Raloxifene and ICI182,780 increase estrogen receptor-alpha association with a nuclear compartment via overlapping sets of hydrophobic amino acids in activation function 2 helix 12.

Raloxifene and ICI182,780 increase estrogen receptor-alpha association with a nuclear compartment via overlapping sets of hydrophobic amino acids in activation function 2 helix 12. Research Abstract Details 

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Raloxifene and ICI182,780 increase estrogen receptor-alpha association with a nuclear compartment via overlapping sets of hydrophobic amino acids in activation function 2 helix 12. Abstract Text:

Mathieu Lupien,M Jeyakumar,Elise ,Khalid Hilmi,David Cotnoir-White,Caroline Loch,Anick Auger,Guila Dayan, Pinard,Jean-Marie Wurtz,Dino Moras,John Katzenellenbogen,Sylvie Mader,

The basis for the differential repressive effects of antiestrogens on transactivation by estrogen receptor-alpha (ERalpha) remains incompletely understood. Here, we show that the full antiestrogen ICI182,780 and, to a lesser extent, the selective ER modulator raloxifene (Ral), induce accumulation of exogenous ERalpha in a poorly soluble fraction in transiently transfected HepG2 or stably transfected MDA-MB231 cells and of endogenous receptor in MCF7 cells. ERalpha remained nuclear in HepG2 cells treated with either compound. Replacement of selected hydrophobic residues of ERalpha ligand-binding domain helix 12 (H12) enhanced receptor solubility in the presence of ICI182,780 or Ral. These mutations also increased transcriptional activity with Ral or ICI182,780 on reporter genes or on the endogenous estrogen target gene TFF1 in a manner requiring the integrity of the N-terminal AF-1 domain. The antiestrogen-specific effects of single mutations suggest that they affect receptor function by mechanisms other than a simple decrease in hydrophobicity of H12, possibly due to relief from local steric hindrance between these residues and the antiestrogen side chains. Fluorescence anisotropy experiments indicated an enhanced regional stabilization of mutant ligand-binding domains in the presence of antiestrogens. H12 mutations also prevent the increase in bioluminescence resonance energy transfer between ERalpha monomers induced by Ral or ICI182,780 and increase intranuclear receptor mobility in correlation with transcriptional activity in the presence of these antiestrogens. Our data indicate that ICI182,780 and Ral locally alter the ERalpha ligand binding structure via specific hydrophobic residues of H12 and decrease its transcriptional activity through tighter association with an insoluble nuclear structure.

Raloxifene and ICI182,780 increase estrogen receptor-alpha association with a nuclear compartment via overlapping sets of hydrophobic amino acids in activation function 2 helix 12. Publishing Authors By Initials

M Lupien,M Jeyakumar,E ,K Hilmi,D Cotnoir-White,C Loch,A Auger,G Dayan,GA Pinard,JM Wurtz,D Moras,J Katzenellenbogen,S Mader,

For similar proteins: neoplasm proteins: tumor suppressor proteins research abstracts see: proteins: neoplasm proteins: tumor suppressor proteins research

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Raloxifene and ICI182,780 increase estrogen receptor-alpha association with a nuclear compartment via overlapping sets of hydrophobic amino acids in activation function 2 helix 12. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Molecular endocrinology (Baltimore, Md.)

VOLUME: 21

Page Numbers: 797-816

Journal Abbreviation: Mol. Endocrinol.

ISSN: 0888-8809

DAY: 13

MONTH: 02

YEAR: 2007

Raloxifene and ICI182,780 increase estrogen receptor-alpha association with a nuclear compartment via overlapping sets of hydrophobic amino acids in activation function 2 helix 12. Information

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LANGUAGE: eng

NlmUniqueID: 8801431

Raloxifene and ICI182,780 increase estrogen receptor-alpha association with a nuclear compartment via overlapping sets of hydrophobic amino acids in activation function 2 helix 12. Keywords Mesh Terms:

KEYWORDS: Tumor Suppressor Proteins

MESH TERMS: genetics

Chemical & Substance for Abstract: Raloxifene and ICI182,780 increase estrogen receptor-alpha association with a nuclear compartment via overlapping sets of hydrophobic amino acids in activation function 2 helix 12. Information

Substance Name: Raloxifene

Registry Number: 84449-90-1

Grant and Affiliation Information for Raloxifene and ICI182,780 increase estrogen receptor-alpha association with a nuclear compartment via overlapping sets of hydrophobic amino acids in activation function 2 helix 12.

AFFILIATION: Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, Québec, Canada.

Country: United States

AGENCY: United States NIDDK

GRANT: 5R37 DK15556

ACRONYM: DK

MEDLINETA: Mol Endocrinol

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