PIASy inhibits LRH-1-dependent CYP11A1 expression by competing for SRC-1 binding

Hsiang Tsan Hsieh, Chih Hung Wang, Mei Ling Wu, Feng Ming Yang, Yu Chen Tai, Meng Chun Hu

研究成果: 雜誌貢獻文章同行評審

13 引文 斯高帕斯(Scopus)

摘要

The orphan nuclear receptor LRH-1 (liver receptor homologue-1; NR5A2) plays a critical role in development, bile acid synthesis and cholesterol metabolism. LRH-1 is also expressed in the ovary where it is implicated in the regulation of steroidogenic genes for steroid hormone synthesis. In the present study, we investigated the molecular mechanisms of the transcriptional regulation of CYP11A1 by LRH-1 and found that LRH-1-mediated transactivation was markedly repressed by PIASy [protein inhibitor of activated STAT (signal transducer and activator of transcription) y], the shortest member of the PIAS family. The suppression of LRH-1 activity requires the N-terminal repression domain. Although PIAS proteins also function as E3 SUMO (small ubiquitin-related modifier) ligases and enhance SUMO conjugation, PIASy-mediated repression was independent of LRH-1 SUMOylation status. In addition, histone deacetylase activity was not involved in the inhibition of LRH-1 by PIASy. Immunoprecipitation and mammalian two-hybrid analyses indicated that PIASy interacted with LRH-1 through the C-terminal region, including the AF-2 (activation function-2) motif, which was also involved in the interaction between LRH-1 and the co-activator SRC-1 (steroid receptor co-activator-1). PIASy inhibited the binding of SRC-1 to LRH-1, although overexpression of SRC-1 partially overcame the PIASy inhibition of LRH-1 induction of the CYP11A1 promoter. The results of the present study suggest that competition with co-activators may be an important mechanism underlying the PIASy repression of LRH-1-mediated transactivation.
原文英語
頁(從 - 到)201-209
頁數9
期刊Biochemical Journal
419
發行號1
DOIs
出版狀態已發佈 - 四月 1 2009
對外發佈

ASJC Scopus subject areas

  • 生物化學
  • 分子生物學
  • 細胞生物學

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