High impact information on PIAS4

• The E3 SUMO ligase PIASy is a regulator of cellular senescence and apoptosis [1].
• Here we show that overexpression of the E3 SUMO ligase PIASy in normal human fibroblasts recruits the p53 and Rb tumor suppressor pathways to provoke a senescence arrest [1].
• Induction of senescence requires PIASy E3 activity and is specific for this member of the PIAS ligase family [1].
• PIASy-NEMO interaction is increased by genotoxic stress and occurs in the nucleus in a manner mutually exclusive with IKK interaction [2].
• In addition, hydrogen peroxide (H2O2) also increases PIASy-NEMO interaction and NEMO sumoylation, whereas antioxidants prevent these events induced by DNA-damaging agents [2].

Biological context of PIAS4

• We have identified PIASy in a search for new GATA-2 interacting proteins that can regulate GATA-2-mediated endothelial gene expression [3].
• These results suggest that sumoylation of Lys(35) in PIASy determines the nuclear localization of PIASy and that it is necessary for PIASy-dependent sumoylation and transcriptional activation of Tcf-4 [4].
• PIASy represses TRIF-induced ISRE and NF-kappaB activation but not apoptosis [5].
• Our findings demonstrate that PIASy is the first SUMO ligase for NEMO whose substrate specificity seems to be controlled by IKK interaction, subcellular targeting and oxidative stress conditions [2].
• 3) The SUMO ligases, PIAS1 and PIASxbeta, have broader substrate specificities than does PIASy [6].

Anatomical context of PIAS4

• Notably, among the cell populations comprising vascular walls, PIASy mRNA is selectively expressed in endothelial cells, and its expression can be regulated by angiogenic growth factors [3].
• Convergence of interferon-gamma and progesterone signaling pathways in human endometrium: role of PIASy (protein inhibitor of activated signal transducer and activator of transcription-y) [7].
• Finally, we show that fibroblasts lacking PIASy exhibit a highly reduced propensity to undergo senescence in response to a prosenescence stimulus [1].
• This cleavage occurs at the plasma membrane and generates an ICA512 cytosolic fragment that is targeted to the nucleus, where it binds the E3-SUMO ligase protein inhibitor of activated signal transducer and activator of transcription-y (PIASy) and up-regulates insulin expression [8].
• Conversely, Piasy inhibited NFkappaB activity under the same conditions and sensitized keratinocytes to apoptosis induced by TNFalpha and UVB [9].

Associations of PIAS4 with chemical compounds

• Furthermore, beta-catenin and PIASy activated Tcf-4(K297R), in which Lys297 was changed to arginine, less than wild-type Tcf-4 [10].
• Here, we report that DJ-1 was sumoylated on a lysine residue at amino-acid number 130 (K130) by PIASxalpha or PIASy [11].

Physical interactions of PIAS4

• We show that AR binds to the RING-finger like domain of PIASy [12].
• Direct analyses indicated that PIASx and PIASy also interacted with TBP [13].
• Furthermore, BMP-2-regulated Smads directly bound to PIASy [14].
• Binding studies demonstrate that coilin (a Cajal body protein) directly interacts with PIASy (a PML body protein) [15].
• Here we report that Trim32 interacts with Piasy and promotes Piasy ubiquitination and degradation [9].

Regulatory relationships of PIAS4

• Our results suggest that PIASy may repress AR by recruiting histone deacetylases, independent of its SUMO ligase activity [12].
• Furthermore, PIASy also inhibits IRF-3, IRF-7 and Sendai virus-induced ISRE activation [5].
• We here provide evidence that the inhibitory action of PIASy on BMP-regulated Smad activity was due to direct physical interactions between Smads and PIASy through its RING domain [14].
• We report here that the PIASy member of the protein inhibitor of activated STAT family inhibited p53's transactivation function without compromising its ability to induce apoptosis of the H1299 nonsmall cell lung carcinoma cell line [16].
• PIASy enhanced beta-catenin-dependent transcriptional activity of Tcf-4, whereas Axam inhibited it [10].

Other interactions of PIAS4

• We report here that a member of the protein inhibitor of activated STAT family, PIASy, is a transcriptional corepressor of Stat1 [17].
• RD1, but not RD2, is required for PIASy-mediated repression of AR [12].
• In contrast, proteins of the PIAS family (except PIASy) bound to both BPV and HPV11 E1 and stimulated their sumoylation [18].
• Our results suggest that PIASy is an inhibitor of TRIF-induced ISRE and NF-kappaB activation but not apoptosis [5].
• Promyelocytic leukemia protein, which is involved in transcriptional regulation, was associated with PIASy(K35R) more frequently than wild-type PIASy in the nucleus [4].

Analytical, diagnostic and therapeutic context of PIAS4

• The p53 protein bound to PIASy in yeast two-hybrid assays and coprecipitated in complexes with p53 in immunoprecipitates from mammalian cells [16].

References