REGULATION OF THE STEROIDOGENIC ACUTE REGULATORY PROTEIN

营养性类固醇激素合成的急性调节中的一个关键成分 激素是胆固醇从线粒体外膜转运， 膜到内膜，在那里它被转化为双烯醇酮。 胆固醇侧链裂解酶。 类固醇生成性急性 调节蛋白（星星）在其中具有不可或缺的作用 胆固醇线粒体内易位，因此在急性类固醇激素 生产 这一点在先天性类脂质的研究中得到了证实。 肾上腺皮质增生（LCAH），一种遗传性和致命性疾病， 肾上腺和性腺类固醇生成明显受损， 不能将胆固醇递送到侧链裂解酶。 最近，星星基因的突变，导致产生 截短的无功能蛋白质，已被确定为唯一的病变 在LCAH患者中。 此外，营养激素或电解质 刺激肾上腺皮质激活不同的第二信使 途径介导相同的反应;即，增加类固醇 生产 这些激动剂也诱导星星蛋白表达。 因此，在本发明中， 星星表达的调节可能代表了一种共同的机制， 不同的信号传导途径，以急性控制类固醇的生产。 基于 关于星星在调节类固醇生成方面的直接和重要作用， 了解控制星星表达的分子机制， 功能将阐明营养激素作用的潜在机制 在类固醇生成细胞中。 因此，拟议的研究将评估 星星基因的转录激活，转录后 调节星星mRNA和星星磷酸化。 具体而言是 该提案的目标是：1。 为了研究翻译的作用， 星星mRNA和星星mRNA稳定性的调节 星星蛋白的表达。 2. 为了定义顺式作用调节 星星基因的区域负责依赖于细胞和组织- 星星的特异性表达。 3. 检查PKA的要求 星星表达的活性。 4. 审查追回星星的作用 磷酸化对其功能的影响。

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.