Kim Y C, Ariyoshi N, Artemenko I, Elliott M E, Bhattacharyya K K, Jefcoate C R
Department of Pharmacology, University of Wisconsin-Madison Medical School 53706, USA.
Steroids. 1997 Jan;62(1):10-20. doi: 10.1016/s0039-128x(96)00153-5.
Cholesterol conversion to pregnenolone by cytochrome P450scc in steroidogenic cells, including those of the adrenal cortex, is determined by hormonal control of cholesterol availability. Intramitochondrial cholesterol movement to P450scc, which retains hormonal activation in isolated mitochondria, is apparently dependent on peripheral benzodiazepine receptor and the recently cloned steroidogenic acute regulatory (StAR) protein. In rat adrenal cells, StAR is formed as a 37-kDa precursor that is transferred to the mitochondrial inner membrane following phosphorylation by hormonally activated protein kinase A, and processed to multiple forms, some of which turn over very rapidly. In bovine cells, StAR undergoes three modifications forming a set of eight proteins seen in both glomerulosa and fasciculata cells. In the former, cyclic AMP and angiotensin II each decrease two forms and elevate six forms. Significantly, the major change seen after activation may not involve phosphorylation of StAR. Cholesterol transfer across mitochondrial membranes is also activated in isolated mitochondria by GTP and low concentrations of Ca2+, apparently prior to activation by StAR. Depletion of StAR by cycloheximide inhibits cholesterol transfer but is overcome by uptake of Ca2+ into the matrix. This activation of cellular cholesterol transport is sustained in adrenal cells permeabilized by Streptolysin O. In rat adrenal cells cAMP elevates 3.5- and 1.6-kb mRNA, hybridized by a 1.0-kb StAR cDNA. A 3.5-kb rat adrenal cDNA that encodes all except the 5' end of the longest StAR mRNA has been characterized. The corresponding gene sequence is distributed across seven exons. The shorter mRNA may arise from polyadenylation signals early in exon 7. However, the 3.5-kb mRNA comprises 80-90% of untreated rat adrenal StAR mRNA and may therefore provide the prime source for in vivo translation of StAR protein.
在包括肾上腺皮质细胞在内的类固醇生成细胞中，细胞色素P450scc将胆固醇转化为孕烯醇酮，这一过程由胆固醇可用性的激素控制决定。线粒体内的胆固醇向P450scc的移动（P450scc在分离的线粒体中保持激素激活作用）显然依赖于外周苯二氮䓬受体和最近克隆的类固醇生成急性调节（StAR）蛋白。在大鼠肾上腺细胞中，StAR以37 kDa的前体形式形成，该前体在激素激活的蛋白激酶A磷酸化后转移到线粒体内膜，并加工成多种形式，其中一些形式的周转非常迅速。在牛细胞中，StAR经历三种修饰，形成一组在球状带和束状带细胞中都可见的八种蛋白质。在球状带细胞中，环磷酸腺苷（cAMP）和血管紧张素II各自降低两种形式并升高六种形式。值得注意的是，激活后看到的主要变化可能不涉及StAR的磷酸化。在分离的线粒体中，GTP和低浓度的Ca2+也能激活胆固醇跨线粒体膜的转运，显然这发生在StAR激活之前。用放线菌酮使StAR耗竭会抑制胆固醇转运，但通过将Ca2+摄入基质可克服这种抑制。细胞胆固醇转运的这种激活在经链球菌溶血素O通透处理的肾上腺细胞中得以维持。在大鼠肾上腺细胞中，cAMP使与1.0 kb StAR cDNA杂交的3.5 kb和1.6 kb mRNA升高。一个编码除最长StAR mRNA的5'端之外所有序列的3.5 kb大鼠肾上腺cDNA已被鉴定。相应的基因序列分布在七个外显子上。较短的mRNA可能来自外显子7早期的聚腺苷酸化信号。然而，3.5 kb mRNA占未处理大鼠肾上腺StAR mRNA的80 - 90%，因此可能是体内StAR蛋白翻译的主要来源。
