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Gene Review

PIAS1  -  protein inhibitor of activated STAT, 1

Homo sapiens

Synonyms: DDXBP1, DEAD/H box-binding protein 1, E3 SUMO-protein ligase PIAS1, GBP, GU/RH-II, ...
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Disease relevance of PIAS1


Psychiatry related information on PIAS1

  • Even less data exist for other available AEDs, and consensus is growing that someAEDs (eg, GBP) have little or no specific effect in bipolar disorder [6].
  • 80% were unemployed; significant mental health issues (e.g., schizophrenia) were present in 18%; 15% had alcohol dependence; heroin was the most frequently used drug (93%); crack cocaine -- 87%; mean daily cost of drugs -- heroin GBP 76 (range 20-240), crack GBP 81 (range 20-300). >50% users inject crack and heroin simultaneously [7].

High impact information on PIAS1

  • This inhibition arises from impaired STAT1-DNA binding due to an increased association of the STAT inhibitor PIAS1 with phosphorylated STAT1 dimers in the absence of arginine methylation [8].
  • The refined 1.9-A resolution structure of the periplasmic D-galactose-binding protein (GBP) reveals a calcium ion surrounded by seven ligands, all protein oxygen atoms [9].
  • The entire GBP Ca2+-binding site adopts a conformation very similar to the site in the 'helix-loop-helix' or 'EF-hand' unit commonly found in intracellular calcium-binding proteins, but without the two helices [9].
  • PIAS proteins and transcriptional regulation--more than just SUMO E3 ligases [10]?
  • We show that PIAS1 is required for the appropriate localization and retention of Msx1 at the nuclear periphery in myoblast cells [11].

Chemical compound and disease context of PIAS1


Biological context of PIAS1


Anatomical context of PIAS1


Associations of PIAS1 with chemical compounds

  • Furthermore, we show that silencing of PIAS1 not only enhances PR-dependent transcription but also induces expression of prolactin, a decidual marker gene, in progestin-treated HESCs without the need of simultaneous activation of the cAMP pathway [24].
  • Binding of PIAS1 to human AR DNA+ligand binding domains was androgen dependent in the yeast liquid beta-galactosidase assay [2].
  • [35S] PIAS1 bound a glutathione S-transferase-AR-DNA binding domain (amino acids 544-634) fusion protein in affinity matrix assays [2].
  • 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 [25].
  • ZNF76 is sumoylated by PIAS1 at lysine 411, which is in the minimal TBP-interacting region [26].

Physical interactions of PIAS1

  • We demonstrate that PIAS1 interacts with the PR and serves as its E3 SUMO ligase upon activation of the receptor [24].
  • It also was proposed that the N-terminal domain of PIAS1 interacts with DNA as well as p53 [27].
  • Taken together, our results identify a novel function for PIAS1 which interacts with the N-terminal domain of hMR and represses its ligand-dependent transcriptional activity, at least in part, through SUMO modifications [4].
  • We report here that a region near the COOH terminus of PIAS1 (amino acids 392-541) directly interacts with the NH(2)-terminal domain of Stat1 (amino acids 1-191) [28].
  • The PIAS family also bound the androgen receptor DNA binding domain, and binding required the second zinc finger of this domain [19].

Enzymatic interactions of PIAS1

  • PIAS1 catalyzed the sumoylation of p53 both in U2OS cells and in vitro in a domain-dependent manner [16].

Regulatory relationships of PIAS1

  • The same amounts of PIAS proteins that modulate steroid receptor-dependent transcription influence only marginally transactivation mediated by various STAT proteins [25].
  • Ectopic expression of PIAS1 in U2OS cells activated JNK1 (c-Jun NH(2)-terminal kinase) [1].
  • In this study, we demonstrated that the protein inhibitor of activated STAT1 (PIAS1) regulates the signaling potential of Smad4 through a sumoylation-dependent mechanism [29].
  • In COS-7 cells, PIAS proteins stimulated the SOX9-dependent transcriptional activity of a Col2a1 promoter-enhancer reporter [21].
  • GBP gene transcription was regulated by alpha IFN in a manner identical to that of previously described IFN-stimulated genes (ISGs): rapid induction, without a need for protein synthesis, followed by a protein synthesis-dependent suppression of transcription to basal levels within 6 h [30].
  • We demonstrate that hSiah2 regulates specifically the proteasome-dependent degradation of Pias proteins [31].

Other interactions of PIAS1

  • These data suggest that PIAS1 functions as a SUMO ligase, or possibly as a tightly bound regulator of it, toward p53 [16].
  • The effects of PIAS proteins on AR are competitive [3].
  • Incomplete responders expressed larger amounts of STAT3, IRF2, and protein inhibitor of activated STAT1 (PIAS1) mRNAs compared to complete responders before IQ treatment [32].
  • Involvement of PIAS1 in the sumoylation of tumor suppressor p53 [16].
  • Interaction of Protein Inhibitor of Activated STAT (PIAS) Proteins with the TATA-binding Protein, TBP [33].
  • Our results identify a signaling pathway in which proinflammatory stimuli activate the IKKalpha-mediated sumoylation-dependent phosphorylation of PIAS1 for the immediate repression of inflammatory gene activation [34].

Analytical, diagnostic and therapeutic context of PIAS1


  1. Induction of apoptosis by protein inhibitor of activated Stat1 through c-Jun NH2-terminal kinase activation. Liu, B., Shuai, K. J. Biol. Chem. (2001) [Pubmed]
  2. Protein inhibitor of activated STAT-1 (signal transducer and activator of transcription-1) is a nuclear receptor coregulator expressed in human testis. Tan, J., Hall, S.H., Hamil, K.G., Grossman, G., Petrusz, P., Liao, J., Shuai, K., French, F.S. Mol. Endocrinol. (2000) [Pubmed]
  3. Distinct effects of PIAS proteins on androgen-mediated gene activation in prostate cancer cells. Gross, M., Liu, B., Tan , J., French, F.S., Carey, M., Shuai, K. Oncogene (2001) [Pubmed]
  4. Protein inhibitor of activated signal transducer and activator of transcription 1 interacts with the N-terminal domain of mineralocorticoid receptor and represses its transcriptional activity: implication of small ubiquitin-related modifier 1 modification. Tallec, L.P., Kirsh, O., Lecomte, M.C., Viengchareun, S., Zennaro, M.C., Dejean, A., Lombès, M. Mol. Endocrinol. (2003) [Pubmed]
  5. The manifold actions of the protein inhibitor of activated STAT proteins on the transcriptional activity of mineralocorticoid and glucocorticoid receptors in neural cells. Tirard, M., Jasbinsek, J., Almeida, O.F., Michaelidis, T.M. J. Mol. Endocrinol. (2004) [Pubmed]
  6. Anticonvulsants in bipolar disorder. Singh, V., Muzina, D.J., Calabrese, J.R. Psychiatr. Clin. North Am. (2005) [Pubmed]
  7. Patterns of illicit drug use of prisoners in police custody in London, UK. Payne-James, J.J., Wall, I.J., Bailey, C. Journal of clinical forensic medicine. (2005) [Pubmed]
  8. Arginine methylation of STAT1 modulates IFNalpha/beta-induced transcription. Mowen, K.A., Tang, J., Zhu, W., Schurter, B.T., Shuai, K., Herschman, H.R., David, M. Cell (2001) [Pubmed]
  9. A novel calcium binding site in the galactose-binding protein of bacterial transport and chemotaxis. Vyas, N.K., Vyas, M.N., Quiocho, F.A. Nature (1987) [Pubmed]
  10. PIAS proteins and transcriptional regulation--more than just SUMO E3 ligases? Sharrocks, A.D. Genes Dev. (2006) [Pubmed]
  11. PIAS1 confers DNA-binding specificity on the Msx1 homeoprotein. Lee, H., Quinn, J.C., Prasanth, K.V., Swiss, V.A., Economides, K.D., Camacho, M.M., Spector, D.L., Abate-Shen, C. Genes Dev. (2006) [Pubmed]
  12. Purification and antigenicity of a novel glucan-binding protein of Streptococcus mutans. Smith, D.J., Akita, H., King, W.F., Taubman, M.A. Infect. Immun. (1994) [Pubmed]
  13. Evaluation of gabapentin and ethosuximide for treatment of acute nonconvulsive seizures following ischemic brain injury in rats. Williams, A.J., Bautista, C.C., Chen, R.W., Dave, J.R., Lu, X.C., Tortella, F.C., Hartings, J.A. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  14. A novel reagentless sensing system for measuring glucose based on the galactose/glucose-binding protein. Salins, L.L., Ware, R.A., Ensor, C.M., Daunert, S. Anal. Biochem. (2001) [Pubmed]
  15. PIAS1 selectively inhibits interferon-inducible genes and is important in innate immunity. Liu, B., Mink, S., Wong, K.A., Stein, N., Getman, C., Dempsey, P.W., Wu, H., Shuai, K. Nat. Immunol. (2004) [Pubmed]
  16. Involvement of PIAS1 in the sumoylation of tumor suppressor p53. Kahyo, T., Nishida, T., Yasuda, H. Mol. Cell (2001) [Pubmed]
  17. Inhibition of Stat1-mediated gene activation by PIAS1. Liu, B., Liao, J., Rao, X., Kushner, S.A., Chung, C.D., Chang, D.D., Shuai, K. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  18. PIAS proteins promote SUMO-1 conjugation to STAT1. Ungureanu, D., Vanhatupa, S., Kotaja, N., Yang, J., Aittomaki, S., Jänne, O.A., Palvimo, J.J., Silvennoinen, O. Blood (2003) [Pubmed]
  19. Protein inhibitors of activated STAT resemble scaffold attachment factors and function as interacting nuclear receptor coregulators. Tan, J.A., Hall, S.H., Hamil, K.G., Grossman, G., Petrusz, P., French, F.S. J. Biol. Chem. (2002) [Pubmed]
  20. Activation of p53 by protein inhibitor of activated Stat1 (PIAS1). Megidish, T., Xu, J.H., Xu, C.W. J. Biol. Chem. (2002) [Pubmed]
  21. Interactions between PIAS proteins and SOX9 result in an increase in the cellular concentrations of SOX9. Hattori, T., Eberspaecher, H., Lu, J., Zhang, R., Nishida, T., Kahyo, T., Yasuda, H., de Crombrugghe, B. J. Biol. Chem. (2006) [Pubmed]
  22. PIAS1-mediated sumoylation of focal adhesion kinase activates its autophosphorylation. Kadaré, G., Toutant, M., Formstecher, E., Corvol, J.C., Carnaud, M., Boutterin, M.C., Girault, J.A. J. Biol. Chem. (2003) [Pubmed]
  23. Ubc9 and Protein Inhibitor of Activated STAT 1 Activate Chicken Ovalbumin Upstream Promoter-Transcription Factor I-mediated Human CYP11B2 Gene Transcription. Kurihara, I., Shibata, H., Kobayashi, S., Suda, N., Ikeda, Y., Yokota, K., Murai, A., Saito, I., Rainey, W.E., Saruta, T. J. Biol. Chem. (2005) [Pubmed]
  24. Regulation of the SUMO pathway sensitizes differentiating human endometrial stromal cells to progesterone. Jones, M.C., Fusi, L., Higham, J.H., Abdel-Hafiz, H., Horwitz, K.B., Lam, E.W., Brosens, J.J. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  25. ARIP3 (androgen receptor-interacting protein 3) and other PIAS (protein inhibitor of activated STAT) proteins differ in their ability to modulate steroid receptor-dependent transcriptional activation. Kotaja, N., Aittomäki, S., Silvennoinen, O., Palvimo, J.J., Jänne, O.A. Mol. Endocrinol. (2000) [Pubmed]
  26. ZNF76, a novel transcriptional repressor targeting TATA-binding protein, is modulated by sumoylation. Zheng, G., Yang, Y.C. J. Biol. Chem. (2004) [Pubmed]
  27. NMR structure of the N-terminal domain of SUMO ligase PIAS1 and its interaction with tumor suppressor p53 and A/T-rich DNA oligomers. Okubo, S., Hara, F., Tsuchida, Y., Shimotakahara, S., Suzuki, S., Hatanaka, H., Yokoyama, S., Tanaka, H., Yasuda, H., Shindo, H. J. Biol. Chem. (2004) [Pubmed]
  28. Distinct roles of the NH2- and COOH-terminal domains of the protein inhibitor of activated signal transducer and activator of transcription (STAT) 1 (PIAS1) in cytokine-induced PIAS1-Stat1 interaction. Liao, J., Fu, Y., Shuai, K. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  29. Regulation of Smad4 sumoylation and transforming growth factor-beta signaling by protein inhibitor of activated STAT1. Liang, M., Melchior, F., Feng, X.H., Lin, X. J. Biol. Chem. (2004) [Pubmed]
  30. Interactions of alpha- and gamma-interferon in the transcriptional regulation of the gene encoding a guanylate-binding protein. Decker, T., Lew, D.J., Cheng, Y.S., Levy, D.E., Darnell, J.E. EMBO J. (1989) [Pubmed]
  31. A crosstalk between hSiah2 and Pias E3-ligases modulates Pias-dependent activation. Depaux, A., Regnier-Ricard, F., Germani, A., Varin-Blank, N. Oncogene (2007) [Pubmed]
  32. Correlation between pretreatment levels of interferon response genes and clinical responses to an immune response modifier (Imiquimod) in genital warts. Arany, I., Tyring, S.K., Brysk, M.M., Stanley, M.A., Tomai, M.A., Miller, R.L., Smith, M.H., McDermott, D.J., Slade, H.B. Antimicrob. Agents Chemother. (2000) [Pubmed]
  33. Interaction of Protein Inhibitor of Activated STAT (PIAS) Proteins with the TATA-binding Protein, TBP. Prigge, J.R., Schmidt, E.E. J. Biol. Chem. (2006) [Pubmed]
  34. Proinflammatory stimuli induce IKKalpha-mediated phosphorylation of PIAS1 to restrict inflammation and immunity. Liu, B., Yang, Y., Chernishof, V., Loo, R.R., Jang, H., Tahk, S., Yang, R., Mink, S., Shultz, D., Bellone, C.J., Loo, J.A., Shuai, K. Cell (2007) [Pubmed]
  35. Gastrointestinal hormone responses to meals before and after gastric bypass and vertical banded gastroplasty. Kellum, J.M., Kuemmerle, J.F., O'Dorisio, T.M., Rayford, P., Martin, D., Engle, K., Wolf, L., Sugerman, H.J. Ann. Surg. (1990) [Pubmed]
  36. Remedial surgery following failed gastroplasty for morbid obesity. Eckhauser, F.E., Knol, J.A., Strodel, W.E. Ann. Surg. (1983) [Pubmed]
  37. Risks and benefits of gastric bypass in morbidly obese patients with severe venous stasis disease. Sugerman, H.J., Sugerman, E.L., Wolfe, L., Kellum, J.M., Schweitzer, M.A., DeMaria, E.J. Ann. Surg. (2001) [Pubmed]
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