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This version published online on November 4, 2004
Molecular Endocrinology, doi:10.1210/me.2004-0298
A more recent version of this article appeared on March 1, 2005
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Submitted on July 23, 2004
Accepted on October 28, 2004

The Src Kinase Pathway Promotes Tamoxifen Agonist Action in Ishikawa Endometrial Cells through Phosphorylation-Dependent Stabilization of Estrogen Receptor {alpha} Promoter Interaction and Elevated SRC-1 Activity

Yatrik M. Shah and Brian G. Rowan*

Department of Biochemistry & Molecular Biology, Medical College of Ohio, Toledo, OH

* To whom correspondence should be addressed. E-mail: browan{at}mco.edu.

Tamoxifen is the most widely used selective estrogen receptor modulator (SERM) for breast cancer in clinical use today. However, tamoxifen agonist action in endometrium remains a major hurdle for tamoxifen therapy. Activation of the non-receptor tyrosine kinase src promotes tamoxifen agonist action, although the mechanisms remain unclear. To examine these mechanisms, the effect of src kinase on estrogen and tamoxifen signaling in tamoxifen-resistant Ishikawa endometrial adenocarcinoma cells was assessed. A novel connection was identified between src kinase and serine 167 phosphorylation in estrogen receptor-{alpha} (ER) via activation of AKT kinase. Serine 167 phosphorylation stabilized ER interaction with endogenous ER-dependent promoters. Src kinase exhibited the additional function of potentiating the transcriptional activity of Gal-SRC-1 and Gal-CREB binding protein (CBP) in endometrial cancer cells while having no effect on Gal-PCAF and Gal fusions of the other p160 coactivators GRIP1 (TIF-2/NcoA-2/SRC-2) and AIB-1 (RAC-3/ACTR/SRC-3). Src effects on ER phosphorylation and SRC-1 activity both contributed to tamoxifen agonist action on ER-dependent gene expression in Ishikawa cells. Taken together, these data demonstrate that src kinase potentiates tamoxifen agonist action through serine 167-dependent stabilization of ER promoter interaction and through elevation of SRC-1 and CBP coactivation of ER.
Key words: Estrogen Receptor • Endometrium • Tamoxifen • Src Kinase

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα
Coregulators:   P/CAF  |  p300  |  SRC-1  |  GRIP1  |  AIB1  |  NCOR
Ligands:   17β-Estradiol



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