PIAS3 enhances the transcriptional activity of HIF-1α by increasing its protein stability

Koji Nakagawa; Toshihisa Kohara; Yasuko Uehata; Yui Miyakawa; Maremi Sato-Ueshima; Naoto Okubo; Masahiro Asaka; Hiroshi Takeda; Masanobu Kobayashi

doi:10.1016/j.bbrc.2015.12.047

PIAS3 enhances the transcriptional activity of HIF-1α by increasing its protein stability

Biochem Biophys Res Commun. 2016 Jan 15;469(3):470-6. doi: 10.1016/j.bbrc.2015.12.047. Epub 2015 Dec 15.

Authors

Koji Nakagawa¹, Toshihisa Kohara², Yasuko Uehata², Yui Miyakawa³, Maremi Sato-Ueshima³, Naoto Okubo³, Masahiro Asaka⁴, Hiroshi Takeda⁵, Masanobu Kobayashi⁶

Affiliations

¹ 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.
² Department of Gastroenterology and Hematology, Graduate School of Medicine, Hokkaido University, N15 W7 Kita-ku, Sapporo, Hokkaido 060-8638, Japan.
³ Department of Pathophysiology and Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, N12 W6, Kita-ku, Sapporo, Hokkaido 060-0812, Japan.
⁴ 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.
⁵ 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.
⁶ 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.

PMID: 26697750
DOI: 10.1016/j.bbrc.2015.12.047

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.

Keywords: HIF-1α; PIAS3; SUMO E3 ligase; Stabilization; Transcriptional regulation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

HEK293 Cells
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
Molecular Chaperones / metabolism*
Protein Inhibitors of Activated STAT / metabolism*
Protein Stability
Signal Transduction / physiology*
Transcriptional Activation / physiology*

Substances

HIF1A protein, human
Hypoxia-Inducible Factor 1, alpha Subunit
Molecular Chaperones
PIAS3 protein, human
Protein Inhibitors of Activated STAT