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The Pure Estrogen Receptor Antagonist ICI 182,780 Promotes a Novel Interaction of Estrogen Receptor- with the 3',5'-Cyclic Adenosine Monophosphate Response Element-Binding Protein-Binding Protein/p300 Coactivators

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

Address all correspondence and requests for reprints to: Carolyn L. Smith, Ph.D., Molecular and Cellular Biology, One Baylor Plaza, Houston, Texas 77030. E-mail: carolyns{at}bcm.tmc.edu.

Estrogen receptor- (ER) is a member of the nuclear receptor superfamily of ligand-activated transcription factors. Abundant evidence demonstrates that ER agonists promote, whereas antagonists inhibit, receptor binding to coactivators. In this report we demonstrate that binding of the ICI 182,780 (ICI) pure antiestrogen to ER promotes its interaction with the cAMP response element-binding protein-binding protein (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 ligand-binding domain revealed that CBP binds to this region of the ICI-liganded receptor. The carboxy-terminal cysteine-histidine rich domain 3 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. Chromatin immunoprecipitation 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. Chromatin immunoprecipitation assays for pS2 and cytochrome P450 1B1 promoter regions revealed that ICI-dependent recruitment of CBP, but not receptor, to ER targets is gene specific. ICI treatment did not recruit the steroid receptor coactivator 1 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 steroid receptor coactivator 1 to ER is insufficient to promote transcription of ER target genes.

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