Frigeri Claudia, Tsao Jennivine, Cordova Martha, Schimmer Bernard P
Department of Pharmacology, University of Toronto, Ontario, Canada M5G 1L6.
Endocrinology. 2002 Oct;143(10):4031-7. doi: 10.1210/en.2002-220349.
ACTH resistance in mutant derivatives of the Y1 mouse adrenocortical tumor cell line results from a defect that affects the activity of steroidogenic factor-1 (SF1), thereby preventing the expression of the melanocortin-2 receptor. In this report, we show that the SF1 genes in ACTH-resistant mutants differ from the gene in ACTH-responsive Y1 cells by two base changes-one that changes an Ala to Ser at codon 172, and one in the third position of codon 3 that does not affect the protein sequence. Furthermore, several of the mutants contain multiple copies of this alternate SF1 gene (SF1(S172)) on acentric chromosome fragments. The SF1(S172) allele represents a polymorphism rather than a spontaneous mutation because the two SF1 alleles can be traced to the hybrid mouse strain (C57L/J x A/HeJ) from which the original adrenal tumor was derived. The SF1(A172) allele also is found in C57Bl/6J and C57Bl/10J mice, whereas the SF1(S172) allele also is found in C3H/HeJ and DBA/2J mice. The two forms of SF1 had only modest differences in activity suggesting that the SF1 polymorphism per se is not directly responsible for ACTH resistance. Our results indicate that the SF1(S172) allele is a marker of ACTH resistance in this family of adrenocortical tumor cells.
Y1小鼠肾上腺皮质肿瘤细胞系的突变衍生物中促肾上腺皮质激素（ACTH）抵抗源于一种影响类固醇生成因子-1（SF1）活性的缺陷，从而阻止了促黑素细胞激素-2受体的表达。在本报告中，我们表明，ACTH抵抗突变体中的SF1基因与ACTH反应性Y1细胞中的基因存在两个碱基变化——一个在密码子172处将丙氨酸变为丝氨酸，另一个在密码子3的第三位，不影响蛋白质序列。此外，一些突变体在无着丝粒染色体片段上含有多个这种替代SF1基因（SF1(S172)）的拷贝。SF1(S172)等位基因代表一种多态性而非自发突变，因为这两个SF1等位基因可追溯到原始肾上腺肿瘤所源自的杂交小鼠品系（C57L/J×A/HeJ）。SF1(A172)等位基因也存在于C57Bl/6J和C57Bl/10J小鼠中，而SF1(S172)等位基因也存在于C3H/HeJ和DBA/2J小鼠中。两种形式的SF1在活性上只有适度差异，这表明SF1多态性本身并非直接导致ACTH抵抗的原因。我们的结果表明，SF1(S172)等位基因是该肾上腺皮质肿瘤细胞家族中ACTH抵抗的一个标志物。
