TY - JOUR
T1 - Tamoxifen activation of the estrogen receptor/AP-1 pathway
T2 - Potential origin for the cell-specific estrogen-like effects of antiestrogens
AU - Webb, Paul
AU - Lopez, Gabriela N.
AU - Uht, Rosalie M.
AU - Kushner, Peter J.
PY - 1995/4
Y1 - 1995/4
N2 - 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 promoter 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 α (DBD-dependent) pathway activated by tamoxifen, and a β (DBD-independent) pathway activated by estrogen. Fusing VP16 transcriptional activation functions to ER potentiates the β, but not the α, 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.
AB - 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 promoter 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 α (DBD-dependent) pathway activated by tamoxifen, and a β (DBD-independent) pathway activated by estrogen. Fusing VP16 transcriptional activation functions to ER potentiates the β, but not the α, 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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U2 - 10.1210/mend.9.4.7659088
DO - 10.1210/mend.9.4.7659088
M3 - Article
C2 - 7659088
AN - SCOPUS:0028901194
VL - 9
SP - 443
EP - 456
JO - Molecular Endocrinology
JF - Molecular Endocrinology
SN - 0888-8809
IS - 4
ER -