REGULATION OF THE STEROIDOGENIC ACUTE REGULATORY PROTEIN

营养性激素对类固醇生成的急性调节中的关键成分 荷尔蒙是胆固醇从线粒体外部的移位 膜到内膜，在那里它被T转化为孕烯醇酮 他的胆固醇侧链裂解酶。类固醇激素性急性发作 调控蛋白(STAR)在这一过程中起着不可或缺的作用 胆固醇在线粒体内的移位，从而在急性类固醇中 制作。这一点从类脂先天性的研究中可见一斑。 肾上腺增生症(LCAH)是一种遗传性和致命性疾病，在这种疾病中 肾上腺和性腺类固醇激素的生成明显受损，原因是 不能将胆固醇输送到侧链裂解酶。 最近，STAR基因的突变导致了 截短的、无功能的蛋白质已被确认为唯一的病变 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 调节相同反应的途径；即类固醇的增加 制作。这些激动剂还可以诱导STAR蛋白的表达。因此， 对STAR表达的调节可能代表了一种共同的机制 不同的信号通路，以精确控制类固醇的产生。基座 关于STAR在调节类固醇合成中的直接和重要作用， 了解控制STAR表达的分子机制和 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，建议的研究将评估 转录后的STAR基因的转录激活 STAR mRNA的调控，以及STAR的磷酸化。具体地说， 该提案的目标是：1.检查翻译人员的作用 激素依赖状态下STAR及其稳定性的调节 STAR蛋白的表达。2.定义顺式代理监管 STAR基因的区域负责激素依赖和组织- STAR的具体表达。3.研究公钥基础设施的要求 关于STAR表达的活动。4.审视明星的角色 其功能上的磷酸化。

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.