward androgen receptor and repress androgen receptor-dependent transcription.
Nishida T, Yasuda H.
J Biol Chem. 2002 Nov 1;277(44):41311-7. Epub 2002 Aug 9.
PMID 12177000
 
The SUMO E3-ligase PIAS1 regulates the tumor suppressor PML and its oncogenic counterpart PML-RARA.
Rabellino A, Carter B, Konstantinidou G, Wu SY, Rimessi A, Byers LA, Heymach JV, Girard L, Chiang CM, Teruya-Feldstein J, Scaglioni PP.
Cancer Res. 2012 May 1;72(9):2275-84. doi: 10.1158/0008-5472.CAN-11-3159. Epub 2012 Mar 9.
PMID 22406621
 
PIAS proteins: pleiotropic interactors associated with SUMO.
Rytinki MM, Kaikkonen S, Pehkonen P, Jaaskelainen T, Palvimo JJ.
Cell Mol Life Sci. 2009 Sep;66(18):3029-41. doi: 10.1007/s00018-009-0061-z. Epub 2009 Jun 13. (REVIEW)
PMID 19526197
 
PIAS/SUMO: new partners in transcriptional regulation.
Schmidt D, Muller S.
Cell Mol Life Sci. 2003 Dec;60(12):2561-74. (REVIEW)
PMID 14685683
 
Regulation of gene-activation pathways by PIAS proteins in the immune system.
Shuai K, Liu B.
Nat Rev Immunol. 2005 Aug;5(8):593-605. (REVIEW)
PMID 16056253
 
Phospho-regulated SUMO interaction modules connect the SUMO system to CK2 signaling.
Stehmeier P, Muller S.
Mol Cell. 2009 Feb 13;33(3):400-9. doi: 10.1016/j.molcel.2009.01.013.
PMID 19217413
 
PRMT1-mediated arginine methylation of PIAS1 regulates STAT1 signaling.
Weber S, Maass F, Schuemann M, Krause E, Suske G, Bauer UM.
Genes Dev. 2009 Jan 1;23(1):118-32. doi: 10.1101/gad.489409.
PMID 19136629
 
LIM-domain protein cysteine- and glycine-rich protein 2 (CRP2) is a novel marker of hepatic stellate cells and binding partner of the protein inhibitor of activated STAT1.
Weiskirchen R, Moser M, Weiskirchen S, Erdel M, Dahmen S, Buettner R, Gressner AM.
Biochem J. 2001 Nov 1;359(Pt 3):485-96.
PMID 11672422
 

Citation

This paper should be referenced as such :
Rabellino, A ; Scaglioni, PP
PIAS1 (protein inhibitor of activated STAT, 1)
Atlas Genet Cytogenet Oncol Haematol. 2014;18(2):106-109.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/PIAS1ID45688ch15q23.html


External links

Nomenclature
HGNC (Hugo)PIAS1   2752
Cards
AtlasPIAS1ID45688ch15q23
Entrez_Gene (NCBI)PIAS1  8554  protein inhibitor of activated STAT 1
AliasesDDXBP1; GBP; GU/RH-II; ZMIZ3
GeneCards (Weizmann)PIAS1
Ensembl hg19 (Hinxton)ENSG00000033800 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000033800 [Gene_View]  chr15:68054576-68191466 [Contig_View]  PIAS1 [Vega]
ICGC DataPortalENSG00000033800
TCGA cBioPortalPIAS1
AceView (NCBI)PIAS1
Genatlas (Paris)PIAS1
WikiGenes8554
SOURCE (Princeton)PIAS1
Genetics Home Reference (NIH)PIAS1
Genomic and cartography
GoldenPath hg38 (UCSC)PIAS1  -     chr15:68054576-68191466 +  15q23   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)PIAS1  -     15q23   [Description]    (hg19-Feb_2009)
EnsemblPIAS1 - 15q23 [CytoView hg19]  PIAS1 - 15q23 [CytoView hg38]
Mapping of homologs : NCBIPIAS1 [Mapview hg19]  PIAS1 [Mapview hg38]
OMIM603566   
Gene and transcription
Genbank (Entrez)AA837658 AF077951 AF167160 AK094641 AK314515
RefSeq transcript (Entrez)NM_001320687 NM_016166
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)PIAS1
Cluster EST : UnigeneHs.694796 [ NCBI ]
CGAP (NCI)Hs.694796
Alternative Splicing GalleryENSG00000033800
Gene ExpressionPIAS1 [ NCBI-GEO ]   PIAS1 [ EBI - ARRAY_EXPRESS ]   PIAS1 [ SEEK ]   PIAS1 [ MEM ]
Gene Expression Viewer (FireBrowse)PIAS1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)8554
GTEX Portal (Tissue expression)PIAS1
Protein : pattern, domain, 3D structure
UniProt/SwissProtO75925   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtO75925  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProO75925
Splice isoforms : SwissVarO75925
Catalytic activity : Enzyme6.3.2.- [ Enzyme-Expasy ]   6.3.2.-6.3.2.- [ IntEnz-EBI ]   6.3.2.- [ BRENDA ]   6.3.2.- [ KEGG ]   
PhosPhoSitePlusO75925
Domaine pattern : Prosite (Expaxy)PINIT (PS51466)    SAP (PS50800)    ZF_SP_RING (PS51044)   
Domains : Interpro (EBI)PIAS1    PINIT    SAP_dom    Znf_MIZ   
Domain families : Pfam (Sanger)PINIT (PF14324)    zf-MIZ (PF02891)   
Domain families : Pfam (NCBI)pfam14324    pfam02891   
Domain families : Smart (EMBL)SAP (SM00513)  
Conserved Domain (NCBI)PIAS1
DMDM Disease mutations8554
Blocks (Seattle)PIAS1
PDB (SRS)1V66   
PDB (PDBSum)1V66   
PDB (IMB)1V66   
PDB (RSDB)1V66   
Structural Biology KnowledgeBase1V66   
SCOP (Structural Classification of Proteins)1V66   
CATH (Classification of proteins structures)1V66   
SuperfamilyO75925
Human Protein AtlasENSG00000033800
Peptide AtlasO75925
HPRD16029
IPIIPI01011206   IPI00220424   
Protein Interaction databases
DIP (DOE-UCLA)O75925
IntAct (EBI)O75925
FunCoupENSG00000033800
BioGRIDPIAS1
STRING (EMBL)PIAS1
ZODIACPIAS1
Ontologies - Pathways
QuickGOO75925
Ontology : AmiGOG1/S transition of mitotic cell cycle  negative regulation of transcription from RNA polymerase II promoter  DNA binding  transcription coactivator activity  transcription corepressor activity  protein binding  nucleus  nucleoplasm  transcription, DNA-templated  JAK-STAT cascade  spermatogenesis  protein C-terminus binding  transcription factor binding  zinc ion binding  visual learning  PML body  nuclear speck  ligase activity  protein sumoylation  protein sumoylation  protein sumoylation  protein sumoylation  SUMO transferase activity  enzyme binding  protein domain specific binding  androgen receptor signaling pathway  ubiquitin protein ligase binding  positive regulation of proteasomal ubiquitin-dependent protein catabolic process  positive regulation of protein sumoylation  regulation of cell proliferation  negative regulation of apoptotic process  fat cell differentiation  positive regulation of transcription, DNA-templated  androgen receptor binding  positive regulation of smooth muscle cell differentiation  regulation of interferon-gamma-mediated signaling pathway  SUMO ligase activity  protein-DNA complex assembly  
Ontology : EGO-EBIG1/S transition of mitotic cell cycle  negative regulation of transcription from RNA polymerase II promoter  DNA binding  transcription coactivator activity  transcription corepressor activity  protein binding  nucleus  nucleoplasm  transcription, DNA-templated  JAK-STAT cascade  spermatogenesis  protein C-terminus binding  transcription factor binding  zinc ion binding  visual learning  PML body  nuclear speck  ligase activity  protein sumoylation  protein sumoylation  protein sumoylation  protein sumoylation  SUMO transferase activity  enzyme binding  protein domain specific binding  androgen receptor signaling pathway  ubiquitin protein ligase binding  positive regulation of proteasomal ubiquitin-dependent protein catabolic process  positive regulation of protein sumoylation  regulation of cell proliferation  negative regulation of apoptotic process  fat cell differentiation  positive regulation of transcription, DNA-templated  androgen receptor binding  positive regulation of smooth muscle cell differentiation  regulation of interferon-gamma-mediated signaling pathway  SUMO ligase activity  protein-DNA complex assembly  
Pathways : BIOCARTASumoylation by RanBP2 Regulates Transcriptional Repression [Genes]   
Pathways : KEGGUbiquitin mediated proteolysis    Jak-STAT signaling pathway    Hepatitis C   
REACTOMEO75925 [protein]
REACTOME PathwaysR-HSA-877312 [pathway]   
NDEx NetworkPIAS1
Atlas of Cancer Signalling NetworkPIAS1
Wikipedia pathwaysPIAS1
Orthology - Evolution
OrthoDB8554
GeneTree (enSembl)ENSG00000033800
Phylogenetic Trees/Animal Genes : TreeFamPIAS1
HOVERGENO75925
HOGENOMO75925
Homologs : HomoloGenePIAS1
Homology/Alignments : Family Browser (UCSC)PIAS1
Gene fusions - Rearrangements
Fusion : MitelmanPIAS1/ZNF609 [15q23/15q22.31]  
Fusion: TCGAPIAS1 15q23 ZNF609 15q22.31 PRAD
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerPIAS1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)PIAS1
dbVarPIAS1
ClinVarPIAS1
1000_GenomesPIAS1 
Exome Variant ServerPIAS1
ExAC (Exome Aggregation Consortium)PIAS1 (select the gene name)
Genetic variants : HAPMAP8554
Genomic Variants (DGV)PIAS1 [DGVbeta]
DECIPHERPIAS1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisPIAS1 
Mutations
ICGC Data PortalPIAS1 
TCGA Data PortalPIAS1 
Broad Tumor PortalPIAS1
OASIS PortalPIAS1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICPIAS1  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDPIAS1
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 PIAS1
DgiDB (Drug Gene Interaction Database)PIAS1
DoCM (Curated mutations)PIAS1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)PIAS1 (select a term)
intoGenPIAS1
NCG5 (London)PIAS1
Cancer3DPIAS1(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM603566   
Orphanet
MedgenPIAS1
Genetic Testing Registry PIAS1
NextProtO75925 [Medical]
TSGene8554
GENETestsPIAS1
Target ValidationPIAS1
Huge Navigator PIAS1 [HugePedia]
snp3D : Map Gene to Disease8554
BioCentury BCIQPIAS1
ClinGenPIAS1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD8554
Chemical/Pharm GKB GenePA33285
Clinical trialPIAS1
Miscellaneous
canSAR (ICR)PIAS1 (select the gene name)
Probes
Litterature
PubMed159 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMinePIAS1
EVEXPIAS1
GoPubMedPIAS1
iHOPPIAS1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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