title: Genetic removal of Smad3 from inhibin-null mice attenuates tumor progression by uncoupling extracellular mitogenic signals from the cell cycle machinery.
abstract: Inhibin and activin are members of the TGFbeta 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.
authors.affiliation: Cellular and Molecular Biology Graduate Program, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan 48109-2200, USA.
authors.forename: Brendan D
authors.initials: BD
authors.lastname: Looyenga
authors.forename: Gary D
authors.initials: GD
authors.lastname: Hammer
mesh_terms: D028341:Activins / Q000378:metabolism; D000302:Adrenal Cortex / Q000378:metabolism / Q000473:pathology; D000306:Adrenal Cortex Neoplasms / Q000235:genetics* / Q000473:pathology; D000818:Animals; D002453:Cell Cycle; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D056742:Cyclin D2; D016213:Cyclins / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D005640:Follicle Stimulating Hormone / Q000378:metabolism / Q000494:pharmacology; D020869:Gene Expression Profiling; D006062:Gonadotropins / Q000378:metabolism; D007265:Inhibins / Q000235:genetics / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics; D051900:Smad3 Protein / Q000235:genetics / Q000502:physiology*; D013736:Testicular Neoplasms / Q000235:genetics*
chemical_list: C486196:Ccnd2 protein, mouse; D056742:Cyclin D2; D016213:Cyclins; D006062:Gonadotropins; C472089:Mxd3 protein, mouse; D012097:Repressor Proteins; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C094377:inhibin-alpha subunit; D028341:Activins; D007265:Inhibins; D007334:Insulin-Like Growth Factor I; D005640:Follicle Stimulating Hormone; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt