Regulation of the Steroidogenic Acute Regulatory Protein

描述：(申请人提供)肾上腺和性腺的类固醇合成 受促性激素的强烈控制，通过调节 类固醇合成急性调节(STAR)蛋白。恒星合成对于 胆固醇跨线粒体外膜向内膜的转运 类固醇合成的第一步发生的膜；胆固醇 胆固醇侧链裂解酶转化为孕烯醇酮。 STAR基因突变(S)导致产生无功能的 蛋白质是类脂性先天性肾上腺疾病的遗传基础 增生(LCAH)。LCAH患者的肾上腺和性腺明显受损 由于不能将胆固醇转运到 线粒体。因此，了解控制STAR表达的机制 功能从根本上说是重要的。多条信号通路已经被 显示在转录和转录后调节STAR 级别以特定于细胞的方式。启动子转录和蛋白表达， 然而，cAMP-蛋白激酶a似乎是独立调节的。 路径。这项研究的总体目标是阐明分子 CAMP依赖的STAR表达调控机制 小鼠转录、翻译和翻译后水平的研究 间质细胞和肾上腺细胞。本提案中概述的研究将确定 是否i)依赖cAMP的STAR基因激活增加既涉及 抑制物的丧失和激活剂的获得，功能，2)水平 CAMP依赖的蛋白激酶A活性区分STAR(急性)和CyP1 IA(慢性)基因表达，3)蛋白激酶A在 转录后水平控制STAR蛋白的表达，以及4)STAR是 翻译在与线粒体相关的多聚体上。定义特定的 一种细胞类型内cAMP依赖的STAR调节机制很重要 在定义促性腺激素作用的异同时 肾上腺、卵巢和睾丸产生类固醇。这最终将是 有助于更好地了解潜在的发育或疾病状态 这是由于在细胞特异性启动子异常过表达或表达不足所致 举止。

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.