protein inhibitors of activated stat


Summary: A family of structurally related proteins that are constitutively expressed and that negatively regulate cytokine-mediated SIGNAL TRANSDUCTION PATHWAYS. PIAS proteins inhibit the activity of signal transducers and activators of transcription.

Top Publications

  1. Dahle Ø, Andersen T, Nordgård O, Matre V, Del Sal G, Gabrielsen O. Transactivation properties of c-Myb are critically dependent on two SUMO-1 acceptor sites that are conjugated in a PIASy enhanced manner. Eur J Biochem. 2003;270:1338-48 pubmed
    ..We propose that the negative influence on transactivation properties by the negative regulatory domain region of c-Myb depends on the sumoylation sites located here. ..
  2. Liu B, Shuai K. Induction of apoptosis by protein inhibitor of activated Stat1 through c-Jun NH2-terminal kinase activation. J Biol Chem. 2001;276:36624-31 pubmed
    ..Our results identify a novel function of PIAS1 in the induction of JNK-dependent apoptosis, independent of the previously known inhibitory activity of PIAS1 in STAT-mediated gene activation. ..
  3. Azuma Y, Arnaoutov A, Anan T, Dasso M. PIASy mediates SUMO-2 conjugation of Topoisomerase-II on mitotic chromosomes. EMBO J. 2005;24:2172-82 pubmed
  4. Albor A, El Hizawi S, Horn E, Laederich M, Frosk P, Wrogemann K, et al. The interaction of Piasy with Trim32, an E3-ubiquitin ligase mutated in limb-girdle muscular dystrophy type 2H, promotes Piasy degradation and regulates UVB-induced keratinocyte apoptosis through NFkappaB. J Biol Chem. 2006;281:25850-66 pubmed
    ..Our results indicate that, by controlling Piasy stability, Trim32 regulates UVB-induced keratinocyte apoptosis through induction of NFkappaB and suggests loss of function of Trim32 in LGMD2H...
  5. Mabb A, Wuerzberger Davis S, Miyamoto S. PIASy mediates NEMO sumoylation and NF-kappaB activation in response to genotoxic stress. Nat Cell Biol. 2006;8:986-93 pubmed
    ..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. ..
  6. Wong K, Kim R, Christofk H, Gao J, Lawson G, Wu H. Protein inhibitor of activated STAT Y (PIASy) and a splice variant lacking exon 6 enhance sumoylation but are not essential for embryogenesis and adult life. Mol Cell Biol. 2004;24:5577-86 pubmed
    ..Our study demonstrates that at steady state, PIASy is either dispensable or compensated for by other PIAS family members or by other mechanisms when deleted. ..
  7. Morris J, Boutell C, Keppler M, Densham R, Weekes D, Alamshah A, et al. The SUMO modification pathway is involved in the BRCA1 response to genotoxic stress. Nature. 2009;462:886-90 pubmed publisher
    ..These data demonstrate that the SUMOylation pathway plays a significant role in mammalian DNA damage response. ..
  8. Nelson V, Davis G, Maxwell S. A putative protein inhibitor of activated STAT (PIASy) interacts with p53 and inhibits p53-mediated transactivation but not apoptosis. Apoptosis. 2001;6:221-34 pubmed
    ..PIASy did not effect the incidence of apoptosis in H1299 cells upregulated for p53. PIASy appears to regulate p53-mediated functions and may direct p53 into a transactivation-independent mode of apoptosis. ..
  9. Brock M, Trenkmann M, Gay R, Gay S, Speich R, Huber L. MicroRNA-18a enhances the interleukin-6-mediated production of the acute-phase proteins fibrinogen and haptoglobin in human hepatocytes. J Biol Chem. 2011;286:40142-50 pubmed publisher
    ..Our data reveal, for the first time, a microRNA-mediated positive feedback loop of IL-6 signal transduction leading to an enhanced acute-phase response in human hepatocytes. ..

More Information


  1. Oh H, Kido T, Lau Y. PIAS1 interacts with and represses SOX9 transactivation activity. Mol Reprod Dev. 2007;74:1446-55 pubmed
    ..Thus, PIAS1 appears to repress SOX9 activity by at least two SUMO-ligase dependent mechanisms: (1) the SUMOylation of SOX9 and (2) SUMOylation of unknown factors associated with SOX9 and/or PIAS1. ..
  2. Agostinho M, Santos V, Ferreira F, Costa R, Cardoso J, Pinheiro I, et al. Conjugation of human topoisomerase 2 alpha with small ubiquitin-like modifiers 2/3 in response to topoisomerase inhibitors: cell cycle stage and chromosome domain specificity. Cancer Res. 2008;68:2409-18 pubmed publisher
  3. Sonnenblick A, Levy C, Razin E. Interplay between MITF, PIAS3, and STAT3 in mast cells and melanocytes. Mol Cell Biol. 2004;24:10584-92 pubmed
    ..This regulatory mechanism is of considerable importance since it is likely to advance the deciphering of a role for MITF and STAT3 in mast cells and melanocytes. ..
  4. Ungureanu D, Vanhatupa S, Kotaja N, Yang J, Aittomaki S, Janne O, et al. PIAS proteins promote SUMO-1 conjugation to STAT1. Blood. 2003;102:3311-3 pubmed
    ..These results indicate that STAT1 is covalently modified by SUMO-1 in cytokine signaling and that PIAS proteins promote SUMO-1 conjugation to STAT1. ..
  5. Marongiu M, Deiana M, Meloni A, Marcia L, Puddu A, Cao A, et al. The forkhead transcription factor Foxl2 is sumoylated in both human and mouse: sumoylation affects its stability, localization, and activity. PLoS ONE. 2010;5:e9477 pubmed publisher
    ..It is intriguing that similar sumoylation and regulatory consequences have also been reported for SOX9, the male counterpart of FOXL2 in somatic gonadal tissues. ..
  6. Long J, Matsuura I, He D, Wang G, Shuai K, Liu F. Repression of Smad transcriptional activity by PIASy, an inhibitor of activated STAT. Proc Natl Acad Sci U S A. 2003;100:9791-6 pubmed
    ..Taken together, our studies indicate that PIASy can inhibit TGF-beta/Smad transcriptional responses through interactions with Smad proteins and HDAC. ..
  7. Lyst M, Nan X, Stancheva I. Regulation of MBD1-mediated transcriptional repression by SUMO and PIAS proteins. EMBO J. 2006;25:5317-28 pubmed
    ..Here we show that MBD1 is a target for sumoylation by PIAS1 (Protein Inhibitors of Activated STAT 1) and PIAS3 E3 SUMO (small ubiquitin-like modifier)-ligases, at two conserved lysine residues ..
  8. Yamashina K, Yamamoto H, Chayama K, Nakajima K, Kikuchi A. Suppression of STAT3 activity by Duplin, which is a negative regulator of the Wnt signal. J Biochem. 2006;139:305-14 pubmed
    ..These results demonstrate that Duplin inhibits not only Tcf-4 but also STAT3, suggesting that Duplin may act as a repressor for multiple transcriptional factors. ..
  9. Yang Y, Do H, Tian X, Zhang C, Liu X, Dada L, et al. E3 ubiquitin ligase Mule ubiquitinates Miz1 and is required for TNFalpha-induced JNK activation. Proc Natl Acad Sci U S A. 2010;107:13444-9 pubmed publisher
    ..Thus, our study reveals a molecular mechanism by which Mule regulates TNFalpha-induced JNK activation and apoptosis by catalyzing the polyubiquitination of Miz1. ..
  10. Suda N, Shibata H, Kurihara I, Ikeda Y, Kobayashi S, Yokota K, et al. Coactivation of SF-1-mediated transcription of steroidogenic enzymes by Ubc9 and PIAS1. Endocrinology. 2011;152:2266-77 pubmed publisher
    ..These results showed the physiological roles of Ubc9 and PIAS1 as SF-1 coactivators beyond sumoylation enzymes in adrenocortical steroidogenesis and suggested their possible pathophysiological roles in human cortisol-producing adenomas...
  11. Megidish T, Xu J, Xu C. Activation of p53 by protein inhibitor of activated Stat1 (PIAS1). J Biol Chem. 2002;277:8255-9 pubmed
    ..Taken together, our results suggest that PIAS1 is a novel activator of p53. ..
  12. Du J, Yun C, Bialkowska A, Yang V. Protein inhibitor of activated STAT1 interacts with and up-regulates activities of the pro-proliferative transcription factor Krüppel-like factor 5. J Biol Chem. 2007;282:4782-93 pubmed
    ..Importantly, PIAS1 increased the ability of KLF5 to enhance cell proliferation in transfected cells. These results indicate that PIAS1 is a functional partner of KLF5 and enhances the ability of KLF5 to promote proliferation. ..
  13. Levy C, Sonnenblick A, Razin E. Role played by microphthalmia transcription factor phosphorylation and its Zip domain in its transcriptional inhibition by PIAS3. Mol Cell Biol. 2003;23:9073-80 pubmed
    ..Thus, phosphorylation of MITF could be considered a fine, and alternative, tuning of its transcriptional machinery. ..
  14. Imoto S, Sugiyama K, Muromoto R, Sato N, Yamamoto T, Matsuda T. Regulation of transforming growth factor-beta signaling by protein inhibitor of activated STAT, PIASy through Smad3. J Biol Chem. 2003;278:34253-8 pubmed
    ..These findings provide the first evidence that a PIAS family protein, PIASy, associates with Smads and involves the regulation of TGF-beta signaling using the negative feedback loop. ..
  15. Castillo Lluva S, Tatham M, Jones R, Jaffray E, Edmondson R, Hay R, et al. SUMOylation of the GTPase Rac1 is required for optimal cell migration. Nat Cell Biol. 2010;12:1078-85 pubmed publisher
    ..The finding that a Ras superfamily member can be SUMOylated provides an insight into the regulation of these critical mediators of cell behaviour. Our data reveal a role for SUMO in the regulation of cell migration and invasion. ..
  16. Onishi A, Peng G, Hsu C, Alexis U, Chen S, Blackshaw S. Pias3-dependent SUMOylation directs rod photoreceptor development. Neuron. 2009;61:234-46 pubmed publisher
    ..Our data thus identify Pias3-mediated SUMOylation of photoreceptor-specific transcription factors as a key mechanism of rod specification. ..
  17. Kahyo T, Nishida T, Yasuda H. Involvement of PIAS1 in the sumoylation of tumor suppressor p53. Mol Cell. 2001;8:713-8 pubmed
    ..PIAS1 catalyzed the sumoylation of p53 both in U2OS cells and in vitro in a domain-dependent manner. These data suggest that PIAS1 functions as a SUMO ligase, or possibly as a tightly bound regulator of it, toward p53. ..
  18. Greenhalgh C, Hilton D. Negative regulation of cytokine signaling. J Leukoc Biol. 2001;70:348-56 pubmed
    ..These three classes of molecules form what is now emerging as an integrated system for deactivating cytokine signaling at a number of levels, from the receptor to the transcription factor. ..
  19. Betz A, Lampen N, Martinek S, Young M, Darnell J. A Drosophila PIAS homologue negatively regulates stat92E. Proc Natl Acad Sci U S A. 2001;98:9563-8 pubmed
    ..To this end we use a LOF allele and conditionally overexpressed dpias in JAK-STAT pathway mutant backgrounds. We conclude that the correct dpias/stat92E ratio is crucial for blood cell and eye development. ..
  20. Prigge J, Schmidt E. Interaction of protein inhibitor of activated STAT (PIAS) proteins with the TATA-binding protein, TBP. J Biol Chem. 2006;281:12260-9 pubmed
  21. Galanty Y, Belotserkovskaya R, Coates J, Polo S, Miller K, Jackson S. Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks. Nature. 2009;462:935-9 pubmed publisher
    ..These findings thus identify PIAS1 and PIAS4 as components of the DDR and reveal how protein recruitment to DSB sites is controlled by coordinated SUMOylation and ubiquitylation. ..
  22. Herrmann A, Vogt M, Mönnigmann M, Clahsen T, Sommer U, Haan S, et al. Nucleocytoplasmic shuttling of persistently activated STAT3. J Cell Sci. 2007;120:3249-61 pubmed
    ..We propose passage of persistently activated STAT3 through the nuclear pore complex as a new target for intervention in cancer. ..
  23. Palvimo J. PIAS proteins as regulators of small ubiquitin-related modifier (SUMO) modifications and transcription. Biochem Soc Trans. 2007;35:1405-8 pubmed
    ..PIAS proteins may act as platforms that facilitate both removal and recruitment of other regulatory proteins in the transcription complexes. ..
  24. Stehmeier P, Muller S. Phospho-regulated SUMO interaction modules connect the SUMO system to CK2 signaling. Mol Cell. 2009;33:400-9 pubmed publisher
    ..CK2-regulated phosphoSIM modules were also dissected in the tumor suppressor PML and the exosome component PMSCL1, indicating that these modules serve as general platforms that integrate CK2- and SUMO-regulated signaling networks. ..
  25. Souza Neto J, Sim S, Dimopoulos G. An evolutionary conserved function of the JAK-STAT pathway in anti-dengue defense. Proc Natl Acad Sci U S A. 2009;106:17841-6 pubmed publisher
    ..Our data suggest that the JAK-STAT pathway is part of the A. aegypti mosquito's anti-dengue defense and may act independently of the Toll pathway and the RNAi-mediated antiviral defenses. ..
  26. Rodel B, Tavassoli K, Karsunky H, Schmidt T, Bachmann M, Schaper F, et al. The zinc finger protein Gfi-1 can enhance STAT3 signaling by interacting with the STAT3 inhibitor PIAS3. EMBO J. 2000;19:5845-55 pubmed
  27. Liu J, Yan J, Jiang S, Wen J, Chen L, Zhao Y, et al. Site-specific ubiquitination is required for relieving the transcription factor Miz1-mediated suppression on TNF-?-induced JNK activation and inflammation. Proc Natl Acad Sci U S A. 2012;109:191-6 pubmed publisher
  28. Nishida T, Yasuda H. PIAS1 and PIASxalpha function as SUMO-E3 ligases toward androgen receptor and repress androgen receptor-dependent transcription. J Biol Chem. 2002;277:41311-7 pubmed
    ..Thus, PIAS1 and PIASxalpha modulate the AR-dependent transactivation, which, at least in part, can be attributed to their SUMO-E3 activity toward AR. ..
  29. Rogers R, Horvath C, Matunis M. SUMO modification of STAT1 and its role in PIAS-mediated inhibition of gene activation. J Biol Chem. 2003;278:30091-7 pubmed
    The PIAS (protein inhibitors of activated STAT) family of proteins were first discovered as inhibitors of activated signal transducers and activators of transcription (STATs)...
  30. Sharrocks A. PIAS proteins and transcriptional regulation--more than just SUMO E3 ligases?. Genes Dev. 2006;20:754-8 pubmed
  31. Sun Y, Perera J, Rubin B, Huang J. SYT-SSX1 (synovial sarcoma translocated) regulates PIASy ligase activity to cause overexpression of NCOA3 protein. J Biol Chem. 2011;286:18623-32 pubmed publisher
    ..Such a mechanistic finding provides an opportunity to design specific therapeutic interventions to treat synovial sarcoma. ..
  32. Dobreva G, Dambacher J, Grosschedl R. SUMO modification of a novel MAR-binding protein, SATB2, modulates immunoglobulin mu gene expression. Genes Dev. 2003;17:3048-61 pubmed
    ..Sumoylation is also involved in targeting SATB2 to the nuclear periphery, raising the possibility that this reversible modification of a MAR-binding protein may contribute to the modulation of subnuclear DNA localization. ..
  33. Liu J, Zhao Y, Eilers M, Lin A. Miz1 is a signal- and pathway-specific modulator or regulator (SMOR) that suppresses TNF-alpha-induced JNK1 activation. Proc Natl Acad Sci U S A. 2009;106:18279-84 pubmed publisher
    ..Thus, our results show that in addition to being a transcription factor Miz1 acts as a signal- and pathway-specific modulator or regulator that specifically regulates TNF-alpha-induced JNK1 activation and cell death. ..
  34. Gocke C, Yu H, Kang J. Systematic identification and analysis of mammalian small ubiquitin-like modifier substrates. J Biol Chem. 2005;280:5004-12 pubmed
    ..Therefore, sumoylation appears to regulate the functions of its substrates through multiple, context-dependent mechanisms. ..
  35. Lee J, Park S, Kim O, Lee C, Woo J, Park S, et al. Differential SUMOylation of LXRalpha and LXRbeta mediates transrepression of STAT1 inflammatory signaling in IFN-gamma-stimulated brain astrocytes. Mol Cell. 2009;35:806-17 pubmed publisher
    ..Together, our data show that SUMOylation is required for the suppression of STAT1-dependent inflammatory responses by LXRs in IFN-gamma-stimulated brain astrocytes. ..
  36. Rytinki M, Kaikkonen S, Pehkonen P, Jääskeläinen T, Palvimo J. PIAS proteins: pleiotropic interactors associated with SUMO. Cell Mol Life Sci. 2009;66:3029-41 pubmed publisher
    The interactions and functions of protein inhibitors of activated STAT (PIAS) proteins are not restricted to the signal transducers and activators of transcription (STATs), but PIAS1, -2, -3 and -4 interact with and regulate a variety of ..
  37. Liu B, Yang R, Wong K, Getman C, Stein N, Teitell M, et al. Negative regulation of NF-kappaB signaling by PIAS1. Mol Cell Biol. 2005;25:1113-23 pubmed
    ..Consistently, Pias1 null mice showed elevated proinflammatory cytokines. Our results identify PIAS1 as a novel negative regulator of NF-kappaB. ..
  38. Pascual G, Fong A, Ogawa S, Gamliel A, Li A, Perissi V, et al. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature. 2005;437:759-63 pubmed
    ..This mechanism provides an explanation for how an agonist-bound nuclear receptor can be converted from an activator of transcription to a promoter-specific repressor of NF-kappaB target genes that regulate immunity and homeostasis. ..
  39. Ihara M, Yamamoto H, Kikuchi A. SUMO-1 modification of PIASy, an E3 ligase, is necessary for PIASy-dependent activation of Tcf-4. Mol Cell Biol. 2005;25:3506-18 pubmed
    ..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. ..
  40. Zhao X, Zheng B, Huang Y, Yang D, Katzman S, Chang C, et al. Interaction between GATA-3 and the transcriptional coregulator Pias1 is important for the regulation of Th2 immune responses. J Immunol. 2007;179:8297-304 pubmed
    ..In contrast, IL-5 promoter was modestly enhanced by Pias1 and no effect was observed on IL-4 promoter. Thus, both promoter activation and additional mechanisms are responsible for regulation by Pias1. ..
  41. Gross M, Yang R, Top I, Gasper C, Shuai K. PIASy-mediated repression of the androgen receptor is independent of sumoylation. Oncogene. 2004;23:3059-66 pubmed
    ..Our results suggest that PIASy may repress AR by recruiting histone deacetylases, independent of its SUMO ligase activity. ..
  42. Okumura F, Matsunaga Y, Katayama Y, Nakayama K, Hatakeyama S. TRIM8 modulates STAT3 activity through negative regulation of PIAS3. J Cell Sci. 2010;123:2238-45 pubmed publisher
    ..Furthermore, expression of TRIM8 in NIH3T3 cells enhances Src-dependent tumorigenesis. These findings indicate that TRIM8 enhances the STAT3-dependent signal pathway by inhibiting the function of PIAS3. ..
  43. Gebhardt A, Kosan C, Herkert B, Moroy T, Lutz W, Eilers M, et al. Miz1 is required for hair follicle structure and hair morphogenesis. J Cell Sci. 2007;120:2586-93 pubmed
    ..Our data show that Miz1 is involved in controlling proliferation and differentiation in hair follicles and in hair fiber morphogenesis. ..
  44. Kosan C, Saba I, Godmann M, Herold S, Herkert B, Eilers M, et al. Transcription factor miz-1 is required to regulate interleukin-7 receptor signaling at early commitment stages of B cell differentiation. Immunity. 2010;33:917-28 pubmed publisher
    ..Only the combined re-expression of Bcl2 and Ebf1 could reconstitute the ability of Miz-1-deficient precursors to develop into CD19(+) B cells. ..
  45. Nishida T, Terashima M, Fukami K, Yamada Y. PIASy controls ubiquitination-dependent proteasomal degradation of Ets-1. Biochem J. 2007;405:481-8 pubmed
    ..Our results suggested that PIASy controls Ets-1 function, at least in part, by inhibiting Ets-1 protein turnover via the ubiquitin-proteasome system. ..
  46. Wrighton K, Liang M, Bryan B, Luo K, Liu M, Feng X, et al. Transforming growth factor-beta-independent regulation of myogenesis by SnoN sumoylation. J Biol Chem. 2007;282:6517-24 pubmed
    ..Our study suggests a novel role for SUMO modification in the regulation of myogenic differentiation. ..
  47. Hari K, Cook K, Karpen G. The Drosophila Su(var)2-10 locus regulates chromosome structure and function and encodes a member of the PIAS protein family. Genes Dev. 2001;15:1334-48 pubmed
    ..We propose that Su(var2-10 controls multiple aspects of chromosome structure and function by establishing/maintaining chromosome organization in interphase nuclei. ..
  48. Perdomo J, Verger A, Turner J, Crossley M. Role for SUMO modification in facilitating transcriptional repression by BKLF. Mol Cell Biol. 2005;25:1549-59 pubmed
    ..These results link SUMO modification to transcriptional repression and demonstrate that both recruitment of CtBP and sumoylation are required for full repression by BKLF. ..
  49. Wanzel M, Russ A, Kleine Kohlbrecher D, Colombo E, Pelicci P, Eilers M. A ribosomal protein L23-nucleophosmin circuit coordinates Mizl function with cell growth. Nat Cell Biol. 2008;10:1051-61 pubmed
    ..As L23 is encoded by a direct target gene of Myc, this regulatory circuit may provide a feedback mechanism that links translation of Myc target genes and cell growth to Miz1-dependent cell-cycle arrest. ..
  50. Sentis S, Le Romancer M, Bianchin C, Rostan M, Corbo L. Sumoylation of the estrogen receptor alpha hinge region regulates its transcriptional activity. Mol Endocrinol. 2005;19:2671-84 pubmed
    ..These findings identify sumoylation as a new mechanism modulating ERalpha-dependent cellular response and provide a link between the SUMO and estrogen pathways. ..
  51. Wang L, Banerjee S. Differential PIAS3 expression in human malignancy. Oncol Rep. 2004;11:1319-24 pubmed
    ..Differential PIAS3 expression and the specific patterns may be useful as a molecular marker of human cancer. ..
  52. Yan W, Santti H, Janne O, Palvimo J, Toppari J. Expression of the E3 SUMO-1 ligases PIASx and PIAS1 during spermatogenesis in the rat. Gene Expr Patterns. 2003;3:301-8 pubmed
    ..Since PIASx and PIAS1 accumulate in developing male germ cells, their regulatory functions are not only restricted to AR in Sertoli cells, but they also participate in molecular processes during meiosis. ..
  53. Liu B, Liao J, Rao X, Kushner S, Chung C, Chang D, et al. Inhibition of Stat1-mediated gene activation by PIAS1. Proc Natl Acad Sci U S A. 1998;95:10626-31 pubmed
    ..These results identify PIAS1 as a specific inhibitor of Stat1-mediated gene activation and suggest that there may exist a specific PIAS inhibitor in every STAT signaling pathway. ..