MCB
Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
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 Chen, D.
Right arrow Articles by Ali, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chen, D.
Right arrow Articles by Ali, S.

Molecular and Cellular Biology, February 1999, p. 1002-1015, Vol. 19, No. 2
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Phosphorylation of Human Estrogen Receptor alpha  by Protein Kinase A Regulates Dimerization

Dongsheng Chen, Paul E. Pace, R. Charles Coombes, and Simak Ali*

CRC Laboratories, Department of Cancer Medicine, Division of Medicine, Imperial College of Science, Technology and Medicine, London W6 8RP, United Kingdom

Received 18 September 1998/Accepted 29 October 1998

Phosphorylation provides an important mechanism by which transcription factor activity is regulated. Estrogen receptor alpha  (ERalpha ) is phosphorylated on multiple sites, and stimulation of a number of growth factor receptors and/or protein kinases leads to ligand-independent and/or synergistic increase in transcriptional activation by ERalpha in the presence of estrogen. Here we show that ERalpha is phosphorylated by protein kinase A (PKA) on serine-236 within the DNA binding domain. Mutation of serine-236 to glutamic acid prevents DNA binding by inhibiting dimerization by ERalpha , whereas mutation to alanine has little effect on DNA binding or dimerization. Furthermore, PKA overexpression or activation of endogenous PKA inhibits dimerization in the absence of ligand. This inhibition is overcome by the addition of 17beta -estradiol or the partial agonist 4-hydroxy tamoxifen. Interestingly, treatment with the complete antagonist ICI 182,780 does not overcome the inhibitory effect of PKA activation. Our results indicate that in the absence of ligand ERalpha forms dimers through interaction between DNA binding domains and that dimerization mediated by the ligand binding domain only occurs upon ligand binding but that the complete antagonist ICI 182,780 prevents dimerization through the ligand-binding domain. Heterodimer formation between ERalpha and ERbeta is similarly affected by PKA phosphorylation of serine 236 of ERalpha . However, 4-hydroxytamoxifen is unable to overcome inhibition of dimerization by PKA. Thus, phosphorylation of ERalpha in the DNA binding domain provides a mechanism by which dimerization and thereby DNA binding by the estrogen receptor is regulated.

* Corresponding author. Mailing address: CRC Laboratories, Department of Cancer Medicine, Division of Medicine, Imperial College of Science, Technology, and Medicine, Charing Cross Campus, St. Dunstan's Rd., London W6 8RP, United Kingdom. Phone: 44-0181-846-1413. Fax: 44-0181-846-1413. E-mail: simak.ali{at}ic.ac.uk.

Molecular and Cellular Biology, February 1999, p. 1002-1015, Vol. 19, No. 2
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:



Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
J. Bacteriol. J. Virol. Eukaryot. Cell
Microbiol. Mol. Biol. Rev. Clin. Vaccine Immunol. All ASM Journals

Copyright © 1999 by the American Society for Microbiology. All rights reserved.