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* To whom correspondence should be addressed. E-mail: jacques-j.tremblay{at}crchul.ulaval.ca.
The Nur77 (Nr4a1) gene, encoding the orphan nuclear receptor NUR77 (NR4A1), is an immediate early response gene whose expression is rapidly induced by a variety of physiological stimuli. Nur77 is expressed in several organs including the classic steroidogenic tissues: gonads and adrenal. In MA-10 Leydig cells, NUR77 has been shown to regulate expression of several genes involved in steroidogenesis and male sex differentiation. In Leydig cells, androgen biosynthesis is primarily controlled by the pituitary gonadotropin luteinizing hormone (LH) acting via its receptor (LH-R) which in turns activates the adenylate cyclase/cAMP signaling pathway. Even though Nur77 expression is induced both at the mRNA and protein levels in response to LH/forskolin/cAMP in Leydig cells, the mechanisms involved remain largely unknown. Here we report that cAMP-mediated induction of Nur77 expression at the protein, mRNA, and promoter level in MA-10 cells involves different mechanisms. We found that increased NUR77 protein requires transcription and translation while increased Nur77 mRNA does not require de novo protein synthesis and would therefore rely on transcription factors already present in the cell. In addition, our detailed analysis of the Nur77 promoter in MA-10 cells revealed that distinct regulatory elements are involved in basal and cAMP-induced Nur77 transcription. Finally, we found that maximal cAMP-mediated increase in Nur77 promoter activity involves a Ca2+/calmodulin kinase (CaMK)-dependent pathway and that CaMKI regulates Nur77 promoter activity in Leydig cells. Thus, our findings demonstrate the involvement of various mechanisms in the regulation of Nur77 expression in MA-10 Leydig cells including a previously uncharacterized CaMK pathway.
Key words: Hormone •
Gene expression •
Leydig cells •
Nuclear receptor •
Transcription factor •
cAMP signaling
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