Kananen K, Markkula M, Mikola M, Rainio E M, McNeilly A, Huhtaniemi I
Department of Physiology, University of Turku, Finland.
Mol Endocrinol. 1996 Dec;10(12):1667-77. doi: 10.1210/mend.10.12.8961275.
We have developed a transgenic (TG) mouse model for gonadal tumorigenesis expressing the Simian virus 40 T-antigen (Tag) under the mouse inhibin alpha-subunit promoter. Gonadal tumors appear with 100% penetrance by the age of 5-8 months in the TG mice. When 1-month-old TG mice were gonadectomized, adrenal gland tumors were observed in each animal (12 females, 11 males) at the age of 6-8 months. No adrenal tumors were detected in gonadectomized non-TG mice (nine females, nine males) or in the intact TG mice (n > 100). The tumors appeared to originate from the X zone of the adrenal cortex. The TG mice with adrenocortical tumors had elevated serum levels of progesterone, estradiol, and immunoreactive inhibin (including dimeric forms), but corticosterone secretion was reduced. The lack of adrenal tumors in intact TG mice suggested that the tumorous gonads secrete factor(s) inhibiting adrenal tumorigenesis. As a candidate molecule, we studied the effects of inhibin, which was high in the serum of control females and TG females with ovarian tumors, as well as in TG males with testicular tumors. The DNA synthesis, as well as the levels of inhibin-alpha and Tag mRNA expression, were significantly reduced by recombinant human inhibin A in cell cultures derived from the adrenal tumors. In accordance, the expression level of inhibin-alpha mRNA in the normal adrenal gland was elevated 2 weeks after gonadectomy. These findings suggest that gonadal inhibin can down-regulate the expression of the inhibin alpha-subunit gene in the adrenal gland. When circulating inhibin is eliminated by gonadectomy, Tag expression and tumorigenesis are stimulated in the adrenal glands of the TG mice. The results demonstrate a novel mechanism of autoregulation in inhibin alpha-subunit gene expression.
我们构建了一种用于性腺肿瘤发生的转基因（TG）小鼠模型，该模型在小鼠抑制素α亚基启动子的控制下表达猿猴病毒40 T抗原（Tag）。TG小鼠在5 - 8月龄时性腺肿瘤的发生率为100%。1月龄的TG小鼠接受性腺切除术后，在6 - 8月龄时每只动物（12只雌性，11只雄性）均观察到肾上腺肿瘤。在接受性腺切除的非TG小鼠（9只雌性，9只雄性）或完整的TG小鼠（n > 100）中未检测到肾上腺肿瘤。这些肿瘤似乎起源于肾上腺皮质的X区。患有肾上腺皮质肿瘤的TG小鼠血清中孕酮、雌二醇和免疫反应性抑制素（包括二聚体形式）水平升高，但皮质酮分泌减少。完整TG小鼠中缺乏肾上腺肿瘤表明肿瘤性腺分泌抑制肾上腺肿瘤发生的因子。作为候选分子，我们研究了抑制素的作用，抑制素在对照雌性小鼠、患有卵巢肿瘤的TG雌性小鼠以及患有睾丸肿瘤的TG雄性小鼠的血清中含量较高。在源自肾上腺肿瘤的细胞培养物中，重组人抑制素A显著降低了DNA合成以及抑制素α和Tag mRNA的表达水平。相应地，性腺切除术后2周，正常肾上腺中抑制素α mRNA的表达水平升高。这些发现表明性腺抑制素可下调肾上腺中抑制素α亚基基因的表达。当通过性腺切除术消除循环中的抑制素时，TG小鼠肾上腺中的Tag表达和肿瘤发生受到刺激。结果证明了抑制素α亚基基因表达中一种新的自动调节机制。
