GONADECTOMY PERMITS ADRENOCORTICAL TUMORIGENESIS IN MICE TRANSGENIC FOR THE MOUSE INHIBIN ALPHA-SUBUNIT PROMOTER SIMIAN VIRUS-40 T-ANTIGEN FUSION GENE - EVIDENCE FOR NEGATIVE AUTOREGULATION OF THE INHIBIN ALPHA-SUBUNIT GENE/

We have developed a transgenic (TG) mouse model for gonadal tumorigene sis expressing the Simian virus 40 T-antigen (Tag) under the mouse inh ibin alpha-subunit promoter. Gonadal tumors appear with 100% penetranc e by the age of 5-8 months in the TG mice. When 1-month-old TG mice we re 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-TO 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 tum ors had elevated serum levels of progesterone, estradiol, and immunore active inhibin (including dimeric forms), but corticosterone secretion was reduced. The tack of adrenal tumors in intact TG mice suggested t hat the tumorous gonads secrete factor(s) inhibiting adrenal tumorigen esis. As a candidate molecule, we studied the effects of inhibin, whic h was high in the serum of control females and TO females with ovarian tumors, as well as in TG males with testicular tumors. The DNA synthe sis, as well as the levels of inhibin-alpha and Tag mRNA expression, w ere significantly reduced by recombinant human inhibin A in cell cultu res derived from the adrenal tumors. In accordance, the expression lev el of inhibin-alpha mRNA in the normal adrenal gland was elevated 2 we eks 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 autoregu lation in inhibin alpha-subunit gene expression.