A crucial component in the acute regulation of steroidogenesis by trophic hormones is the translocation of cholesterol from the mitochondrial outer membrane to the inner membrane where it is converted to pregnenolone by t he cholesterol side-chain cleavage enzyme. The Steroidogenic Acute Regulatory (StAR) protein has an indispensable role in this intramitochondrial translocation of cholesterol and thus in acute steroid production. This point is evident by the studies on lipoid congenital adrenal hyperplasia (LCAH), an inherited and lethal disease in which both adrenal and gonadal steroidogenesis is markedly impaired due to the inability to deliver cholesterol to the side-chain cleavage enzyme. Recently, mutations in the StAR gene, which lead to the production of truncated, non-functional proteins, have been identified as the only lesion in patients with LCAH. In addition, trophic hormone or electrolyte stimulation of the adrenal cortex activates different second messenger pathways which mediate the same response; namely, increases in steroid production. These agonists also induce StAR protein expression. Thus, regulation of StAR expression may represent a common mechanism for divergent signalling pathways to acutely control steroid production. Based on StAR's direct and essential role in regulating steroidogenesis, understanding the molecular mechanisms controlling StAR's expression and function will elucidate the underlying mechanisms of trophic hormone action in steroidogenic cells. Therefore, the studies proposed will evaluate the transcriptional activation of the StAR gene, the post-transcriptional regulation of the StAR mRNA, and StAR phosphorylation. Specifically, the goals of the proposal are; 1. To examine the role of a translational regulation of StAR mRNA and StAR mRNA stability in the hormone-dependent expression of the StAR protein. 2. To define the cis-acting regulatory regions of the StAR gene responsible for the hormone-dependent and tissue- specific expression of StAR. 3. To examine the requirement for PKA activity on StAR expression. 4. To examine the role of StAR phosphorylation on its function.
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