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Cellular and Molecular Biology Graduate Program (B.D.L., G.D.H.), and Department of Internal Medicine (G.D.H.), Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan 48109-2200
Address all correspondence and requests for reprints to: Gary D. Hammer, M.D., Ph.D., BSRB 1502, 109 Zina Pitcher Place, Ann Arbor, Michigan 48109-2200. E-mail: ghammer{at}umich.edu.
Inhibin and activin are members of the TGFß family that perform mutually antagonistic signaling roles in the anterior pituitary, gonads, and adrenal gland. Unopposed activin signaling in inhibin-null (Inha–/–) mice causes the formation of granulosa cell tumors in the gonads and adrenal cortex, which depend upon FSH for efficient growth and progression. In this study, we demonstrate that Smad3, a key effector of activin signaling, is expressed at high levels and is constitutively activated in tumors from these mice. Removal of Smad3 from Inha–/– mice by a genetic cross to Smad3-null (Madh3–/–) mice leads to a significant decrease in cyclinD2 expression and a significant attenuation of tumor progression in the gonads and adrenal. The decrease in cyclinD2 levels in compound knockout mice is related to a reduction in mitogenic signaling through the phosphoinositide-3-kinase (PI3-kinase)/Akt pathway, which is required for normal cell cycle progression in tumor cells. Loss of PI3-kinase/Akt signaling cannot be attributed to alterations in IGF expression, suggesting instead that signaling through the FSH receptor is attenuated. Gene expression profiling in the ovaries of Madh3–/– and Inha–/–:Madh3–/– compound knockout mice supports this hypothesis and further suggests that Smad3 is specifically required for FSH to activate PI3-kinase/Akt, but not protein kinase A. Together these observations imply that activin/Smad3 signaling is necessary for efficient signaling by FSH in Inha–/– tumor cells and that interruption of this pathway uncouples FSH from its intracellular mitogenic effectors.
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