Coactivation of SF-1-Mediated Transcription of Steroidogenic Enzymes by Ubc9 and PIAS1
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- Noriko Suda
- Departments of Internal Medicine (N.S., H.S., I.K., S.K., K.Y., A.M.-T., T.S., H.I.), School of Medicine, Keio University, Tokyo 160-8582, Japan;
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- Hirotaka Shibata
- Departments of Internal Medicine (N.S., H.S., I.K., S.K., K.Y., A.M.-T., T.S., H.I.), School of Medicine, Keio University, Tokyo 160-8582, Japan;
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- Isao Kurihara
- Departments of Internal Medicine (N.S., H.S., I.K., S.K., K.Y., A.M.-T., T.S., H.I.), School of Medicine, Keio University, Tokyo 160-8582, Japan;
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- Yayoi Ikeda
- Department of Histology and Cell Biology (Y.I.), Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan;
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- Sakiko Kobayashi
- Departments of Internal Medicine (N.S., H.S., I.K., S.K., K.Y., A.M.-T., T.S., H.I.), School of Medicine, Keio University, Tokyo 160-8582, Japan;
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- Kenichi Yokota
- Departments of Internal Medicine (N.S., H.S., I.K., S.K., K.Y., A.M.-T., T.S., H.I.), School of Medicine, Keio University, Tokyo 160-8582, Japan;
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- Ayano Murai-Takeda
- Departments of Internal Medicine (N.S., H.S., I.K., S.K., K.Y., A.M.-T., T.S., H.I.), School of Medicine, Keio University, Tokyo 160-8582, Japan;
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- Ken Nakagawa
- Urology (K.N., M.O., M.M.), School of Medicine, Keio University, Tokyo 160-8582, Japan;
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- Mototsugu Oya
- Urology (K.N., M.O., M.M.), School of Medicine, Keio University, Tokyo 160-8582, Japan;
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- Masaru Murai
- Urology (K.N., M.O., M.M.), School of Medicine, Keio University, Tokyo 160-8582, Japan;
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- William E. Rainey
- Department of Physiology (W.E.R.), Medical College of Georgia, Augusta, Goergia 30912
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- Takao Saruta
- Departments of Internal Medicine (N.S., H.S., I.K., S.K., K.Y., A.M.-T., T.S., H.I.), School of Medicine, Keio University, Tokyo 160-8582, Japan;
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- Hiroshi Itoh
- Departments of Internal Medicine (N.S., H.S., I.K., S.K., K.Y., A.M.-T., T.S., H.I.), School of Medicine, Keio University, Tokyo 160-8582, Japan;
Description
<jats:p>Steroidogenic factor-1 (SF-1) is a nuclear orphan receptor, which is essential for adrenal development and regulation of steroidogenic enzyme expression. SF-1 is posttranslationally modified by small ubiquitin-related modifier-1 (SUMO-1), thus mostly resulting in attenuation of transcription. We investigated the role of sumoylation enzymes, Ubc9 and protein inhibitors of activated STAT1 (PIAS1), in SF-1-mediated transcription of steroidogenic enzyme genes in the adrenal cortex. Coimmunoprecipitation assays showed that both Ubc9 and PIAS1 interacted with SF-1. Transient transfection assays in adrenocortical H295R cells showed Ubc9 and PIAS1 potentiated SF-1-mediated transactivation of reporter constructs containing human CYP17, CYP11A1, and CYP11B1 but not CYP11B2 promoters. Reduction of endogenous Ubc9 and PIAS1 by introducing corresponding small interfering RNA significantly reduced endogenous CYP17, CYP11A1, and CYP11B1 mRNA levels, indicating that they normally function as coactivators of SF-1. Wild type and sumoylation-inactive mutants of Ubc9 and PIAS1 can similarly enhance the SF-1-mediated transactivation of the CYP17 gene, indicating that the coactivation potency of Ubc9 and PIAS1 is independent of sumoylation activity. Chromatin immunoprecipitation assays demonstrated that SF-1, Ubc9, and PIAS1 were recruited to an endogenous CYP17 gene promoter in the context of chromatin in vivo. Immunohistochemistry and Western blotting showed that SF-1, Ubc9, and PIAS1 were expressed in the nuclei of the human adrenal cortex. In cortisol-producing adenomas, the expression pattern of SF-1 and Ubc9 were markedly increased, whereas that of PIAS1 was decreased compared with adjacent normal adrenals. 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.</jats:p>
Journal
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- Endocrinology
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Endocrinology 152 (6), 2266-2277, 2011-04-05
The Endocrine Society
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Details 詳細情報について
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- CRID
- 1360567186890918272
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- ISSN
- 19457170
- 00137227
- http://id.crossref.org/issn/00137227
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- Data Source
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- Crossref
- KAKEN