Expression of Adrenocorticotropin Receptor Gene in Adrenocortical Adenomas From Patients With Cushing Syndrome: Possible Contribution for the Autonomous Production of Cortisol
Expression of Adrenocorticotropin Receptor Gene in Adrenocortical Adenomas From Patients With Cushing Syndrome: Possible Contribution for the Autonomous Production of Cortisol
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库欣综合征患者肾上腺皮质腺瘤中促肾上腺皮质激素受体基因的表达：可能对皮质醇自主产生的贡献
作者：
T. Imai;D. Sarkar;A. Shibata;H. Funahashi;T. Morita;T. Kikumori;S. Ohmori;H. Seo
目的探讨库欣综合征患者内源性促肾上腺皮质激素（ACTH）分泌抑制对肾上腺皮质腺瘤及其附属萎缩正常腺体ACTH受体（ACTH R）基因表达的影响。ACTH通过促肾上腺皮质激素受体促进肾上腺细胞生长和类固醇合成。体内和体外研究表明，在几个物种中，ACTH-R的表达被其自身的配体ACTH上调。在肾上腺皮质腺瘤引起的库欣综合征患者中，腺瘤可自主产生皮质醇。这强烈抑制内源性ACTH分泌，从而引起推测，在这些患者中ACTH-R基因的表达也被抑制。然而，以前的研究表明，这些患者给予外源性ACTH会导致皮质醇的产生进一步增加，这表明腺瘤中功能性ACTH-R的表达。因此，作者检测了这些患者中ACTH-R基因的表达。方法14例库欣综合征患者。肾上腺皮质激素过多导致自主生产的腺瘤被确定，并进行单侧肾上腺切除术。用北方印迹法测定ACTH R和细胞色素P450侧链裂解酶（P450 SCC）mRNA水平。对这些患者的ACTH-R基因的整个编码区进行测序。结果萎缩的正常肾上腺ACTH-R mRNA表达量明显低于肾癌患者的正常肾上腺。然而，ACTH-R mRNA的表达没有被抑制在任何腺瘤。ACTH-R mRNA在腺瘤中的表达是附在萎缩腺体中的4 - 6倍。在所有患者中均未检测到腺瘤中ACTH-R基因编码序列的突变。腺瘤中的mRNA似乎被翻译成功能活性受体，因为肌内注射ACTH导致手术前血浆皮质醇显著增加，但手术后3个月则没有。腺瘤组织中ACTH-R和P450 SCC mRNA的表达呈线性正相关。结论库欣综合征患者ACTH分泌受抑导致非肿瘤性肾上腺皮质细胞ACTH-R mRNA表达减少。而腺瘤中ACTH-R表达的调节机制可能不同。在腺瘤中持续表达单独的ACTH-R，即使在没有ACTH的情况下，可能会导致基础腺苷酸环化酶活性增加，如在促甲状腺激素受体的情况下观察到的，从而可能在皮质醇的自主生产中发挥作用。
ObjectiveTo examine whether inhibition of endogenous adrenocorticotropin (ACTH) secretion in patients with Cushing syndrome affects the expression of the ACTH receptor (ACTH-R) gene in adrenocortical adenoma and attached atrophic normal gland. Summary Background DataACTH increases adrenal cell growth and steroidogenesis by means of ACTH-R. In vivo and in vitro studies have shown that expression of ACTH-R is upregulated by its own ligand ACTH in several species. In patients with Cushing syndrome resulting from adrenocortical adenoma, there is autonomous production of cortisol from the adenoma. This strongly inhibits endogenous ACTH secretion, giving rise to the speculation that the expression of the ACTH-R gene in these patients is also suppressed. However, previous studies have shown that administration of exogenous ACTH to these patients leads to a further increase in the production of cortisol, suggesting the expression of functional ACTH-R in the adenoma. The authors, therefore, examined the expression of the ACTH-R gene in these patients. MethodsFourteen patients with Cushing syndrome were studied. Glucocorticoid excess resulting from autonomous production from the adenomas was ascertained, and unilateral adrenalectomy was performed. The levels of ACTH-R and cytochrome P450 side chain cleavage enzyme (P450scc) mRNAs were determined by Northern blot analysis. The entire coding region of the ACTH-R gene in these patients was sequenced. ResultsACTH-R mRNA abundance in the attached atrophic normal adrenals was suppressed and invariably less than that in the normal gland obtained from a patient with renal cancer. However, the expression of ACTH-R mRNA was not suppressed in any of the adenomas. Expression of ACTH-R mRNA in the adenomas was four- to sixfold greater than that in the attached atrophic gland. No mutation in the coding sequence of the ACTH-R gene in the adenoma was detected in any of the patients. The mRNA in the adenomas appeared to be translated into functionally active receptor because intramuscular administration of ACTH resulted in significant increases in plasma cortisol before surgery but not 3 months after surgery. In addition, there was a positive linear correlation between the expressions of ACTH-R and P450scc mRNAs in the adenoma tissue. ConclusionsSuppressed ACTH secretion in patients with Cushing syndrome results in reduction of the ACTH-R mRNA expression in nonneoplastic adrenocortical cells. However, the regulatory mechanism of ACTH-R expression might be different in adenoma. Persistent expression in the adenoma of ACTH-R alone, even in the absence of ACTH, might result in increased basal adenyl cyclase activity, as observed in the case of thyroid-stimulating hormone receptor, and thereby might play a role in the autonomous production of cortisol.
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影响因子：
56.9
作者：
MOUNTJOY, KG;ROBBINS, LS;CONE, RD
通讯作者：
CONE, RD
ACTH 对肾上腺皮质类固醇激素生物合成的调节。
DOI：
10.1139/o83-088
发表时间：
1983
期刊：
Canadian journal of biochemistry and cell biology = Revue canadienne de biochimie et biologie cellulaire
影响因子：
--
作者：
Simpson,ER;Waterman,MR
通讯作者：
Waterman,MR
通过荧光原位杂交将编码 melanocortin-2（促肾上腺皮质激素）和 melanocortin-3 受体的基因定位于染色体 18p11.2 和 20q13.2-q13.3。
影响因子：
4.4
作者：
Gantz,I;Tashiro,T;Barcroft,C;Konda,Y;Shimoto,Y;Miwa,H;Glover,T;Munzert,G;Yamada,T
通讯作者：
Yamada,T
DOI：
10.1073/pnas.88.24.11354
发表时间：
1991-12-01
影响因子：
11.1
作者：
ALLEN, LF;LEFKOWITZ, RJ;COTECCHIA, S
通讯作者：
COTECCHIA, S