van Wijk P A, Rijnberk A, Croughs R J, Meij B P, van Leeuwen I S, Sprang E P, Mol J A
Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, The Netherlands.
J Endocrinol Invest. 1997 Jan;20(1):1-7. doi: 10.1007/BF03347964.
Pituitary tumorigenesis is now generally regarded as a multistep process of genomic damage leading to uncoupling of interdependent systems that control cell proliferation and differentiation. The alterations include mutations in genes encoding for proteins involved in signal transduction pathways, such as G-proteins and the p21 protein encoded for by the ras genes. Apart from their excessive secretion of ACTH, corticotropic adenomas are characterized by decreased sensitivity to inhibition by glucocorticoids. Therefore, mutations in the glucocorticoid receptor leading to decreased sensitivity to glucocorticoids may contribute to corticotropic tumor formation. In this study, 16 corticotropic adenomas of dogs with pituitary-dependent hyperadrenocorticism were screened for mutations in the Gs alpha, H-, K-, N-ras genes and the coding region of the DNA-binding domain of the glucocorticoid receptor. The cDNA fragment of the Gs alpha gene encompassed codons 159-240. The K-, and N-ras fragments spanned codons 1-71. The H-ras gene was only screened for mutations in codons 12/13 by direct sequencing of the PCR product. The cDNA fragment of the DNA-binding domain of the glucocorticoid receptor encompassed codons 410-500. The Gs alpha, K-ras, N-ras genes and the DNA-binding domain of the glucocorticoid receptor were screened by single-strand conformation polymorphism analysis. No mutations were found in the Gs alpha gene, the ras genes and the DNA-binding domain of the glucocorticoid receptor. It is concluded that mutations in the Gs alpha gene (codons 159-240), the K- and N-ras genes (codons 1-71), the H-ras gene (codons 12/13) and mutations in the DNA-binding domain of the glucocorticoid receptor do not play a role in the tumorigenesis of canine corticotropic adenomas.
垂体肿瘤发生现在通常被视为一个多步骤的基因组损伤过程，导致控制细胞增殖和分化的相互依存系统解偶联。这些改变包括参与信号转导途径的蛋白质编码基因的突变，如G蛋白和ras基因编码的p21蛋白。除了促肾上腺皮质激素过度分泌外，促肾上腺皮质激素腺瘤的特征是对糖皮质激素抑制的敏感性降低。因此，糖皮质激素受体的突变导致对糖皮质激素敏感性降低可能促成促肾上腺皮质激素肿瘤的形成。在本研究中，对16例患有垂体依赖性肾上腺皮质功能亢进的犬促肾上腺皮质激素腺瘤进行了Gsα、H-、K-、N-ras基因以及糖皮质激素受体DNA结合域编码区的突变筛查。Gsα基因的cDNA片段包含密码子159 - 240。K-和N-ras片段跨越密码子1 - 71。通过对PCR产物直接测序，仅对H-ras基因的密码子12/13进行突变筛查。糖皮质激素受体DNA结合域的cDNA片段包含密码子410 - 500。通过单链构象多态性分析对Gsα、K-ras、N-ras基因以及糖皮质激素受体的DNA结合域进行筛查。在Gsα基因、ras基因和糖皮质激素受体的DNA结合域未发现突变。得出结论：Gsα基因（密码子159 - 240）、K-和N-ras基因（密码子1 - 71）、H-ras基因（密码子12/13）的突变以及糖皮质激素受体DNA结合域的突变在犬促肾上腺皮质激素腺瘤的肿瘤发生中不起作用。
