Expression of a nuclear transcription factor "Ad4BP" , a common factor to regulate steroidogenic cytochrome P450, in adrenal tumor

肾上腺皮质肿瘤可分为功能性和非功能性两类。功能性腺瘤患者表现为库欣综合征或康氏综合征等临床症状。近年来的研究表明，类固醇合成酶的表达受多种转录因子的调控，如Ad4-BP、NGFI-B和COUP-TT等，但这些转录因子在肾上腺中如何调控的报道很少。同样未知的是这些因子在肾上腺皮质肿瘤中的表达。因此，研究促肾上腺皮质激素(ACTH)是否调节Ad4-BP、NGFI-B和COUP-TF3在大鼠体内的表达。还研究了这些因子在手术中获得的人肾上腺皮质肿瘤中的表达。在大鼠实验中，地塞米松完全抑制了ACTH的分泌。然后用促肾上腺皮质激素治疗，每隔一段时间取肾上腺。Northern印迹分析表明，NGFI-B…的表达在ACTH干预前，MORE和COUP-TFm RNA处于检测不到的水平。ACTH可迅速诱导NGF-IB基因的表达(ACTH后30min即可检测到NGF-1b的表达，60min达高峰)。在ACTH后180min检测不到COUP-Tf的表达。NGF-IB和COUP-Tf对ACTH的诱导在NGF-IB后有所滞后，但在ACTH后180min仍维持升高水平。当研究ACTH受体的mRNA水平时，清楚地表明ACTH增加了它自己的受体mRNA的表达。结果表明，ACTH是其表达所必需的。用人的肾上腺皮质标本进行的研究表明，在库欣综合征患者的腺瘤和原发性醛固酮腺瘤中总是检测到Ad4BP的mRNA。对两例库欣综合征患者的肾上腺标本进行ACTH受体mRNA分析，发现腺瘤组织中含有丰富的ACTH受体mRNA，而邻近正常肾上腺组织中ACTH受体mRNA的丰度极低。正常组织中受抑制的ACTH受体mRNA与大鼠实验中发现的ACTH需要ACTH才能表达的结果相一致，腺瘤组织中ACTH受体mRNA的表达高于正常组织。提示腺瘤组织中ACTH受体mRNA的调控发生了改变。较少

Adrenocortical tumors can be divided in two categories, functioning and non-functioning. The patients with functioning ademona manifest clinical symptoms such as Cushing's syndrome or Conn's syndrome. Recently it has been shown that the expression of steroidogenic enzymes is under the control of several transcription factors such as Ad4-BP,NGFI-B and COUP-TF.However there is few report how these transcription factors are regulated in the adrenal glands. Also no known is the expression of these factors in adrenocortical tumors. It is thus studied whether adrenocorticotropin (ACTH) regulates the expression of Ad4-BP,NGFI-B and COUP-TFin rats. Also studied was the expression of these factors in human adrenocortical tumors obtained at surgery.In the experiment using rat, dexamethsone was administered to completely suppress ACTH secretion. The animals were then treated with ACTH and the adrenal glands were obtained at intervals. Northern blot analysis revealed that the expression of NGFI-B … More and COUP-TF mRNA was at undetectable level before ACTH aministration. NGF-IB mRNA was rapidly induced by ACTH (detectable at 30 min and a peak at 60 min after ACTH). The mRNA became undetectable at 180 min after ACTH.Induction of COUP-TF was somewhat lagged after NGF-IB but the increased level was maintained even 180 min after ACTH.These results indicate that NGF-IB and COUP-TF mediate ACTH action through induction of their mRNAs. When ACTH-receptor mRNA level was studied, it was clearly demonstrated that ACTH increases its own receptor mRNA.The result indicates that ACTH is required for the expression of its mRNA.The study with human adrenocortical samples revealed that Ad4BP mRNA isalways detectable in the adenoma obtained from the patients with Cushing's syndrome as well as primary aldosterone producing adenoma. When ACTH-receptor mRNA was analyzed in two adrenal samples from the patients with Cushing's syndrome, it was noted that adenoma contained abundant ACTH-receptor mRNA.However, the abundance of the mRNA was extremely low in the adjacent normal adrenal tissues. The suppressed ACTH-receptor mRNA in the normal tissue is compatible with the finding from the experiments with rats that ACTH is required for the expression of its mRNA.The expression of ACTH-receptor mRNA in the adenoma tissue was surprizing. It suggest that regulation of ACTH-receptor mRNA is altered in the adenoma tissue. Less