Inhibins are heterodimeric (alpha:betaA and alpha:betaB) endocrine, paracrine, and autocrine factors of the
TGFbeta superfamily that are produced predominantly by ovarian granulosa cells in females and testicular Sertoli cells in males. Control of granulosa and Sertoli cell proliferation is lost in the
inhibin alpha (Inhalpha) knockout mouse model, leading to
gonadotropin-dependent gonadal
tumors of the granulosa/Sertoli cell lineage in both females and males. Castrate Inhalpha knockout mice develop sex steroidogenic
tumors of the adrenal cortex. Physiological control of granulosa/Sertoli cell cycle progression depends on p27Kip1 and
cyclin D2, which function in the G1-->S phase transition. To study the cell cycle-regulatory factors involved in ovarian, testicular, and adrenal
tumor development in vivo, we have bred Inhalpha mutant mice to mice with targeted disruptions of the p27 and
cyclin D2 genes. Our previous studies demonstrated that
inhibins act cooperatively with p27 to negatively regulate granulosa cell proliferation, as double mutant mice lacking
inhibins and p27 develop and succumb to ovarian
tumors more rapidly than Inhalpha knockout mice. Here, we report that
cyclin D2 antagonizes this inhibition and is key in promoting gonadal growth and
tumor development, and
tumor development is markedly suppressed in double-mutant mice. We found that double-knockout females lacking
cyclin D2 and Inhalpha lived longer than mice lacking
inhibins alone; the majority of these double-knockout mice lived longer than 17 wk, as opposed to
inhibin alpha single-knockout females with 50% survival at between 12 and 13 wk of age. Moreover, 95% of
inhibin alpha knockout males succumb to
testicular tumor development by 12 wk of age, whereas double knockouts were protected from early signs of
tumor development and had a 50% survival of 40 wk. Interestingly, the results of these studies reflect tissue-specific consequences of loss of these cell cycle regulators. In castrate mice, loss of p27 has little effect on adrenal cortical
tumor progression in the absence of
inhibins, whereas loss of
cyclin D2 prolongs the lifespan of
cyclin D2, Inhalpha double knockouts. After
gonadectomy, 50% of
cyclin D2, Inhalpha double-knockout males live to more than 46 wk of age, 10 wk longer than 50% of littermates lacking only
inhibins. Similarly, 50% of female
cyclin D2,
inhibin alpha double knockouts live to 47 wk of age before succumbing to adrenal
tumor development, in contrast to the 50% survival of Inhalpha single-knockout females at between 27 and 28 wk. Thus, identification of genetic modifiers of the Inhalpha knockout
tumor phenotype has led us to a better appreciation of how specific components of the cell cycle machinery contribute to
tumorigenesis in the ovary, testis, and adrenal gland.