Abstract
Transforming growth factor- β1 (TGF-β1) has been reported to inhibit luteinizing hormone (LH) mediated-steroidogenesis in testicular Leydig cells. However, the mechanism by which TGF-β1 controls the steroidogenesis in Leydig cells is not well understood. Here, we investigated the possibility that TGF-β1 represses steroidogenesis through cross-talk with the orphan nuclear receptor Nur77. Nur77, which is induced by LH/cAMP signaling, is one of major transcription factors that regulate the expression of steroidogenic genes in Leydig cells. TGF-β1 signaling inhibited cAMP-induced testosterone production and the expression of steroidogenic genes such as P450c17, StAR and 3β-HSD in mouse Leydig cells. Further, TGF-β1/ALK5 signaling repressed cAMP-induced and Nur77-activated promoter activity of steroidogenic genes. In addition, TGF-β1/ALK5-activated Smad3 repressed Nur77 transactivation of steroidogenic gene promoters by interfering with Nur77 binding to DNA. In primary Leydig cells isolated from Tgfbr2flox/flox Cyp17iCre mice, TGF-β1-mediated repression of cAMP-induced steroidogenic gene expression was significantly less than that in primary Leydig cells from Tgfbr2flox/flox mice. Taken together, these results suggest that TGF-β1/ALK5/Smad3 signaling represses the expression of steroidogenic genes via the suppression of Nur77 transactivation in testicular Leydig cells. These findings may provide a molecular mechanism involved in the TGF-β1-mediated repression of testicular steroidogenesis.
Highlights
Steroidogenesis, the process of testosterone production, in testicular Leydig cells is controlled by luteinizing hormone (LH), which is synthesized and secreted from the pituitary
We investigated whether Transforming growth factor- b1 (TGF-b1)/activin receptor-like kinase-5 (ALK5) signaling inhibits the expression of steroidogenic genes by affecting their promoter activity using the natural promoter-reporter construct of steroidogenic genes in the mouse Leydig MA-10 cell line
MA-10 cells, which respond to LH/cAMP signals resulting in the upregulation of steroidogenic gene expression, rarely express the TGF-bRII receptor gene (Fig. 1E)
Summary
Steroidogenesis, the process of testosterone production, in testicular Leydig cells is controlled by luteinizing hormone (LH), which is synthesized and secreted from the pituitary. The intracellular second messenger for LH, cAMP, stimulates steroidogenesis by increasing the expression of several steroidogenic genes, including steroidogenic acute regulatory protein (StAR), cholesterol side chain cleavage cytochrome P450 (P450scc), 3b-hydroxysteroid dehydrogenase/isomerase (3bHSD) and cytochrome P450 17a-hydroxylase/C17–20 lyase (P450c17) [1]. The orphan nuclear receptor Nur ( known as NR4A1, NGFI-B, TR3, and NAK-1) is one of the major transcription factors involved in the regulation of steroidogenic gene expression in Leydig cells [2,3]. Previous studies demonstrated that LH, the regulator of testicular steroidogenesis, induces Nur gene expression in Leydig cells [8] and that Nur regulates the expression of steroidogenic genes, including steroid 21-hydroxylase, 20a-hydroxysteroid dehydrogenase, and P450c17 [2,9,10]. Nur77-binding regions have been defined within the promoters of rat P450c17 [2], mouse StAR [11], and human 3bHSD type 2 (3b-HSD2) [12] genes
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