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 Park, S.-E.
Right arrow Articles by Katzenellenbogen, B. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Park, S.-E.
Right arrow Articles by Katzenellenbogen, B. S.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, March 2005, p. 1989-1999, Vol. 25, No. 5
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.5.1989-1999.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Genetic Deletion of the Repressor of Estrogen Receptor Activity (REA) Enhances the Response to Estrogen in Target Tissues In Vivo

Seong-Eun Park,1 Jianming Xu,2 Antonina Frolova,1 Lan Liao,2 Bert W. O'Malley,2 and Benita S. Katzenellenbogen1*

Department of Molecular and Integrative Physiology, University of Illinois, Urbana, Illinois,1 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas2

Received 25 August 2004/ Returned for modification 10 October 2004/ Accepted 1 December 2004

We previously identified a coregulator, repressor of estrogen receptor activity (REA), that directly interacts with estrogen receptor (ER) and represses ER transcriptional activity. Decreasing the intracellular level of REA by using small interfering RNA knockdown or antisense RNA approaches in cells in culture resulted in a significant increase in the level of up-regulation of estrogen-stimulated genes. To elucidate the functional activities of REA in vivo, we have used targeted disruption to delete the REA gene in mice. The targeting vector eliminated, by homologous recombination, the REA exon sequences encoding amino acids 12 to 201, which are required for REA repressive activity and for interaction with ER. The viability of heterozygous animals was similar to that of the wild type, whereas homozygous animals did not develop, suggesting a crucial role for REA in early development. Female, but not male, heterozygous animals had an increased body weight relative to age-matched wild-type animals beginning after puberty. REA mRNA and protein levels in uteri of heterozygous animals were half that of the wild type, and studies with heterozygous animals revealed a greater uterine weight gain and epithelial hyperproliferation in response to estradiol (E2) and a substantially greater stimulation by E2 of a number of estrogen up-regulated genes in the uterus. Even more dramatic in REA heterozygous animals was the loss of down regulation by E2 of genes in the uterus that are normally repressed by estrogen in wild-type animals. Mouse embryo fibroblasts derived from heterozygous embryos also displayed a greater transcriptional response to E2. These studies demonstrate that REA is a significant modulator of estrogen responsiveness in vivo: it normally restrains estrogen actions, moderating ER stimulation and enhancing ER repression of E2-regulated genes.

* Corresponding author. Mailing address: University of Illinois, Department of Molecular and Integrative Physiology, 524 Burrill Hall, 407 South Goodwin Ave., Urbana, IL 61801-3704. Phone: (217) 333-9769. Fax: (217) 244-9906. E-mail: katzenel{at}uiuc.edu.

Molecular and Cellular Biology, March 2005, p. 1989-1999, Vol. 25, No. 5
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.5.1989-1999.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Cao, G., van der Wijst, J., van der Kemp, A., van Zeeland, F., Bindels, R. J., Hoenderop, J. G. (2009). Regulation of the Epithelial Mg2+ Channel TRPM6 by Estrogen and the Associated Repressor Protein of Estrogen Receptor Activity (REA). J. Biol. Chem. 284: 14788-14795 [Abstract] [Full Text]  
  • Pabona, J M P, Velarde, M C, Zeng, Z, Simmen, F A, Simmen, R C M (2009). Nuclear receptor co-regulator Kruppel-like factor 9 and prohibitin 2 expression in estrogen-induced epithelial cell proliferation in the mouse uterus. J Endocrinol 200: 63-73 [Abstract] [Full Text]  
  • Ross, J. A., Nagy, Z. S., Kirken, R. A. (2008). The PHB1/2 Phosphocomplex Is Required for Mitochondrial Homeostasis and Survival of Human T Cells. J. Biol. Chem. 283: 4699-4713 [Abstract] [Full Text]  
  • Merkwirth, C., Dargazanli, S., Tatsuta, T., Geimer, S., Lower, B., Wunderlich, F. T., von Kleist-Retzow, J.-C., Waisman, A., Westermann, B., Langer, T. (2008). Prohibitins control cell proliferation and apoptosis by regulating OPA1-dependent cristae morphogenesis in mitochondria. Genes Dev. 22: 476-488 [Abstract] [Full Text]  
  • He, B., Feng, Q., Mukherjee, A., Lonard, D. M., DeMayo, F. J., Katzenellenbogen, B. S., Lydon, J. P., O'Malley, B. W. (2008). A Repressive Role for Prohibitin in Estrogen Signaling. Mol. Endocrinol. 22: 344-360 [Abstract] [Full Text]  
  • Kasashima, K., Ohta, E., Kagawa, Y., Endo, H. (2006). Mitochondrial Functions and Estrogen Receptor-dependent Nuclear Translocation of Pleiotropic Human Prohibitin 2. J. Biol. Chem. 281: 36401-36410 [Abstract] [Full Text]  
  • Mussi, P., Liao, L., Park, S.-E., Ciana, P., Maggi, A., Katzenellenbogen, B. S., Xu, J., O'Malley, B. W. (2006). Haploinsufficiency of the corepressor of estrogen receptor activity (REA) enhances estrogen receptor function in the mammary gland. Proc. Natl. Acad. Sci. USA 103: 16716-16721 [Abstract] [Full Text]  
  • Zubovych, I., Doundoulakis, T., Harran, P. G., Roth, M. G. (2006). A missense mutation in Caenorhabditis elegans prohibitin 2 confers an atypical multidrug resistance. Proc. Natl. Acad. Sci. USA 103: 15523-15528 [Abstract] [Full Text]  
  • Corcoran, D, Fair, T, Park, S, Rizos, D, Patel, O V, Smith, G W, Coussens, P M, Ireland, J J, Boland, M P, Evans, A C O, Lonergan, P (2006). Suppressed expression of genes involved in transcription and translation in in vitro compared with in vivo cultured bovine embryos.. Reproduction 131: 651-660 [Abstract] [Full Text]  
  • Rastogi, S., Joshi, B., Fusaro, G., Chellappan, S. (2006). Camptothecin Induces Nuclear Export of Prohibitin Preferentially in Transformed Cells through a CRM-1-dependent Mechanism. J. Biol. Chem. 281: 2951-2959 [Abstract] [Full Text]  
  • Hall, J. M., McDonnell, D. P. (2005). Coregulators in Nuclear Estrogen Receptor Action: From Concept to Therapeutic Targeting. Mol. Interv. 5: 343-357 [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»