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Transcriptional regulation of translocator protein (Tspo) via a SINE B2-mediated natural antisense transcript in MA-10 Leydig cells.

ABSTRACT: Translocator protein (18 kDa; TSPO) is a mitochondrial cholesterol- and drug-binding protein involved in cholesterol import into mitochondria, the rate-limiting step in steroidogenesis. TSPO is expressed at high levels in Leydig cells of the testis, and its expression levels dictate the ability of the cells to form androgen. In search of mechanisms that regulate Tspo expression, a number of transcription factors acting on its promoter region have been identified. We report herein the presence of a mechanism of regulation of Tspo expression via complementation with a natural antisense transcript (NAT). At the Tspo locus, a short interspersed repetitive element (SINE) of the SINE B2 family has the potential for high transcriptional activity. The extension of the SINE B2 element-mediated transcript overlapped with exon 3 of the Tspo gene and formed a NAT specific for Tspo (Tspo-NAT) in MA-10 mouse tumor Leydig cells. The identified Tspo-NAT was also found in testis and kidney tissues. Overexpression of the Tspo-NAT regulated Tspo gene expression and its function in steroid formation in MA-10 cells. Time-course studies have indicated that Tspo-NAT expression is regulated by cAMP and could regulate TSPO levels to maintain optimal steroid production by MA-10 Leydig cells. Taken together, these results suggest a new micro-transcriptional mechanism that regulates Tspo expression and thus steroidogenesis via an intron-based SINE B2-driven NAT specific for the Tspo gene.

SUBMITTER: Fan J

PROVIDER: S-EPMC3364927 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Steroid hormones regulate essential physiological processes and inadequate levels are associated with various pathological conditions. In testosterone-producing Leydig cells, steroidogenesis is strongly stimulated by LH via its receptor leading to increased cAMP production and expression of the steroidogenic acute regulatory (STAR) protein, which is essential for the initiation of steroidogenesis. Leydig cell steroidogenesis then passively decreases following the rapid degradation of cAMP into AMP by phosphodiesterases. In this study, we show that AMP-activated protein kinase (AMPK) is activated following cAMP breakdown in MA-10 and MLTC-1 Leydig cells. Activated AMPK then actively inhibits cAMP-induced steroidogenesis by repressing the expression of key regulators of steroidogenesis including Star and Nr4a1. Similar results were obtained in Y-1 adrenal cells and in the constitutive steroidogenic cell line R2C. Our data identify AMPK as an active repressor of steroid hormone biosynthesis in steroidogenic cells that is essential to preserve cellular energy and prevent excess steroid production. Steroid hormones regulate essential physiological processes and inadequate levels are associated with various pathological conditions. In testosterone-producing Leydig cells, steroidogenesis is strongly stimulated by LH via its receptor leading to increased cAMP production and expression of the steroidogenic acute regulatory (STAR) protein, which is essential for the initiation of steroidogenesis. Leydig cell steroidogenesis then passively decreases following the rapid degradation of cAMP into AMP by phosphodiesterases. In this study, we show that AMP-activated protein kinase (AMPK) is activated following cAMP breakdown in MA-10 and MLTC-1 Leydig cells. Activated AMPK then actively inhibits cAMP-induced steroidogenesis by repressing the expression of key regulators of steroidogenesis including Star and Nr4a1. Similar results were obtained in Y-1 adrenal cells and in the constitutive steroidogenic cell line R2C. Our data identify AMPK as an active repressor of steroid hormone biosynthesis in steroidogenic cells that is essential to preserve cellular energy and prevent excess steroid production.

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Transcriptional regulation of translocator protein (Tspo) via a SINE B2-mediated natural antisense transcript in MA-10 Leydig cells.

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