Cytokines & Cells Online Pathfinder Encyclopaedia
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[protein inhibitor of activated STAT] These proteins constitute a protein family implicated in the inhibition of cytokine signaling by STAT proteins, latent cytoplasmic transcription factors that become activated in response to stimulation by various cytokines. All PIAS proteins are able to coactivate steroid receptor-dependent transcription but to a differential degree, depending on the receptor, the promoter, and the cell type. Concentrations of PIAS proteins that modulate steroid receptor-dependent transcription influence only marginally transactivation mediated by various STAT proteins. It is not known yet whether PIAS proteins play a more significant physiological role in steroid receptor than in cytokine signaling. For other negative regulators of the activities of STAT proteins see also: SOCS.
PIAS-1 [protein inhibitor of activated STAT1] PIAS-1 (660 amino acids) (Liu et al, 1998) is identical with GBP [human Gu RNA helicase II binding protein], a mammalian nucleolar RNA helicase that is a member of the DEAD box family of proteins (Valdez et al, 1997).
IFN treatment induces the association of PIAS-1 and the signaling molecule STAT1, which blocks the DNA binding activity of STAT1 and results in the inhibition of gene activation mediated by STAT1 (Liu et al, 1998; Liao et al, 2000). The cytokine induced interaction between PIAS-1 and STAT1 is mediated through the specific recognition of the dimeric form of STAT1 by PIAS-1. PIAS-1 specifically interacts with the STAT1 dimer, but not with tyrosine-phosphorylated or unphosphorylated STAT1 monomers. Schmidt and Muller (2002) have reported that PIAS-1 acts as a specific E3-like ligases that promote the attachment of the regulatory protein SUMO to a variety of substrates such as p53 and Jun. Kotaja et al (2002) have reported that PIAS-1 interacts with the small ubiquitin-related modifier SUMO1 and is covalently modified by attachment of SUMO1 (sumoylated). The protein regulates the activities of transcription factors by functioning as a SUMO1 ligase.
The protein has been shown also to interact with the androgen receptor, a nuclear hormone receptor (Tan et al, 2000). PIAS-1 does not bind to STAT2 or STAT3.
Knock-out mice lacking expression of PIAS-1 show increased protection against pathogenic infection. PIAS-1 is a physiologically important negative regulator of STAT1. PIAS-1 selectively regulates a subset of IFN-gamma or IFN-beta inducible genes by interfering with the recruitment of STAT1 to the gene promoter (Liu et al, 2004).
PIAS-2 [protein inhibitor of activated STAT2] This name is used for ARIP-3 (androgen-receptor-interacting protein-3) and Miz-1 [Msx-interacting-zinc finger] (see below)
PIAS-3 [protein inhibitor of activated STAT3] Human PIAS-3 cDNA encodes a predicted protein of 619 amino acids, which has 83 % overall amino acid identity to the mouse counterpart (Ueki et al, 1999). The human PIAS-3 gene maps to chromosome 1q21. PIAS-3 specifically associates with STAT3 when cells are stimulated with ligands that cause the activation of STAT3. PIAS-3 blocks the DNA-binding activity of STAT3 and inhibits gene activation mediated by this signaling molecule (Chung et al, 1997.
A zinc finger protein, the dominant proto-oncogene Gfi-1, has been shown to regulate signal transduction mediated by STAT3. Gfi-1 can overcome the PIAS-3 block and significantly enhances transcriptional activation mediated by STAT3 (Rodel et al, 2000).
It has been shown that early after induction of liver failure in rats the expression of PIAS-3 and SOCS1, another negative regulator of the signaling pathways of some cytokines, is upregulated. In vitro, IL6 induces PIAS-3 expression in rat hepatocytes stimulated by HGF. Massive loss of hepatocytes and the early and rapid rise in blood IL6 levels is thought to weaken the hepatic regenerative response through upregulating the expression of STAT3 inhibitors.
Junicho et al (2000) have reported that PIAS-3 suppresses gene activation in prostate cancer cells by interacting with androgen receptors.
Long et al (2004) have reported that PIAS-3 activates TGF-beta responses through interaction with SMAD proteins.
Kotaja et al (2002) have reported that PIAS-3 interacts with the small ubiquitin-related modifier SUMO1 and is covalently modified by attachment of SUMO1 (sumoylated). The protein regulates the activities of transcription factors by functioning as a SUMO1 ligase.
Wang and Banerjee (2004) have reported that PIAS-3 is increased in 100/103 human cancers including lung, breast, prostate, colon-rectum, and brain tumors.
PIAS-gamma The human PIAS-gamma gene spans approximately 23 kb on chromosome 19 and is organized into ten exons. The size of the mouse PIAS-gamma is 16 kb and also organized into ten exons with the intron/exon structure of the two genes conserved in both species. Murine and human PIAS-gamma are highly homologous proteins (Sturm et al, 2000).
In mouse embryos the PIAS-gamma gene is expressed in the limbs, neuroepithelium, and the inner root sheath of the hair follicle, suggesting a role in the development of these structures. PIAS-gamma protein is localized in the hair follicle of human scalp hair and in monkey neuronal cells (Sturm et al, 2001). Galleguillos et al (2004) have reported that PIAS-gamma is a transcriptional co-regulator of the nuclear receptor Nurr-1 and thus has the potential of regulating the expression of Nurr-1 target genes.
Knock-out mice lacking expression of PIAS-gamma have no obvious morphological defect and display a normal distribution of lymphocyte populations (Wong et al, 2004). Signaling in response to IFN-gamma and Wnt family agonists is modestly subnormal (Roth et al, 2004).
PIAS-NY is an isoform of PIAS isolated from human testis cDNA library that may play important role in testis development and/or spermatogenesis. The sequence from the 15th amino acid to the end of PIAS-NY protein is the same as the N-terminal amino acids of PIASx-alpha and PIASx-beta (Zheng et al, 2004).
PIAS-y PIAS-y is a transcriptional corepressor of STAT1. IFN treatment triggers the in vivo interaction of STAT1 with PIAS-y, which represses STAT1 mediated gene activation without blocking the DNA binding activity of STAT1 (Liu et al, 2001). Sachdev et al (2001) have reported that PIASy is an interaction partner of transcription factor LEF1 and causes modification of this transcription factor by SUMO. Imoto et al (2003) have reported that PIASy associates with SMAD proteins regulates TGF-beta signaling. Imoto et al (2004) have reported that PIASy is involved in the suppression of signaling mediated by bone morphogenetic proteins. PIASy expression is induced by BMP2 stimulation and suppresses BMP2 dependent SMAD protein activity in hepatoma cells by direct interaction between PIASy and SMAD proteins.
PIASy represses STAT1 and androgen receptor without interfering with DNA binding (Gross et al, 2001; Liu et al, 2001).
Bischof et al (2006) have reported that PIAS-y Is a regulator of cellular senescence and apoptosis.
ARIP-3 (androgen-receptor-interacting protein-3) is a protein that recognizes the androgen receptor zinc-finger region both in vivo and in vitro (Janne et al, 2000; Kotaja et al, 2000). It is a member of the PIAS protein family. It is called also PIASx-alpha. Kotaja et al (2002) have reported that PIASx-alpha interacts with the small ubiquitin-related modifier SUMO1 and is covalently modified by attachment of SUMO1 (sumoylated). The protein regulates the activities of transcription factors by functioning as a SUMO1 ligase.
Miz-1 [Msx-interacting-zinc finger] It is a member of the PIAS protein family and is called also PIASx-beta. Schmidt and Muller (2002) have reported that PIASx-beta acts as a specific E3-like ligases that promote the attachment of the regulatory protein SUMO to a variety of substrates such as p53 and Jun. Kotaja et al (2002) have reported that PIASx-beta interacts with the small ubiquitin-related modifier SUMO1 and is covalently modified by attachment of SUMO1 (sumoylated). The protein regulates the activities of transcription factors by functioning as a SUMO1 ligase.
Miz-1 is a zinc finger-containing protein. Miz-1 is a sequence specific DNA binding protein that functions as a positive-acting transcription factor (Wu et al, 1997). Miz-1 interacts directly with the homeobox protein Msx2, mutations of which cause an autosomal dominant disorder of skull morphogenesis (craniosynostosis, Boston type).
Arora et al (2003) have reported that PIASx is a negative regulator of STAT4, to which it becomes associated following IL12 stimulation of cells. PIASx inhibits IL12 stimulated and STAT4 dependent gene activation in human T-cells.
LAST MODIFIED: September 2005
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