Sewer Marion B, Waterman Michael R
Department of Biochemistry and Center in Toxicology, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA.
Microsc Res Tech. 2003 Jun 15;61(3):300-7. doi: 10.1002/jemt.10339.
Steroid hormone biosynthesis in the adrenal cortex and gonads involves the coordinated transcription of the genes encoding the steroid hydroxylases, 3beta-hydroxysteroid dehydrogenase (3betaHSD), the steroidogenic acute regulatory protein (StAR), and adrenodoxin (Adx). Transcriptional regulation of steroidogenic genes is multifactorial, entailing developmental, tissue-specific, constitutive, and cAMP-dependent mechanisms. Optimal steroidogenic capacity is achieved by the actions of ACTH which exerts transcriptional pressure on all steroidogenic genes. The actions of ACTH in the adrenal cortex have been studied in great detail and is mediated by cAMP and protein kinase A (PKA) via two temporally distinct pathways. The acute response leads to mobilization of cholesterol, the initial substrate for all steroidogenic pathways, from cellular stores to the inner mitochondrial membrane where cholesterol sidechain cleavage cytochrome P450 (P45011A1) resides. The slower, chronic response of ACTH in the adrenal cortex directs transcription of the genes encoding the steroidogenic enzymes. Although steroidogenic gene transcription in response to ACTH is cAMP-dependent, the consensus cAMP response pathway (CRE/CREB) is not involved. Instead, each steroidogenic gene utilizes unique cAMP-responsive sequences (CRS) found in the promoters of each gene, which bind a diverse array of transcription factors. Moreover, once specific transcription factors are bound to the promoters of the steroidogenic genes, increased gene expression requires posttranslational modification (phosphorylation/dephosphorylation) of the transcription factors and binding of coactivator proteins. This review provides a general view (with emphasis on the human) of the important factors involved in regulating steroidogenic gene expression and ultimately steroid hormone biosynthesis.
肾上腺皮质和性腺中的类固醇激素生物合成涉及编码类固醇羟化酶、3β-羟基类固醇脱氢酶（3βHSD）、类固醇生成急性调节蛋白（StAR）和肾上腺皮质铁氧化还原蛋白（Adx）的基因的协调转录。类固醇生成基因的转录调控是多因素的，涉及发育、组织特异性、组成性和cAMP依赖性机制。促肾上腺皮质激素（ACTH）的作用可实现最佳的类固醇生成能力，它对所有类固醇生成基因施加转录压力。ACTH在肾上腺皮质中的作用已得到详细研究，它通过两条时间上不同的途径由cAMP和蛋白激酶A（PKA）介导。急性反应导致胆固醇（所有类固醇生成途径的初始底物）从细胞储存库转移到胆固醇侧链裂解细胞色素P450（P45011A1）所在的线粒体内膜。ACTH在肾上腺皮质中的较慢的慢性反应指导编码类固醇生成酶的基因的转录。尽管对ACTH作出反应的类固醇生成基因转录是cAMP依赖性的，但不涉及一致的cAMP反应途径（CRE/CREB）。相反，每个类固醇生成基因利用在每个基因启动子中发现的独特的cAMP反应序列（CRS），这些序列结合多种转录因子。此外，一旦特定转录因子与类固醇生成基因的启动子结合，基因表达的增加需要转录因子的翻译后修饰（磷酸化/去磷酸化）和共激活蛋白的结合。本综述提供了关于调节类固醇生成基因表达并最终调节类固醇激素生物合成的重要因素的总体观点（重点是人类）。
