Coactivator and corepressor regulation of the agonist/antagonist activity of the mixed antiestrogen, 4-hydroxytamoxifen

Carolyn L. Smith, Zafar Nawaz, Bert W. O'Malley

Research output: Contribution to journalArticle

573 Citations (Scopus)

Abstract

Mixed antiestrogens, such as 4-hydroxytamoxifen (4HT), act as either partial agonists or antagonists of estrogen receptor (ER) function in a tissue-, cell-, and promoter-specific manner, suggesting that intracellular factors modulate their ability to regulate transcription. To determine whether coactivators and corepressors have the capacity to modulate the relative agonist/antagonist activity of 4HT, ER-dependent gene expression was measured in the absence or presence of expression vectors for SRC-1 (steroid receptor coactivator-1) or SMRT (silencing mediator of retinoic acid and thyroid hormone receptors). In Hep G2 cells in which 4HT is an agonist, exogenous SRC-1 enhanced estradiol (E2)- and 4HT-stimulated transcription in a dose-dependent manner, while SMRT overexpression strongly reduced basal and 4HT-stimulated gene expression with no effect on E2 activity. These observations were not cell- or promoter-specific inasmuch as similar results were obtained in HeLa cells under conditions in which 4HT is an antagonist. A protein-protein interaction assay indicated that the full-length ER binds to SMRT in vitro. To assess whether relative coactivator and corepressor expression within a given cell could modulate the balance of 4HT agonist/antagonist activity, SRC-1 and SMRT were coexpressed. SMRT overexpression blocked SRC-1 coactivation of 4HT-stimulated gene expression and preferentially inhibited 4HT agonist activity whether or not exogenous SRC-1 was present. The cumulative data in this model system indicate that the relative expression of coactivators and corepressors can modulate 4HT regulation of ER transcriptional activity and suggest they could contribute to the tissue-specific ability of mixed antiestrogens to activate or inhibit ER-mediated gene expression.

Original languageEnglish
Pages (from-to)657-666
Number of pages10
JournalMolecular Endocrinology
Volume11
Issue number6
DOIs
StatePublished - Jun 9 1997
Externally publishedYes

Fingerprint

Co-Repressor Proteins
Estrogen Receptor Modulators
Nuclear Receptor Coactivator 1
Estrogen Receptors
Gene Expression
Nuclear Receptor Co-Repressor 2
afimoxifene
Hep G2 Cells
HeLa Cells
Estradiol
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

Cite this

Coactivator and corepressor regulation of the agonist/antagonist activity of the mixed antiestrogen, 4-hydroxytamoxifen. / Smith, Carolyn L.; Nawaz, Zafar; O'Malley, Bert W.

In: Molecular Endocrinology, Vol. 11, No. 6, 09.06.1997, p. 657-666.

Research output: Contribution to journalArticle

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