THE ORPHAN NUCLEAR RECEPTOR NUR77 REGULATES HORMONE-INDUCED StAR TRANSCRIPTION IN LEYDIG CELLS THROUGH A COOPERATION WITH CaMKI. Molecular endocrinology (Baltimore, Md.) [Mol Endocrinol] Journal article | | Title | THE ORPHAN NUCLEAR RECEPTOR NUR77 REGULATES HORMONE-INDUCED StAR TRANSCRIPTION IN LEYDIG CELLS THROUGH A COOPERATION WITH CaMKI. | | Author(s) | Martin LJ, Boucher N, Brousseau C, Tremblay JJ | | Institution | Reproduction, Perinatal, and Child Health, CHUQ Research Centre, Quebec City, Quebec, Canada; Centre for Research in Biology of Reproduction, Department of Obstetrics and Gynecology, Faculty of Medicine, Université Laval, Quebec City, Quebec, Canada. | | Source | Mol Endocrinol 2008 Jul 3. | | Abstract | Cholesterol transport in the mitochondrial membrane, an essential step of steroid biosynthesis, is mediated by a protein complex containing the steroidogenic acute regulatory (StAR) protein. The importance of this transporter is underscored by mutations in the human StAR gene that cause lipoid congenital adrenal hyperplasia, male pseudohermaphroditism and adrenal insufficiency. StAR transcription in steroidogenic cells is hormonally regulated and involves several transcription factors. The nuclear receptor NUR77 is present in steroidogenic cells and its expression is induced by hormones known to activate StAR expression. We have now established that StAR transcription in cAMP-stimulated Leydig cells requires de novo protein synthesis and involves NUR77. We found that cAMP-induced NUR77 expression precedes that of StAR both at the mRNA and protein levels in Leydig cells. In these cells, siRNA-mediated NUR77 knockdown reduces cAMP-induced StAR expression. ChIP assays revealed a cAMP-dependent increase in NUR77 recruitment to the proximal StAR promoter while transient transfections in MA-10 Leydig cells confirmed that NUR77 can activate the StAR promoter and that this requires an element located at -95 bp. cAMP-induced StAR and NUR77 expression in Leydig cells was found to require a CaMK-dependent signaling pathway. Consistent with this, we show that within the testis CaMKI is specifically expressed in Leydig cells. Finally, we report that CaMKI transcriptionally cooperates with NUR77, but not SF-1, to further enhance StAR promoter activity in Leydig cells. All together, our results implicate NUR77 as a mediator of cAMP action on StAR transcription in steroidogenic Leydig cells and identify a role for CaMKI in this process. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 18599618 |
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