Regulation of the Steroidogenic Acute Regulatory Protein

描述：（由申请人提供）肾上腺和性腺的类固醇生成

DESCRIPTION: (provided by applicant) Steroidogenesis in the adrenal and gonads is acutely controlled by tropic hormones via regulating the synthesis of the steroidogenic acute regulatory (StAR) protein. StAR synthesis is critical for cholesterol translocation across the mitochondrial outer membrane to the inner membrane where the first enzymatic step in steroidogenesis occurs; cholesterol conversion to pregnenolone by the cholesterol side-chain cleavage enzyme. Mutation(s) in the StAR gene that lead to the production of a non-functional protein is the genetic basis for the disorder lipoid congenital adrenal hyperplasia (LCAH). LCAH patients have markedly impaired adrenal and gonadal steroidogenesis due to the inability to transport cholesterol into mitochondria. Thus, understanding the mechanisms that control StAR expression and function is fundamentally important. Multiple signaling pathways have been shown to regulate StAR at both the transcriptional and post-transcriptional level in a cell-specific manner. StAR transcription and protein expression, however, appear to be independently regulated by the cAMP-protein kinase a pathway. The overall objective for this research is to elucidate the molecular mechanisms for the cAMP-dependent regulation of StAR expression at the transcriptional and translational, and post-translational levels in mouse Leydig and adrenal cells. The studies outlined in this proposal will determine whether I) the cAMP-dependent increase in StAR gene activation involves both loss of repressor and gain of activator, functions, 2) the level of cAMP-dependent protein kinase A activity distinguishes StAR (acute) from CYP1 IA (chronic) gene expression, 3) protein kinase A functions at the post-transcriptional level to control StAR protein expression, and 4) StAR is translated on polysomes associated with mitochondria. Defining the specific mechanisms for cAMP-dependent StAR regulation within one cell type is important in defining the similarities and differences in tropic hormone action on adrenal, ovarin, and testicular production of steroids. This will ultimately lead to a better understanding of potential developmental or disease states that result from aberrant over- or under-expression of StAR in a cell-specific manner.