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This version published online on July 13, 2006
Molecular Endocrinology, doi:10.1210/me.2005-0218
A more recent version of this article appeared on November 1, 2006
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Submitted on June 1, 2005
Accepted on July 6, 2006

The Pure Estrogen Receptor Antagonist ICI 182,780 Promotes a Novel Interaction of Estrogen Receptor-{alpha} with the CBP/p300 Coactivators

Basem M. Jaber, Tong Gao, Luping Huang, Sudipan Karmakar, and Carolyn L. Smith*

Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030

* To whom correspondence should be addressed. E-mail: carolyns{at}bcm.tmc.edu.

Estrogen receptor-{alpha} (ER{alpha}) is a member of the nuclear receptor superfamily of ligand-activated transcription factors. Abundant evidence demonstrates that ER{alpha} agonists promote while antagonists inhibit receptor binding to coactivators. In this report we demonstrate that binding of the ICI 182,780 (ICI) pure antiestrogen to ER{alpha} promotes its interaction with the CBP/p300 but not the p160 family of coactivators, demonstrating the specificity of this interaction. Amino acid mutations within the coactivator binding surface of the ER{alpha} ligand binding domain (LBD) revealed that CBP binds to this region of the ICI-liganded receptor. The carboxy-terminal CH3 domain of CBP rather than its amino-terminal nuclear interacting domain, shown previously to mediate agonist-dependent interactions of CBP with nuclear receptors, is required for binding to ICI-liganded ER{alpha}. Chromatin immunoprecipitation (ChIP) assays revealed that ICI but not the partial agonist/antagonist 4-hydroxytamoxifen is able to recruit CBP to the pS2 promoter and this distinguishes ICI from this class of antiestrogens. ChIP assays for pS2 and CYP1B1 promoter regions revealed that ICI-dependent recruitment of CBP, but not receptor, to ER{alpha} targets is gene-specific. ICI treatment did not recruit the SRC-1 coactivator to the pS2 promoter, and it failed to induce the expression of this gene. Taken together these data indicate that recruitment of the CBP coactivator/cointegrator without SRC-1 to ER{alpha} is insufficient to promote transcription of ER{alpha} target genes.
Key words: ER{alpha} • CBP • antagonist • coactivator • receptor

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ
Coregulators:   CBP  |  p300  |  SRC-1  |  GRIP1  |  AIB1
Ligands:   17β-Estradiol  |  4-Hydroxytamoxifen  |  Raloxifene  |  Fulvestrant



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