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¹ Reproduction, Perinatal and Child Health, CHUQ Research Centre, CHUL Room T1-49, 2705 Laurier Boulevard, Quebec City, Quebec, Canada G1V 4G2² Department of Obstetrics and Gynecology, Faculty of Medicine, Centre for Research in Biology of Reproduction, Université Laval, Quebec City, Quebec, Canada G1V 0A6

(Correspondence should be addressed to J J Tremblay; Email: jacques-j.tremblay{at}crchul.ulaval.ca)

It is well established that stress, either physical or psychosocial, causes a decrease in testosterone production by Leydig cells. Glucocorticoids (Gc) are the main mediators of stress response and they convey their repressive effect on Leydig cells through the glucocorticoid receptor (GR). So far, various mechanisms have been proposed to explain the mechanism of action of Gc on Leydig cell steroidogenesis including repression of genes involved in testosterone biosynthesis. Several steroidogenic genes, including steroidogenic acute regulatory (STAR) protein, have been shown to be repressed by Gc in a GR-dependent manner but the underlying mechanisms remain to be fully elucidated. Here, we found that dexamethasone (Dex), a potent synthetic Gc, partly antagonizes the cAMP-dependent stimulation of the mouse Star promoter in MA-10 Leydig cells as revealed by transient transfection assays. This repression requires an element located at –95 bp previously implicated in the activation of the Star promoter by the nuclear receptors, NR4A1 and NR5A1. Dex was found to inhibit NR4A1-dependent transactivation of the Star promoter in Leydig cells by decreasing NR4A1, but not NR5A1, recruitment to the proximal Star promoter as determined by chromatin immunoprecipitation assay. Western blots revealed that Dex did not affect NR4A1 or NR5A1 expression in response to cAMP. These data suggest that NR4A1 would be associated with the GR in a transcriptionally inactive complex as previously demonstrated in pituitary corticotrope cells. Thus, our data provide new molecular insights into the stress-mediated suppression of testosterone production in testicular Leydig cells.

This article has been cited by other articles:

				L. J. Martin, N. Boucher, B. El-Asmar, and J. J. Tremblay cAMP-Induced Expression of the Orphan Nuclear Receptor Nur77 in MA-10 Leydig Cells Involves a CaMKI Pathway J Androl, March 1, 2009; 30(2): 134 - 145. [Abstract] [Full Text] [PDF]

				L. J Martin and J. J Tremblay The nuclear receptors NUR77 and SF1 play additive roles with c-JUN through distinct elements on the mouse Star promoter J. Mol. Endocrinol., February 1, 2009; 42(2): 119 - 129. [Abstract] [Full Text] [PDF]