This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Tong, W.
Right arrow Articles by Pollard, J. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tong, W.
Right arrow Articles by Pollard, J. W.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, March 1999, p. 2251-2264, Vol. 19, No. 3
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Progesterone Inhibits Estrogen-Induced Cyclin D1 and cdk4 Nuclear Translocation, Cyclin E- and Cyclin A-cdk2 Kinase Activation, and Cell Proliferation in Uterine Epithelial Cells in Mice

Wei Tong and Jeffrey W. Pollard*

Departments of Developmental and Molecular Biology and Obstetrics and Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, New York 10461

Received 7 July 1998/Returned for modification 17 August 1998/Accepted 24 November 1998

The response of the uterine epithelium to female sex steroid hormones provides an excellent model to study cell proliferation in vivo since both stimulation and inhibition of cell proliferation can be studied. Thus, when administered to ovariectomized adult mice 17beta -estradiol (E2) stimulates a synchronized wave of DNA synthesis and cell division in the epithelial cells, while pretreatment with progesterone (P4) completely inhibits this E2-induced cell proliferation. Using a simple method to isolate the uterine epithelium with high purity, we have shown that E2 treatment induces a relocalization of cyclin D1 and, to a lesser extent, cdk4 from the cytoplasm into the nucleus and results in the orderly activation of cyclin E- and cyclin A-cdk2 kinases and hyperphosphorylation of pRb and p107. P4 pretreatment did not alter overall levels of cyclin D1, cdk4, or cdk6 nor their associated kinase activities but instead inhibited the E2-induced nuclear localization of cyclin D1 to below the control level and, to a lesser extent, nuclear cdk4 levels, with a consequent inhibition of pRb and p107 phosphorylation. In addition, it abrogated E2-induced cyclin E-cdk2 activation by dephosphorylation of cdk2, followed by inhibition of cyclin A expression and consequently of cyclin A-cdk2 kinase activity and further inhibition of phosphorylation of pRb and p107. P4 is used therapeutically to oppose the effect of E2 during hormone replacement therapy and in the treatment of uterine adenocarcinoma. This study showing a novel mechanism of cell cycle inhibition by P4 may provide the basis for the development of new antiestrogens.

* Corresponding author. Mailing address: Departments of Developmental and Molecular Biology and Obstetrics and Gynecology and Women's Health, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Phone: (718) 430-2090. Fax: (718) 430-8567. E-mail: pollard{at}aecom.yu.edu.

Molecular and Cellular Biology, March 1999, p. 2251-2264, Vol. 19, No. 3
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Das, S. K (2009). Cell cycle regulatory control for uterine stromal cell decidualization in implantation. Reproduction 137: 889-899 [Abstract] [Full Text]  
  • Polotsky, A. J., Zhu, L., Santoro, N., Pollard, J. W. (2009). Lithium chloride treatment induces epithelial cell proliferation in xenografted human endometrium. Hum Reprod 0: dep115v1-dep115 [Abstract] [Full Text]  
  • Ray, S., Xu, F., Wang, H., Das, S. K. (2008). Cooperative Control via Lymphoid Enhancer Factor 1/T Cell Factor 3 and Estrogen Receptor-{alpha} for Uterine Gene Regulation by Estrogen. Mol. Endocrinol. 22: 1125-1140 [Abstract] [Full Text]  
  • Girling, J. E., Lederman, F. L., Walter, L. M., Rogers, P. A. W. (2007). Progesterone, But Not Estrogen, Stimulates Vessel Maturation in the Mouse Endometrium. Endocrinology 148: 5433-5441 [Abstract] [Full Text]  
  • Niklaus, A. L., Aubuchon, M., Zapantis, G., Li, P., Qian, H., Isaac, B., Kim, M. Y., Adel, G., Pollard, J. W., Santoro, N. F. (2007). Assessment of the proliferative status of epithelial cell types in the endometrium of young and menopausal transition women. Hum Reprod 22: 1778-1788 [Abstract] [Full Text]  
  • Ivanga, M., Labrie, Y., Calvo, E., Belleau, P., Martel, C., Luu-The, V., Morissette, J., Labrie, F., Durocher, F. (2007). Temporal analysis of E2 transcriptional induction of PTP and MKP and downregulation of IGF-I pathway key components in the mouse uterus. Physiol. Genomics 29: 13-23 [Abstract] [Full Text]  
  • Rider, V., Isuzugawa, K., Twarog, M., Jones, S., Cameron, B., Imakawa, K., Fang, J. (2006). Progesterone initiates Wnt-{beta}-catenin signaling but estradiol is required for nuclear activation and synchronous proliferation of rat uterine stromal cells. J Endocrinol 191: 537-548 [Abstract] [Full Text]  
  • Pan, H., Deng, Y., Pollard, J. W. (2006). Progesterone blocks estrogen-induced DNA synthesis through the inhibition of replication licensing. Proc. Natl. Acad. Sci. USA 103: 14021-14026 [Abstract] [Full Text]  
  • O'Brien, J. E., Peterson, T. J., Tong, M. H., Lee, E.-J., Pfaff, L. E., Hewitt, S. C., Korach, K. S., Weiss, J., Jameson, J. L. (2006). Estrogen-induced Proliferation of Uterine Epithelial Cells Is Independent of Estrogen Receptor {alpha} Binding to Classical Estrogen Response Elements. J. Biol. Chem. 281: 26683-26692 [Abstract] [Full Text]  
  • Ray, S., Hou, X., Zhou, H.-E., Wang, H., Das, S. K. (2006). Bip Is a Molecular Link between the Phase I and Phase II Estrogenic Responses in Uterus. Mol. Endocrinol. 20: 1825-1837 [Abstract] [Full Text]  
  • Shao, R., Weijdegard, B., Ljungstrom, K., Friberg, A., Zhu, C., Wang, X., Zhu, Y., Fernandez-Rodriguez, J., Egecioglu, E., Rung, E., Billig, H. (2006). Nuclear progesterone receptor A and B isoforms in mouse fallopian tube and uterus: implications for expression, regulation, and cellular function. Am. J. Physiol. Endocrinol. Metab. 291: E59-E72 [Abstract] [Full Text]  
  • Velarde, M. C., Geng, Y., Eason, R. R., Simmen, F. A., Simmen, R. C.M. (2005). Null Mutation of Kruppel-Like Factor9/Basic Transcription Element Binding Protein-1 Alters Peri-Implantation Uterine Development in Mice. Biol. Reprod. 73: 472-481 [Abstract] [Full Text]  
  • Chen, B., Pan, H., Zhu, L., Deng, Y., Pollard, J. W. (2005). Progesterone Inhibits the Estrogen-Induced Phosphoinositide 3-Kinase->AKT->GSK-3{beta}->Cyclin D1->pRB Pathway to Block Uterine Epithelial Cell Proliferation. Mol. Endocrinol. 19: 1978-1990 [Abstract] [Full Text]  
  • Walter, L. M, Rogers, P. A W, Girling, J. E (2005). The role of progesterone in endometrial angiogenesis in pregnant and ovariectomised mice. Reproduction 129: 765-777 [Abstract] [Full Text]  
  • Yue, L., Daikoku, T., Hou, X., Li, M., Wang, H., Nojima, H., Dey, S. K., Das, S. K. (2005). Cyclin G1 and Cyclin G2 Are Expressed in the Periimplantation Mouse Uterus in a Cell-Specific and Progesterone-Dependent Manner: Evidence for Aberrant Regulation with Hoxa-10 Deficiency. Endocrinology 146: 2424-2433 [Abstract] [Full Text]  
  • Skildum, A., Faivre, E., Lange, C. A. (2005). Progesterone Receptors Induce Cell Cycle Progression via Activation of Mitogen-Activated Protein Kinases. Mol. Endocrinol. 19: 327-339 [Abstract] [Full Text]  
  • Lahav-Baratz, S., Ben-Izhak, O., Sabo, E., Ben-Eliezer, S., Lavie, O., Ishai, D., Ciechanover, A., Dirnfeld, M. (2004). Decreased level of the cell cycle regulator p27 and increased level of its ubiquitin ligase Skp2 in endometrial carcinoma but not in normal secretory or in hyperstimulated endometrium. Mol Hum Reprod 10: 567-572 [Abstract] [Full Text]  
  • Carta, L., Sassoon, D. (2004). Wnt7a Is a Suppressor of Cell Death in the Female Reproductive Tract and Is Required for Postnatal and Estrogen-Mediated Growth. Biol. Reprod. 71: 444-454 [Abstract] [Full Text]  
  • Spencer, T. E., Johnson, G. A., Burghardt, R. C., Bazer, F. W. (2004). Progesterone and Placental Hormone Actions on the Uterus: Insights from Domestic Animals. Biol. Reprod. 71: 2-10 [Abstract] [Full Text]  
  • Furlow, J. D., Yang, H. Y., Hsu, M., Lim, W., Ermio, D. J., Chiellini, G., Scanlan, T. S. (2004). Induction of Larval Tissue Resorption in Xenopus laevis Tadpoles by the Thyroid Hormone Receptor Agonist GC-1. J. Biol. Chem. 279: 26555-26562 [Abstract] [Full Text]  
  • Davison, E. A., Lee, C. S. L., Naylor, M. J., Oakes, S. R., Sutherland, R. L., Hennighausen, L., Ormandy, C. J., Musgrove, E. A. (2003). The Cyclin-Dependent Kinase Inhibitor p27 (Kip1) Regulates Both DNA Synthesis and Apoptosis in Mammary Epithelium But Is Not Required for Its Functional Development during Pregnancy. Mol. Endocrinol. 17: 2436-2447 [Abstract] [Full Text]  
  • Rider, V., Thomson, E., Seifert, C. (2003). Transit of Rat Uterine Stromal Cells through G1 Phase of the Cell Cycle Requires Temporal and Cell-Specific Hormone-Dependent Changes on Cell Cycle Regulators. Endocrinology 144: 5450-5458 [Abstract] [Full Text]  
  • Hewitt, S. C., Deroo, B. J., Hansen, K., Collins, J., Grissom, S., Afshari, C. A., Korach, K. S. (2003). Estrogen Receptor-Dependent Genomic Responses in the Uterus Mirror the Biphasic Physiological Response to Estrogen. Mol. Endocrinol. 17: 2070-2083 [Abstract] [Full Text]  
  • Lee, W.-S., Liu, C.-W., Juan, S.-H., Liang, Y.-C., Ho, P.-Y., Lee, Y.-H. (2003). Molecular Mechanism of Progesterone-Induced Antiproliferation in Rat Aortic Smooth Muscle Cells. Endocrinology 144: 2785-2790 [Abstract] [Full Text]  
  • Lobenhofer, E. K., Bennett, L., Cable, P. L., Li, L., Bushel, P. R., Afshari, C. A. (2002). Regulation of DNA Replication Fork Genes by 17{beta}-Estradiol. Mol. Endocrinol. 16: 1215-1229 [Abstract] [Full Text]  
  • Buchanan, D. L., Ohsako, S., Tohyama, C., Cooke, P. S., Iguchi, T. (2002). Dioxin Inhibition of Estrogen-Induced Mouse Uterine Epithelial Mitogenesis Involves Changes in Cyclin and Transforming Growth Factor-{beta} Expression. Toxicol Sci 66: 62-68 [Abstract] [Full Text]  
  • Dolci, S., Pellegrini, M., Di Agostino, S., Geremia, R., Rossi, P. (2001). Signaling through Extracellular Signal-regulated Kinase Is Required for Spermatogonial Proliferative Response to Stem Cell Factor. J. Biol. Chem. 276: 40225-40233 [Abstract] [Full Text]  
  • Marcantonio, D., Chalifour, L. E., Alaoui-Jamali, M. A., Alpert, L., Huynh, H. T. (2001). Cloning and Characterization of a Novel Gene That Is Regulated by Estrogen and Is Associated with Mammary Gland Carcinogenesis. Endocrinology 142: 2409-2418 [Abstract] [Full Text]  
  • Foster, J. S., Henley, D. C., Bukovsky, A., Seth, P., Wimalasena, J. (2001). Multifaceted Regulation of Cell Cycle Progression by Estrogen: Regulation of Cdk Inhibitors and Cdc25A Independent of Cyclin D1-Cdk4 Function. Mol. Cell. Biol. 21: 794-810 [Abstract] [Full Text]  
  • Santoro, N., Goldsmith, L. T., Heller, D., Illsley, N., McGovern, P., Molina, C., Peters, S., Skurnick, J. H., Forst, C., Weiss, G. (2000). Luteal Progesterone Relates to Histological Endometrial Maturation in Fertile Women. J. Clin. Endocrinol. Metab. 85: 4207-4211 [Abstract] [Full Text]  
  • Swarbrick, A., Lee, C. S. L., Sutherland, R. L., Musgrove, E. A. (2000). Cooperation of p27Kip1 and p18INK4c in Progestin-Mediated Cell Cycle Arrest in T-47D Breast Cancer Cells. Mol. Cell. Biol. 20: 2581-2591 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»