Tamoxifen activation of the estrogen receptor/AP-1 pathway: Potential origin for the cell-specific estrogen-like effects of antiestrogens

Paul Webb, Gabriela N. Lopez, Rosalie Maire Uht, Peter J. Kushner

Research output: Contribution to journalArticle

631 Citations (Scopus)

Abstract

We find that tamoxifen is a potent activator of estrogen receptor (ER)- mediated induction of promoters regulated by AP-1 sites including the human collagenase gene promoter and constructs in which an AP-1 site is fused to the herpes thymidine kinase promoter. This contrasts with the inability of tamoxifen to activate otherwise identical promoters bearing classical estrogen response elements. Tamoxifen agonism at AP-1 sites is cell type specific, occurring in cell lines of uterine, but not of breast, origin. It thus parallels tamoxifen agonism in vivo. AP-1 proteins such as Jun or Jun/Fos are needed for tamoxifen stimulation, and tamoxifen increases the transcriptional efficiency of these proteins even when they are provided at optimal amounts. The DNA binding domain (DBD) of ER is required for tamoxifen activation at AP-1 sites. In contrast, estrogen activation is partially independent of this domain. This suggests the existence of two pathways of ER action at AP-1: an alpha (DBD-dependent) pathway activated by tamoxifen, and aβ (DBD-independent) pathway activated by estrogen. Fusing VP16 transcriptional activation functions to ER potentiates theβ, but not the alpha, pathway. We discuss models for the two pathways and the possibility that the AP-1 pathway is a major route by which ER affects target tissue growth and differentiation in vivo.

Original languageEnglish
Pages (from-to)443-456
Number of pages14
JournalMolecular Endocrinology
Volume9
Issue number4
DOIs
StatePublished - 1 Jan 1995

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Estrogen Receptor Modulators
Estrogen Receptor alpha
Transcription Factor AP-1
Tamoxifen
Estrogens
Estrogen Receptors
DNA
Thymidine Kinase
Response Elements
Collagenases
Transcriptional Activation
Proteins
Breast
Cell Line
Growth

Cite this

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abstract = "We find that tamoxifen is a potent activator of estrogen receptor (ER)- mediated induction of promoters regulated by AP-1 sites including the human collagenase gene promoter and constructs in which an AP-1 site is fused to the herpes thymidine kinase promoter. This contrasts with the inability of tamoxifen to activate otherwise identical promoters bearing classical estrogen response elements. Tamoxifen agonism at AP-1 sites is cell type specific, occurring in cell lines of uterine, but not of breast, origin. It thus parallels tamoxifen agonism in vivo. AP-1 proteins such as Jun or Jun/Fos are needed for tamoxifen stimulation, and tamoxifen increases the transcriptional efficiency of these proteins even when they are provided at optimal amounts. The DNA binding domain (DBD) of ER is required for tamoxifen activation at AP-1 sites. In contrast, estrogen activation is partially independent of this domain. This suggests the existence of two pathways of ER action at AP-1: an alpha (DBD-dependent) pathway activated by tamoxifen, and aβ (DBD-independent) pathway activated by estrogen. Fusing VP16 transcriptional activation functions to ER potentiates theβ, but not the alpha, pathway. We discuss models for the two pathways and the possibility that the AP-1 pathway is a major route by which ER affects target tissue growth and differentiation in vivo.",
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Tamoxifen activation of the estrogen receptor/AP-1 pathway : Potential origin for the cell-specific estrogen-like effects of antiestrogens. / Webb, Paul; Lopez, Gabriela N.; Uht, Rosalie Maire; Kushner, Peter J.

In: Molecular Endocrinology, Vol. 9, No. 4, 01.01.1995, p. 443-456.

Research output: Contribution to journalArticle

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