PIAS1 (protein inhibitor of activated STAT, 1)

2013-07-01   Andrea Rabellino , Pier Paolo Scaglioni 

Division of Hematology, Oncology, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA

Identity

HGNC
LOCATION
15q23
IMAGE
Atlas Image
LEGEND
Chromosomal mapping of PIAS1. Modified from Weiskirchen et al., 2001.
LOCUSID
ALIAS
DDXBP1,GBP,GU/RH-II,ZMIZ3
FUSION GENES

DNA/RNA

Atlas Image
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.

Proteins

Atlas Image
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.
Atlas Image
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

Entity name
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 name
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 name
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 name
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).

Bibliography

Pubmed IDLast YearTitleAuthors
106948792000SAP - a putative DNA-binding motif involved in chromosomal organization.Aravind L et al
229725212012Protein inhibitor of activated STAT-1 is downregulated in gastric cancer tissue and involved in cell metastasis.Chen P et al
192882702009Substantially reduced expression of PIAS1 is associated with colon cancer development.Coppola D et al
175333772007A crosstalk between hSiah2 and Pias E3-ligases modulates Pias-dependent activation.Depaux A et al
145969242003The 'PINIT' motif, of a newly identified conserved domain of the PIAS protein family, is essential for nuclear retention of PIAS3L.Duval D et al
200166032009Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks.Galanty Y et al
115951792001SP-RING for SUMO: new functions bloom for a ubiquitin-like protein.Hochstrasser M et al
224499522012PIAS1 is increased in human prostate cancer and enhances proliferation through inhibition of p21.Hoefer J et al
170530812006Regulation of the SUMO pathway sensitizes differentiating human endometrial stromal cells to progesterone.Jones MC et al
115836322001Involvement of PIAS1 in the sumoylation of tumor suppressor p53.Kahyo T et al
166009102006PIAS1 confers DNA-binding specificity on the Msx1 homeoprotein.Lee H et al
97247541998Inhibition of Stat1-mediated gene activation by PIAS1.Liu B et al
209662562010The ligase PIAS1 restricts natural regulatory T cell differentiation by epigenetic repression.Liu B et al
175401712007Proinflammatory stimuli induce IKKalpha-mediated phosphorylation of PIAS1 to restrict inflammation and immunity.Liu B et al
121770002002PIAS1 and PIASxalpha function as SUMO-E3 ligases toward androgen receptor and repress androgen receptor-dependent transcription.Nishida T et al
224066212012The SUMO E3-ligase PIAS1 regulates the tumor suppressor PML and its oncogenic counterpart PML-RARA.Rabellino A et al
195261972009PIAS proteins: pleiotropic interactors associated with SUMO.Rytinki MM et al
146856832003PIAS/SUMO: new partners in transcriptional regulation.Schmidt D et al
160562532005Regulation of gene-activation pathways by PIAS proteins in the immune system.Shuai K et al
192174132009Phospho-regulated SUMO interaction modules connect the SUMO system to CK2 signaling.Stehmeier P et al
191366292009PRMT1-mediated arginine methylation of PIAS1 regulates STAT1 signaling.Weber S et al
116724222001LIM-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 et al

Other Information

Locus ID:

NCBI: 8554
MIM: 603566
HGNC: 2752
Ensembl: ENSG00000033800

Variants:

dbSNP: 8554
ClinVar: 8554
TCGA: ENSG00000033800
COSMIC: PIAS1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000033800ENST00000249636O75925
ENSG00000033800ENST00000545237O75925
ENSG00000033800ENST00000562190H3BUL7
ENSG00000033800ENST00000563996H3BS65
ENSG00000033800ENST00000564915H3BSI8

Expression (GTEx)

0
5
10
15
20
25
30

Pathways

PathwaySourceExternal ID
Ubiquitin mediated proteolysisKEGGko04120
Jak-STAT signaling pathwayKEGGko04630
Ubiquitin mediated proteolysisKEGGhsa04120
Jak-STAT signaling pathwayKEGGhsa04630
Hepatitis CKEGGko05160
Hepatitis CKEGGhsa05160
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
SUMOylationREACTOMER-HSA-2990846
SUMO E3 ligases SUMOylate target proteinsREACTOMER-HSA-3108232
SUMOylation of DNA damage response and repair proteinsREACTOMER-HSA-3108214
Immune SystemREACTOMER-HSA-168256
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Interferon SignalingREACTOMER-HSA-913531
Interferon gamma signalingREACTOMER-HSA-877300
Regulation of IFNG signalingREACTOMER-HSA-877312
DNA RepairREACTOMER-HSA-73894
Nucleotide Excision RepairREACTOMER-HSA-5696398
Global Genome Nucleotide Excision Repair (GG-NER)REACTOMER-HSA-5696399
Formation of Incision Complex in GG-NERREACTOMER-HSA-5696395
SUMOylation of transcription factorsREACTOMER-HSA-3232118
SUMOylation of chromatin organization proteinsREACTOMER-HSA-4551638

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA36183STAT1GenePathwayassociated26111151

References

Pubmed IDYearTitleCitations
121770002002PIAS1 and PIASxalpha function as SUMO-E3 ligases toward androgen receptor and repress androgen receptor-dependent transcription.60
153377422004SUMO-1 modification activated GATA4-dependent cardiogenic gene activity.44
128555782003PIAS proteins promote SUMO-1 conjugation to STAT1.38
166009102006PIAS1 confers DNA-binding specificity on the Msx1 homeoprotein.37
176069192007Control of specificity and magnitude of NF-kappa B and STAT1-mediated gene activation through PIASy and PIAS1 cooperation.36
155726772004DNA cross-link repair protein SNM1A interacts with PIAS1 in nuclear focus formation.33
123939062002Sumoylation of Mdm2 by protein inhibitor of activated STAT (PIAS) and RanBP2 enzymes.31
155726662004PIAS-1 is a checkpoint regulator which affects exit from G1 and G2 by sumoylation of p73.30
258951362015c-Myc is targeted to the proteasome for degradation in a SUMOylation-dependent manner, regulated by PIAS1, SENP7 and RNF4.30
117885782002Activation of p53 by protein inhibitor of activated Stat1 (PIAS1).29

Citation

Andrea Rabellino ; Pier Paolo Scaglioni

PIAS1 (protein inhibitor of activated STAT, 1)

Atlas Genet Cytogenet Oncol Haematol. 2013-07-01

Online version: http://atlasgeneticsoncology.org/gene/45688/pias1