| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on July 6, 2004
Accepted on April 12, 2005
-> Cyclin D1 ->pRB Pathway to Block Uterine Epithelial Cell Proliferation
Departments of Developmental and Molecular Biology and Obstetrics, Gynecology and Women's Health, Center for the Study of Reproductive Biology and Women's Health, Albert Einstein College of Medicine, 1300 Morris Park, New York, New York, 10461, USA
* To whom correspondence should be addressed. E-mail: pollard{at}aecom.yu.edu.
The mammalian cell cycle is regulated by the cyclin/cyclin-dependent kinase (CDK) phosphorylation of the retinoblastoma (pRB) family of proteins. Cyclin D1 with its CDK4/6 partners initiates the cell cycle and acts as the link between extra-cellular signals and the cell cycle machinery. Estradiol-17
(E2) stimulates uterine epithelial cell proliferation, a process that is completely inhibited by pre-treatment with progesterone (P4). Previously we identified cyclin D1 localization as a key point of regulation in these cells with E2 causing its nuclear accumulation and P4 retaining it in the cytoplasm with the resultant inhibition of pRB phosphorylation. Here we show that E2 stimulates phosphoinositide (PI) 3-kinase to activate phosphokinase B (PKB/AKT) to effect an inhibitory phosphorylation of glycogen synthase kinase (GSK-3). This pathway is suppressed by P4. Inhibition of the GSK-3 activity in P4 treated uteri by the specific inhibitor, LiCl, reversed the nuclear accumulation of cyclin D1 and in doing so, caused pRB phosphorylation and the induction of downstream genes, proliferating cell nuclear antigen (PCNA) and Ki67. Conversely inhibition of PI3 kinase by LY294002 or Wortmanin reversed the E2-induced GSK-3 Ser (9) inhibitory phosphrylation and blocked nuclear accumulation of cyclin D1. These data show the reciprocal actions of E2 and P4 on the PI3-kinase through to the GSK-3 pathway that in turn regulates cyclin D1 localization and cell cycle progression. These data reveal a novel signaling pathway which links E2 and P4 action to growth factor-mediated signaling in the uterus.
•
AKT •
uterus •
mouse
This article has been cited by other articles:
 |
|
 |
|
  F. J. Steyn, G. M. Anderson, and D. R. Grattan Hormonal Regulation of Suppressors of Cytokine Signaling (SOCS) Messenger Ribonucleic Acid in the Arcuate Nucleus during Late Pregnancy Endocrinology, June 1, 2008; 149(6): 3206 - 3214. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Zhu and J. W. Pollard Estradiol-17beta regulates mouse uterine epithelial cell proliferation through insulin-like growth factor 1 signaling PNAS, October 2, 2007; 104(40): 15847 - 15851. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M.S. Bartlett, I. O. Ellis, M. Dowsett, E. A. Mallon, D. A. Cameron, S. Johnston, E. Hall, R. A'Hern, C. Peckitt, J. M. Bliss, et al. Human Epidermal Growth Factor Receptor 2 Status Correlates With Lymph Node Involvement in Patients With Estrogen Receptor (ER) Negative, but With Grade in Those With ER-Positive Early-Stage Breast Cancer Suitable for Cytotoxic Chemotherapy J. Clin. Oncol., October 1, 2007; 25(28): 4423 - 4430. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Kazi and R. D. Koos Estrogen-Induced Activation of Hypoxia-Inducible Factor-1{alpha}, Vascular Endothelial Growth Factor Expression, and Edema in the Uterus Are Mediated by the Phosphatidylinositol 3-Kinase/Akt Pathway Endocrinology, May 1, 2007; 148(5): 2363 - 2374. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Yang, Y. Zhang, Y. Li, Z. Wu, and D. Zhu Myostatin Induces Cyclin D1 Degradation to Cause Cell Cycle Arrest through a Phosphatidylinositol 3-Kinase/AKT/GSK-3beta Pathway and Is Antagonized by Insulin-like Growth Factor 1 J. Biol. Chem., February 9, 2007; 282(6): 3799 - 3808. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Rider, K. Isuzugawa, M. Twarog, S. Jones, B. Cameron, K. Imakawa, and J. Fang Progesterone initiates Wnt-{beta}-catenin signaling but estradiol is required for nuclear activation and synchronous proliferation of rat uterine stromal cells J. Endocrinol., December 1, 2006; 191(3): 537 - 548. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Pan, L. Zhu, Y. Deng, and J. W. Pollard Microarray Analysis of Uterine Epithelial Gene Expression during the Implantation Window in the Mouse Endocrinology, October 1, 2006; 147(10): 4904 - 4916. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Pan, Y. Deng, and J. W. Pollard Progesterone blocks estrogen-induced DNA synthesis through the inhibition of replication licensing PNAS, September 19, 2006; 103(38): 14021 - 14026. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Salameh, J. P. Helliwell, G. Han, L. McPhaul, and O. Khorram Expression of endometrial glycogen synthase kinase-3{beta} protein throughout the menstrual cycle and its regulation by progesterone Mol. Hum. Reprod., September 1, 2006; 12(9): 543 - 549. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
