Beuschlein F, Fassnacht M, Klink A, Allolio B, Reincke M
Schwerpunkt Endokrinologie, Abteilung Innere Medizin II, Klinikum der Albert-Ludwigs-Universitat, Freiburg, Germany.
Eur J Endocrinol. 2001 Mar;144(3):199-206. doi: 10.1530/eje.0.1440199.
The regulation of the ACTH-receptor gene is unique in that it is up-regulated by its own ligand, ACTH. Ligand-induced up-regulation of ACTH-receptor expression may be an important adaptive process directed towards optimizing adrenal responsiveness to ACTH in the context of physiological stress and the maintenance of metabolic homeostasis in which the adrenals play a pivotal role. Whereas enhancement by ligand-induced up-regulation permits a more efficient and rapid glucocorticoid response, negative feedback regulation of glucocorticoids in the hypothalamus and pituitary inhibits ACTH secretion and allows a balanced adrenal response to stress. Since the cloning of the promoter region of the ACTH receptor, considerable progress in the understanding of the regulatory processes has been made. The effects of ACTH on ACTH-receptor expression is dependent on cAMP, probably mediated through AP-1. The profound effect of three SF-1-binding sites in the ACTH-receptor promoter was demonstrated by deletion experiments. Conversely, ACTH-receptor expression can be suppressed by adrenal-specific transcription factors,like DAX-1. Despite an extensive search, no activating ACTH-receptor mutations have been found in adrenal tumors,excluding the ACTH receptor as a relevant oncogene in adrenal tumorigenesis. However, the ACTH receptor may act as a differentiation factor as suggested by LOH in adrenal carcinomas with an undifferentiated tumor type. In benign adrenal tumors, a strong correlation between ACTH-receptor expression and expression of P450 steroidogenic enzymes is evident. This close regulative relationship is lost in adrenal carcinoma, probably as a result of tumor dedifferentiation. Down-regulation of ACTH-receptor expression in normal and neoplastic tissue can be achieved by adrenostatic compounds such as aminoglutethimide and metyrapone.
促肾上腺皮质激素（ACTH）受体基因的调控具有独特性，即它会被自身配体ACTH上调。配体诱导的ACTH受体表达上调可能是一个重要的适应性过程，旨在在生理应激情况下优化肾上腺对ACTH的反应，并维持肾上腺发挥关键作用的代谢稳态。虽然配体诱导的上调增强可使糖皮质激素反应更高效、快速，但下丘脑和垂体中糖皮质激素的负反馈调节会抑制ACTH分泌，从而使肾上腺对压力产生平衡反应。自ACTH受体启动子区域被克隆以来，在对调控过程的理解方面取得了相当大的进展。ACTH对ACTH受体表达的影响依赖于环磷酸腺苷（cAMP），可能是通过激活蛋白-1（AP-1）介导的。缺失实验证明了ACTH受体启动子中三个类固醇生成因子-1（SF-1）结合位点的深远影响。相反，ACTH受体表达可被肾上腺特异性转录因子如剂量敏感的性反转-肾上腺皮质发育不全蛋白（DAX-1）抑制。尽管进行了广泛搜索，但在肾上腺肿瘤中未发现激活ACTH受体的突变，排除了ACTH受体作为肾上腺肿瘤发生相关癌基因的可能性。然而，正如未分化肿瘤类型的肾上腺皮质癌中杂合性缺失（LOH）所提示的那样，ACTH受体可能作为一种分化因子发挥作用。在良性肾上腺肿瘤中，ACTH受体表达与细胞色素P450类固醇生成酶的表达之间存在明显的强相关性。这种紧密的调控关系在肾上腺皮质癌中丧失，可能是肿瘤去分化的结果。在正常组织和肿瘤组织中，ACTH受体表达的下调可通过氨鲁米特和甲吡酮等肾上腺抑制化合物实现。
