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

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)201-209
Number of pages9
JournalBiochemical Journal
Volume419
Issue number1
DOIs
Publication statusPublished - Apr 1 2009
Externally publishedYes

Keywords

  • Cholesterol side-chain cleavage cytochrome P450 (CYP11A1)
  • Liver receptor homologue-1 (LRH-1)
  • Protein inhibitor of activated STAT (PIAS)
  • Steroid receptor co-activator-1 (SRC-1)
  • Steroidogenesis
  • SUMOylation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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