| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
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.
This article has been cited by other articles:
![]() |
M. A. Edson, A. K. Nagaraja, and M. M. Matzuk The Mammalian Ovary from Genesis to Revelation Endocr. Rev., October 1, 2009; 30(6): 624 - 712. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. C. Kim, F. M. Barlaskar, J. H. Heaton, T. Else, V. R. Kelly, K. T. Krill, J. O. Scheys, D. P. Simon, A. Trovato, W.-H. Yang, et al. In Search of Adrenocortical Stem and Progenitor Cells Endocr. Rev., May 1, 2009; 30(3): 241 - 263. [Abstract] [Full Text] [PDF] |
||||
![]() |
F. M. Barlaskar, A. C. Spalding, J. H. Heaton, R. Kuick, A. C. Kim, D. G. Thomas, T. J. Giordano, E. Ben-Josef, and G. D. Hammer Preclinical Targeting of the Type I Insulin-Like Growth Factor Receptor in Adrenocortical Carcinoma J. Clin. Endocrinol. Metab., January 1, 2009; 94(1): 204 - 212. [Abstract] [Full Text] [PDF] |
||||
![]() |
Q. Li, S. A. Pangas, C. J. Jorgez, J. M. Graff, M. Weinstein, and M. M. Matzuk Redundant Roles of SMAD2 and SMAD3 in Ovarian Granulosa Cells In Vivo Mol. Cell. Biol., December 1, 2008; 28(23): 7001 - 7011. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. A. Pangas, X. Li, L. Umans, A. Zwijsen, D. Huylebroeck, C. Gutierrez, D. Wang, J. F. Martin, S. P. Jamin, R. R. Behringer, et al. Conditional Deletion of Smad1 and Smad5 in Somatic Cells of Male and Female Gonads Leads to Metastatic Tumor Development in Mice Mol. Cell. Biol., January 1, 2008; 28(1): 248 - 257. [Abstract] [Full Text] [PDF] |
||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |