| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Institut für Zellbiologie (Tumorforschung) Universitätsklinikum Essen D-45122 Essen, Germany
Elevated cAMP has been shown to unmask agonist activity of antiprogestin/antiglucocorticoid RU486. In our search for cellular target genes induced through this cross-talk mechanism, we identified human insulin receptor substrate-2 (IRS-2), a cytoplasmic signaling molecule that mediates effects of insulin, insulin-like growth factor-1 (IGF-I), and other cytokines by acting as a molecular adaptor between diverse receptor tyrosine kinases and downstream effectors. Our analysis of the regulation of IRS-2 in HeLa cell models shows that synergistic induction of IRS-2 by cAMP and RU486 can be mediated by progesterone receptors (PR) and glucocorticoid receptors (GR) and occurs through a relative slow mechanism that requires ongoing protein synthesis. Importantly, we demonstrate that IRS-2 mRNA is also inducible by progesterone, while glucocorticoid effects are only observed in the presence of cAMP. Up-regulation of IRS-2 by progesterone depends strictly on the presence of PR and occurs through a rapid mechanism, suggesting that it represents a primary transcriptional response. Furthermore, we show that expression of IRS-1, which also binds to receptors of insulin, IGF-I, and cytokines, is unaffected by progesterone. Thus, our results demonstrate that progesterone alters the ratio of IRS-1 and IRS-2 in PR-positive cells and implicate a mechanism through which progesterone can modulate the effects of insulin, IGF-I, and cytokines on cell proliferation, differentiation, and homeostasis.
This article has been cited by other articles:
 |
|
 |
|
  Y. H. Ibrahim, S. A. Byron, X. Cui, A. V. Lee, and D. Yee Progesterone Receptor-B Regulation of Insulin-Like Growth Factor-Stimulated Cell Migration in Breast Cancer Cells via Insulin Receptor Substrate-2 Mol. Cancer Res., September 1, 2008; 6(9): 1491 - 1498. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Liu, A. Deschamps, K. S. Korach, and E. Murphy Estrogen-Enhanced Gene Expression of Lipoprotein Lipase in Heart Is Antagonized by Progesterone Endocrinology, February 1, 2008; 149(2): 711 - 716. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Yamamoto, M. L. Cremona, and J. E. Rothman Autophagy-mediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway J. Cell Biol., February 27, 2006; 172(5): 719 - 731. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Nagle, Z. Ma, M. A. Byrne, M. F. White, and L. M. Shaw Involvement of Insulin Receptor Substrate 2 in Mammary Tumor Metastasis Mol. Cell. Biol., November 15, 2004; 24(22): 9726 - 9735. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. McMorran, L. Town, E. Costelloe, J. Palmer, J. Engel, D. Hume, and B. Wainwright Effector ExoU from the Type III Secretion System Is an Important Modulator of Gene Expression in Lung Epithelial Cells in Response to Pseudomonas aeruginosa Infection Infect. Immun., October 1, 2003; 71(10): 6035 - 6044. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. V. Lee, P. Zhang, M. Ivanova, S. Bonnette, S. Oesterreich, J. M. Rosen, S. Grimm, R. C. Hovey, B. K. Vonderhaar, C. R. Kahn, et al. Developmental and Hormonal Signals Dramatically Alter the Localization and Abundance of Insulin Receptor Substrate Proteins in the Mammary Gland Endocrinology, June 1, 2003; 144(6): 2683 - 2694. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. R. Wick, E. D. Werner, P. Langlais, F. J. Ramos, L. Q. Dong, S. E. Shoelson, and F. Liu Grb10 Inhibits Insulin-stimulated Insulin Receptor Substrate (IRS)-Phosphatidylinositol 3-Kinase/Akt Signaling Pathway by Disrupting the Association of IRS-1/IRS-2 with the Insulin Receptor J. Biol. Chem., February 28, 2003; 278(10): 8460 - 8467. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. G. Richards, D. M. Klotz, M. R. Bush, D. K. Walmer, and R. P. DiAugustine E2-Induced Degradation of Uterine Insulin Receptor Substrate-2: Requirement for an IGF-I-Stimulated, Proteasome-Dependent Pathway Endocrinology, September 1, 2001; 142(9): 3842 - 3849. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Hadsell, T. Alexeenko, Y. Klemintidis, D. Torres, and A. V. Lee Inability of Overexpressed des(1-3)Human Insulin-Like Growth Factor I (IGF-I) to Inhibit Forced Mammary Gland Involution Is Associated with Decreased Expression of IGF Signaling Molecules Endocrinology, April 1, 2001; 142(4): 1479 - 1488. [Abstract] [Full Text]
|
|
|
|
 |
|
 U. SMITH, S. GOGG, A. JOHANSSON, T. OLAUSSON, V. ROTTER, and B. SVALSTEDT Thiazolidinediones (PPAR{gamma} agonists) but not PPAR{alpha} agonists increase IRS-2 gene expression in 3T3-L1 and human adipocytes FASEB J, January 1, 2001; 15(1): 215 - 220. [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 |
