Strauss J F, Golos T G, Silavin S L, Soto E A, Takagi K
Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine, Philadelphia 19104.
Prog Clin Biol Res. 1988;267:177-200.
The findings reviewed above demonstrate that cAMP can act at several distinct loci to enhance steroidogenesis. Analogs of cAMP stimulate the accumulation of the mRNAs which encode components of the steroidogenic machinery, such as the receptor for LDL and the system for the cleavage of the cholesterol sidechain. This apparently coordinated accumulation of specific mRNAs results from increased transcription of the relevant genes. Transacting factors modulated by cyclic AMP may influence common enhancer sequences (e.g., TGACGTCA), and such interactions would account for the simultaneous increase in expression of specific genes on several different chromosomes. These actions of cyclic AMP enable ovarian cells to support long-term increases in steroid synthesis by increasing the quantities of proteins involved in steroidogenesis. Such changes would obviously be important during luteinization, when the potential of granulosa cells to secrete progesterone is greatly increased. Although we speak of these effects as "long-term", it is evident that they occur within a relatively short time (hours) after exposure of cells to the tropic agent. Cyclic AMP also acts to stimulate steroidogenesis post-transcriptionally. It may influence events at the translational level via interactions in the formation of "labile" proteins. In addition, the regulation of cholesteryl ester hydrolase, as well as of other enzymes involved the metabolism of cholesterol, seems to involve post-translational modifications (e.g., phosphorylation). The effects of cAMP on the cytoskeleton may be another manifestation of a post-translational response. These actions of cAMP promote acute increases in steroidogenesis (i.e., within minutes). They encompass the transport of cholesterol to the mitochondria and the regulation of access of sterol to the inner mitochondrial membranes. Future research should be directed at elucidating the exact mechanisms which permit cAMP to exert coordinate effects on the genome (Figure 8), as well as its post-transcriptional effects on various proteins and enzymes which play a role in the synthesis of steroid hormones.
上述研究结果表明，环磷酸腺苷（cAMP）可作用于多个不同位点以增强类固醇生成。cAMP类似物可刺激编码类固醇生成机制组成成分的mRNA积累，如低密度脂蛋白（LDL）受体和胆固醇侧链裂解系统。这种特定mRNA的明显协同积累是相关基因转录增加的结果。由环磷酸腺苷调节的反式作用因子可能会影响常见的增强子序列（如TGACGTCA），这种相互作用可解释位于几条不同染色体上的特定基因表达同时增加的现象。环磷酸腺苷的这些作用使卵巢细胞能够通过增加参与类固醇生成的蛋白质数量来支持类固醇合成的长期增加。这种变化在黄体化过程中显然很重要，此时颗粒细胞分泌孕酮的能力会大大增强。虽然我们将这些效应称为“长期”效应，但很明显，它们在细胞暴露于促性腺因子后相对较短的时间（数小时）内就会出现。环磷酸腺苷还在转录后发挥作用以刺激类固醇生成。它可能通过在“不稳定”蛋白质形成过程中的相互作用来影响翻译水平的事件。此外，胆固醇酯水解酶以及其他参与胆固醇代谢的酶的调节似乎涉及翻译后修饰（如磷酸化）。环磷酸腺苷对细胞骨架的作用可能是翻译后反应的另一种表现形式。环磷酸腺苷的这些作用促进类固醇生成的急性增加（即几分钟内）。它们包括胆固醇向线粒体的转运以及固醇进入线粒体内膜的调节。未来的研究应致力于阐明使环磷酸腺苷对基因组发挥协同作用的确切机制（图8），以及其对在类固醇激素合成中起作用的各种蛋白质和酶的转录后效应。
