PIAS3 (protein inhibitor of activated STAT, 3)

2010-04-01   Gilles Spoden , Werner Zwerschke 

Identity

HGNC
LOCATION
1q21.1
LOCUSID
ALIAS
ZMIZ5
FUSION GENES

DNA/RNA

Note

The gene codes for a protein of the PIAS family (protein inhibitor of activated STAT (signal transducer and activator of transcription)). PIAS3 regulates the activity of several transcription factors by direct protein-protein interaction. Further, PIAS3 is a SUMO (small ubiquitin-like modifier)-E3 ligase, catalyzing the covalent, post-translational modification of specific target proteins with SUMO. Different splice variants of PIAS3 have been identified but the full-length sequence of some of these variants has not been described.
Atlas Image
Figure 1. PIAS3 gene 10559 bp. Exons 1 to 14 (UTR in white, coding sequence in red) Exon 1: 1-115 (5UTR: 1-91); Exon 2: 2075-2492; Exon 3: 2650-2734; Exon 4: 2963-3013; Exon 5: 3255-3345; Exon 6: 4201-4335; Exon 7: 4518-4623; Exon 8: 5195-5268; Exon 9: 5417-5577; Exon 10: 7928-8061; Exon 11: 8142-8310; Exon 12: 8495-8628; Exon 13: 8812-8849; Exon 14: 9369-10559 (3UTR: 9636-10559).

Description

The human PIAS3 gene is 10559 bp long and consists of 14 exons and 13 introns.

Transcription

Transcript length 2902 bp (CDS 1887 bp ; residues 628 aa).

Pseudogene

No pseudogene reported.

Proteins

Atlas Image
Figure 2. The schematic domain structure of human PIAS3 protein is shown. SAP domain: nuclear localization and binding to DNA, transcription factors, coregulators. PINIT: nuclear retention, transcriptional repression. SP-RING: protein-protein interactions, interacts with the SUMO conjugase Ubc9, sumoylation. SIM: binding to SUMO. S/T: variable region, binding to coactivators.

Description

The human PIAS3 protein is a E3 SUMO-protein ligase consisting of 628 amino acids. It contains 5 conserved regions, the SAP, PINIT, SP-RING, SIM and S/T domains (figure 2).

Expression

PIAS3 is ubiquitously expressed.

Localisation

Nuclear as well as cytoplasmic localization.

Function

PIAS3 belongs to the mammalian protein inhibitor of activated STAT (PIAS) protein family, originally identified as cytokine-induced inhibitors of the STAT family of transcription factors. This protein class, referred to as SUMO-E3 ligases, increases the efficiency of SUMO conjugation. SUMO, a small ubiquitin-like modifier protein, is conjugated to a large number of cellular target proteins. Similar to enzymatic ubiquitination, the conjugation of specific SUMO proteins (SUMO-1-SUMO-3) to target proteins requires an E1-activating enzyme (Aos1/Uba2) as well as an E2-type SUMO-1-conjugating enzyme (Ubc9). Similar to many ubiquitin E3 ligases, these proteins contain a putative RING finger-like structure (SP-RING, figure 2), which is essential for their SUMO-E3 ligase activities toward various target proteins. Sumoylation is a dynamic process with highly diverse outcomes, ranging from changes in subcellular localization, signal transduction, transcriptional regulation to altered activity and stability of the modified protein. PIAS3 do, however, not only operate as SUMO-E3, since its coregulator effects are often independent of its RING-finger like domain but dependent on its capability to interact with sumoylated proteins via its conserved SIM (SUMO-interacting motif) or SAP (scaffold attachment factor-A/B/acinus/PIAS) domain (figure 2). Beside the N-terminal SAP, the SIM and the RING-type zinc-binding domain, a PINIT motif, and a serine/ threonine-rich C-terminal region (S/T) is conserved in PIAS3 (figure 2).
PIAS3 is involved in cytoplasmic regulation, such as functional interaction of PIAS3 with metabotropic glutamate receptor-8, voltage-gated potassium channel Kv1.5 and pyruvate kinase subtype M2, but the majority of so far reported interactions of the PIAS3 protein occurred with transcription factors or other proteins linked to nuclear regulation. PIAS3 can act in both transcriptional repression and activation. PIAS3 has been shown to repress STAT3 and Stat5 dependent transcriptional activation by blocking the DNA-binding of the factor without influencing its sumoylation. It interacts with and promotes sumoylation of the photoreceptor-specific transcription factor Nr2e3 when bound to specific promoters, which converts the factor to a transcriptional repressor. Moreover, PIAS3 was described as a repressor of microphthalmia transcription factor (MITF) and it was shown that PIAS3 blocks NF-kB mediated transcriptional activation by interacting with the p65/RelA subunit. Repression of IRF1-mediated transcription by PIAS3 has also been shown. PIAS3 has been shown to activate transcription mediated by Smad proteins through forming a complex with Smads and coactivator p300/CBP; moreover, PIAS proteins enhance steroid receptor-dependent transcription through an SP-RING-mediated interaction and sumoylation of the coactivator protein GRIP1/SCR2. Finally, PIAS3 was shown to modulate the ability of TIF2 to mediate ligand-enhanced transcription activation positively or negatively, for different steroid receptors.

Homology

The mammalian PIAS family consists of seven structurally related proteins (PIAS1, PIAS3, PIAS3b, PIASxa, PIASxb, PIASy, and PIASyE6) encoded by four genes. PIAS orthologs are found in nonvertebrate animal species, plants and yeasts.

Implicated in

Entity name
Prostate Cancer
Oncogenesis
PIAS3 is expressed in normal prostate and in prostate cancer cells and has been shown to modulate the transcriptional activity of androgen receptor in prostate cancer cells. Moreover, PIAS3 (KChAP) induces increased K+ efflux and apoptosis in prostate cancer lines.
Entity name
Glioblastoma multiforme (GBM)
Oncogenesis
The activation of STATs and loss of their natural inhibitors SOCS and PIAS is common in various human cancers. STAT3, a cytoplasmic transcription factor that becomes activated in response to a variety of cytokines and growth factors is aberrantly activated in GBM tumors. STAT3 activation correlates with strongly reduced PIAS3 protein expression in GBM tissues. Inhibition of PIAS3 resulted in enhanced glioblastoma cellular proliferation, and, conversely, PIAS3 overexpression inhibits STAT3 transcriptional activity, expression of STAT3-regulated genes, and cell proliferation. This suggests that the loss of PIAS3 in GBM contributes to enhanced STAT3 transcriptional activity and subsequent cell proliferation.
Entity name
Melanoma
Oncogenesis
PIAS3 functions as a key molecule in suppressing the transcriptional activity of both MITF and STAT3, two transcription factors that play a major role in the development, proliferation and survival of mast cells and melanocytes. In addition to its role in normal cell signaling, constitutively activated STAT3 signaling directly contributes to oncogenesis in many human cancers. STAT3 cooperates with MITF in the induction of cellular transformation. Evidence was provided suggesting that PIAS3 halt proliferation and induce apoptotic cell death in mast cells and in melanoma cells by inhibiting the transcriptional activity of the two oncogenic factors MITF and STAT3. Therefore PIAS3 may play a role in tumor suppression by inhibiting oncogenic processes induced by STAT3 and MITF.
Entity name
Non-small cell lung cancer (NSCLC)
Disease
The Epidermal Growth Factor Receptor (EGFR)-STAT3 axis plays an important role in oncogenic signaling of non-small cell lung cancer (NSCLC). The negative regulator of STAT3-mediated transcriptional activation, PIAS3, was shown to modulate oncogenic EGFR-STAT3 signaling in lung cancer. Overexpression of PIAS3 decreases STAT3 transcriptional activity and proliferation of NSCLC cells and when used in conjunction with EGFR inhibitors, further increased the anti-proliferative effects. This suggests that PIAS3 acts as an inhibitor of EGFR-STAT3 induced oncogenic action.

Bibliography

Pubmed IDLast YearTitleAuthors
108510462000STATs in oncogenesis.Bowman T et al
186767372008Loss of protein inhibitors of activated STAT-3 expression in glioblastoma multiforme tumors: implications for STAT-3 activation and gene expression.Brantley EC et al
108510452000The role of STATs in transcriptional control and their impact on cellular function.Bromberg J et al
93881841997Specific inhibition of Stat3 signal transduction by PIAS3.Chung CD 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
180005272007Concepts in sumoylation: a decade on.Geiss-Friedlander R et al
114393512001Distinct effects of PIAS proteins on androgen-mediated gene activation in prostate cancer cells.Gross M et al
113903542001The Drosophila Su(var)2-10 locus regulates chromosome structure and function and encodes a member of the PIAS protein family.Hari KL et al
115951792001SP-RING for SUMO: new functions bloom for a ubiquitin-like protein.Hochstrasser M et al
151408842004PIAS3 suppresses NF-kappaB-mediated transcription by interacting with the p65/RelA subunit.Jang HD et al
122085212002PIAS3 (protein inhibitor of activated STAT-3) modulates the transcriptional activation mediated by the nuclear receptor coactivator TIF2.Jiménez-Lara AM et al
151891462004Protein modification by SUMO.Johnson ES et al
147371072004STAT3 and MITF cooperatively induce cellular transformation through upregulation of c-fos expression.Joo A et al
110718472000Protein inhibitor of activated STAT3 regulates androgen receptor signaling in prostate carcinoma cells.Junicho A et al
172361292007Complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia-absent radius syndrome.Klopocki E et al
195692362009Cooperative interaction between protein inhibitor of activated signal transducer and activator of transcription-3 with epidermal growth factor receptor blockade in lung cancer.Kluge A et al
118937292002Androgen receptor-interacting protein 3 and other PIAS proteins cooperate with glucocorticoid receptor-interacting protein 1 in steroid receptor-dependent signaling.Kotaja N et al
163688852006Identifying a common molecular mechanism for inhibition of MITF and STAT3 by PIAS3.Levy C et al
117095562002A new role for the STAT3 inhibitor, PIAS3: a repressor of microphthalmia transcription factor.Levy C et al
146455192003Role played by microphthalmia transcription factor phosphorylation and its Zip domain in its transcriptional inhibition by PIAS3.Levy C et al
146912522004Activation of Smad transcriptional activity by protein inhibitor of activated STAT3 (PIAS3).Long J et al
174860982007SUMOylation regulates kainate-receptor-mediated synaptic transmission.Martin S et al
109619912000Covalent modification of p73alpha by SUMO-1. Two-hybrid screening with p73 identifies novel SUMO-1-interacting proteins and a SUMO-1 interaction motif.Minty A et al
158946202005The Arabidopsis SUMO E3 ligase SIZ1 controls phosphate deficiency responses.Miura K et al
123878932002PIAS3 induces SUMO-1 modification and transcriptional repression of IRF-1.Nakagawa K et al
121770002002PIAS1 and PIASxalpha function as SUMO-E3 ligases toward androgen receptor and repress androgen receptor-dependent transcription.Nishida T et al
170324982006Overexpression of PIAS3 suppresses cell growth and restores the drug sensitivity of human lung cancer cells in association with PI3-K/Akt inactivation.Ogata Y et al
191861662009Pias3-dependent SUMOylation directs rod photoreceptor development.Onishi A et al
180312322007PIAS proteins as regulators of small ubiquitin-related modifier (SUMO) modifications and transcription.Palvimo JJ et al
119974572002The intranuclear prolactin/cyclophilin B complex as a transcriptional inducer.Rycyzyn MA et al
195261972009PIAS proteins: pleiotropic interactors associated with SUMO.Rytinki MM et al
146856832003PIAS/SUMO: new partners in transcriptional regulation.Schmidt D et al
159615052005Sumoylation of the estrogen receptor alpha hinge region regulates its transcriptional activity.Sentis S et al
160562532005Regulation of gene-activation pathways by PIAS proteins in the immune system.Shuai K et al
155726652004Interplay between MITF, PIAS3, and STAT3 in mast cells and melanocytes.Sonnenblick A et al
193089902009The SUMO-E3 ligase PIAS3 targets pyruvate kinase M2.Spoden GA et al
118774182002Protein inhibitors of activated STAT resemble scaffold attachment factors and function as interacting nuclear receptor coregulators.Tan JA et al
103195861999Isolation and chromosomal assignment of a human gene encoding protein inhibitor of activated STAT3 (PIAS3).Ueki N et al
177282422007Ubiquitin-dependent proteolytic control of SUMO conjugates.Uzunova K et al
118774522002Increased K+ efflux and apoptosis induced by the potassium channel modulatory protein KChAP/PIAS3beta in prostate cancer cells.Wible BA et al
95655971998Cloning and expression of a novel K+ channel regulatory protein, KChAP.Wible BA et al
192018702009A specific epitope of protein inhibitor of activated STAT3 is responsible for the induction of apoptosis in rat transformed mast cells.Yagil Z et al

Other Information

Locus ID:

NCBI: 10401
MIM: 605987
HGNC: 16861
Ensembl: ENSG00000131788

Variants:

dbSNP: 10401
ClinVar: 10401
TCGA: ENSG00000131788
COSMIC: PIAS3

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000131788ENST00000369298E9PHH8
ENSG00000131788ENST00000393045Q9Y6X2
ENSG00000131788ENST00000393046E7ESB4
ENSG00000131788ENST00000463514U3KQV1

Expression (GTEx)

0
50
100
150

Pathways

PathwaySourceExternal ID
Ubiquitin mediated proteolysisKEGGko04120
Jak-STAT signaling pathwayKEGGko04630
Ubiquitin mediated proteolysisKEGGhsa04120
Jak-STAT signaling pathwayKEGGhsa04630
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
SUMOylationREACTOMER-HSA-2990846
SUMO E3 ligases SUMOylate target proteinsREACTOMER-HSA-3108232
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 DNA replication proteinsREACTOMER-HSA-4615885

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
151385722004Differential PIAS3 expression in human malignancy.42
151408842004PIAS3 suppresses NF-kappaB-mediated transcription by interacting with the p65/RelA subunit.39
233221972013MicroRNA-18a modulates STAT3 activity through negative regulation of PIAS3 during gastric adenocarcinogenesis.39
146912522004Activation of Smad transcriptional activity by protein inhibitor of activated STAT3 (PIAS3).35
193089902009The SUMO-E3 ligase PIAS3 targets pyruvate kinase M2.35
147152512004ATBF1 enhances the suppression of STAT3 signaling by interaction with PIAS3.27
179871062007Nitric oxide destabilizes Pias3 and regulates sumoylation.25
179871062007Nitric oxide destabilizes Pias3 and regulates sumoylation.25
170324982006Overexpression of PIAS3 suppresses cell growth and restores the drug sensitivity of human lung cancer cells in association with PI3-K/Akt inactivation.23
175659892007PIAS3 interacts with ATF1 and regulates the human ferritin H gene through an antioxidant-responsive element.19

Citation

Gilles Spoden ; Werner Zwerschke

PIAS3 (protein inhibitor of activated STAT, 3)

Atlas Genet Cytogenet Oncol Haematol. 2010-04-01

Online version: http://atlasgeneticsoncology.org/gene/41709/pias3