title: PIAS3 enhances the transcriptional activity of HIF-1α by increasing its protein stability.
abstract: The transcription factor hypoxia-inducible factor-1 (HIF-1) functions as a master regulator of hypoxic response by inducing the transcription of various genes responsible for cellular adaptation to hypoxia. In this study, we investigated the effects of protein inhibitor of activated STAT3 (PIAS3), a small ubiquitin-related modifier (SUMO) E3 ligase, on HIF-1-mediated transcriptional activation. We found that PIAS3 physically associated with HIF-1α. Moreover, PIAS3 overexpression enhanced the transcriptional activity of HIF-1α independently of its SUMO E3 ligase activity. Conversely, quantitative RT-PCR analysis showed that RNAi-mediated PIAS3 knockdown reduced the expression of HIF-1 target genes under hypoxia. In addition, PIAS3 knockdown induced the destabilization of HIF-1α protein, and the destabilization was reversed by the proteasome inhibitor MG132. Taken together, these results suggest that PIAS3 functions as a positive regulator of HIF-1α-mediated transcription by increasing its protein stability.
authors.affiliation: Department of Pathophysiology and Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, N12 W6, Kita-ku, Sapporo, Hokkaido 060-0812, Japan. Electronic address: k_nakagawa@pharm.hokudai.ac.jp.
authors.forename: Koji
authors.initials: K
authors.lastname: Nakagawa
authors.affiliation: Department of Gastroenterology and Hematology, Graduate School of Medicine, Hokkaido University, N15 W7 Kita-ku, Sapporo, Hokkaido 060-8638, Japan.
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Kohara
authors.affiliation: Department of Gastroenterology and Hematology, Graduate School of Medicine, Hokkaido University, N15 W7 Kita-ku, Sapporo, Hokkaido 060-8638, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Uehata
authors.affiliation: Department of Pathophysiology and Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, N12 W6, Kita-ku, Sapporo, Hokkaido 060-0812, Japan.
authors.forename: Yui
authors.initials: Y
authors.lastname: Miyakawa
authors.affiliation: Department of Pathophysiology and Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, N12 W6, Kita-ku, Sapporo, Hokkaido 060-0812, Japan.
authors.forename: Maremi
authors.initials: M
authors.lastname: Sato-Ueshima
authors.affiliation: Department of Pathophysiology and Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, N12 W6, Kita-ku, Sapporo, Hokkaido 060-0812, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Okubo
authors.affiliation: Department of Gastroenterology and Hematology, Graduate School of Medicine, Hokkaido University, N15 W7 Kita-ku, Sapporo, Hokkaido 060-8638, Japan; Department of Cancer Preventive Medicine, Graduate School of Medicine, Hokkaido University, N15 W7 Kita-ku, Sapporo, Hokkaido 060-8638, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Asaka
authors.affiliation: Department of Pathophysiology and Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, N12 W6, Kita-ku, Sapporo, Hokkaido 060-0812, Japan; Department of Gastroenterology and Hematology, Graduate School of Medicine, Hokkaido University, N15 W7 Kita-ku, Sapporo, Hokkaido 060-8638, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takeda
authors.affiliation: Department of Cancer Preventive Medicine, Graduate School of Medicine, Hokkaido University, N15 W7 Kita-ku, Sapporo, Hokkaido 060-8638, Japan; School of Nursing and Social Services, Health Sciences University of Hokkaido, Ishikari-Toubetsu, Hokkaido 061-0293, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kobayashi
mesh_terms: D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism*; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism*; D055550:Protein Stability; D015398:Signal Transduction / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018832:Molecular Chaperones; C484745:PIAS3 protein, human; D050828:Protein Inhibitors of Activated STAT
keywords: HIF-1α; PIAS3; SUMO E3 ligase; Stabilization; Transcriptional regulation