An antiestrogen-responsive estrogen receptor-α mutant (D351Y) shows weak AF-2 activity in the presence of tamoxifen

Paul Webb, Phuong Nguyen, Cathleen Valentine, Ross V. Weatherman, Thomas S. Scanlan, Peter J. Kushner

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Antiestrogens, including tamoxifen and raloxifene, block estrogen receptor (ER) action by blocking the interactions of an estrogen-dependent activation function (AF-2) with p160 coactivators. Although tamoxifen does show some agonist activity in the presence of ERα, this stems from a distinct constitutive activation function (AF-1) that lies within the ERα N terminus. Previous studies identified a naturally occurring mutation (D351Y) that allows ERα to perceive tamoxifen and raloxifene as estrogens. Here, we examine the contributions of ERα activation functions to the D351Y pheno-type. We find that the AF-2 function of ERα D351Y lacks detectable tamoxifen-dependent activity when tested in isolation but does synergize with AF-1 to allow enhanced tamoxifen response. Weak tamoxifen-dependent interactions between the ERα D351Y AF-2 function and GRIP1, a representative p160, can be detected in glutathione S-transferase binding assays and mammalian two-hybrid assays. Furthermore, tamoxifen-dependent AF-2 activity can be detected in the presence of ERα D351Y and high levels of overexpressed GRIP1. We therefore propose that the D351Y mutation allows weak tamoxifen-dependent AF-2 activity but that this activity is only detectable when AF-1 is strong, and AF-1 and AF-2 synergize, or when p160s are overexpressed. We discuss the possible structural basis of this effect.

Original languageEnglish (US)
Pages (from-to)37552-37558
Number of pages7
JournalJournal of Biological Chemistry
Volume275
Issue number48
DOIs
StatePublished - Dec 1 2000

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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