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The Orphan Nuclear Receptor NUR77 Regulates Hormone-Induced StAR Transcription in Leydig Cells through Cooperation with Ca²⁺/Calmodulin-Dependent Protein Kinase I

Reproduction, Perinatal and Child Health (L.J.M., N.B., C.B., J.J.T.), Centre Hospitalier Universitaire of Quebec Research Centre, Quebec City, Quebec, Canada G1V 4G2; and Centre for Research in Biology of Reproduction (J.J.T.), Department of Obstetrics and Gynecology, Faculty of Medicine, Université Laval, Quebec City, Quebec, Canada G1V 0A6

Address all correspondence and requests for reprints to: Dr. Jacques J. Tremblay, Reproduction, Perinatal and Child Health, Centre Hospitalier Universitaire of Quebec Research Centre, CHUL Room T1-49, 2705 Laurier Boulevard, Quebec City, Quebec, Canada G1V 4G2. E-mail: Jacques-J.Tremblay{at}crchul.ulaval.ca.

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, small interfering RNA-mediated NUR77 knockdown reduces cAMP-induced StAR expression. Chromatin immunoprecipitation assays revealed a cAMP-dependent increase in NUR77 recruitment to the proximal StAR promoter, whereas 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 Ca²⁺/calmodulin-dependent protein kinase (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 steroidogenic factor 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.

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