The Steroidogenic Acute Regulatory (StAR) protein mediates the rate-limiting step in steroidogenesis, the transfer of the substrate for all steroid hormones, cholesterol, from the outer to the inner mitochondrial membrane in Steroidogenic cells. As such, this protein plays an indispensable role in the regulation of steroid hormones required for life itself, in the case of adrenal steroids, and for maintaining reproductive capacity, in the case of gonadal steroids. Since StAR occupies a crucial step in the regulation of steroidogenesis, the mechanism surrounding the regulation of this gene is extremely important. The StAR gene is tightly regulated such that it is expressed exclusively in Steroidogenic cells and is acutely regulated by trophic hormones through cAMP dependent mechanisms. We have determined that the proximal 150 bp of the 5'flanking region of the StAR gene, containing numerous transcription factor-binding sites, is capable of conferring cAMP responsiveness. It has become clear that regulation of the StAR gene is a complex process, involving cooperation and/or interaction between one or more transcription factors. Despite our current knowledge surrounding the regulation of the StAR gene, a central unanswered question is how the StAR gene is regulated in vivo such that it is expressed at appropriate times during development and is confined to Steroidogenic cells. We propose to continue to explore these complex mechanisms, uncovering the intricate interactions occurring between the various transcription factors and their co-regulators involved in the regulation of this crucial gene using cultured cells and a transgenic approach which will provide novel insights regarding hormone-induced, developmental, and tissue-specific expression of the StAR gene. Also, we propose to determine if a mitochondrial specific A kinase anchoring protein (AKAP121) is required for the expression and activation of the StAR protein. AKAPs are anchoring proteins that tether protein kinase A (PKA) to specific cellular locations. AKAP121 can also serve as a platform for the binding (to the KH domain) and translation of specific mRNAs. Our recent data indicate that interference with the expression of AKAP121 inhibits steroidogenesis and StAR protein expression. Thus, it is of interest to determine the mechanisms involved in the role of AKAP121 in steroidogenesis and StAR expression. We hypothesize that newly transcribed StAR mRNA exits the nucleus and rapidly binds to the KH domain of AKAP121. The bound StAR mRNA is then translated on adjacent ribosomes and is activated by phosphorylation through the action of PKA. Phosphorylation of StAR was recently shown to be a plausible mechanism for the optimal cholesterol transferring ability of the StAR protein. Elucidation of the precise mechanisms of the regulation of the StAR gene is the key to understanding the regulation of steroidogenesis in the context of both male and female development, reproduction, and the regulation of blood pressure through corticosteroids.
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