Src-JNK Potentiation of Estrogen Receptor AF-1; Mechanism, and Role in Estrogen Action in Breast Cancer
Annual rept. 1 Aug 1999-31 Jul 2000
CALIFORNIA UNIV SAN FRANCISCO
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The activity of Src tyrosine kinase is commonly elevated in breast cancer and breast cancer cell lines, but the significance of this elevation is not known. In preliminary studies we found that increasing Src activity potentiates the ability of the estrogen receptor to stimulate transcription of target genes, and thereby alter cellular functions, and that Src must activate the JNK proteins in order to potentiate the estrogen receptor. We have two objectives. One is to understand in detail the molecular pathway whereby activated Src and JNK leads to an increase in estrogen receptor activity. A second objective is to understand the potential role of Src in estrogen induced mammary ductal development and estrogen-induced breast cancer proliferation. In the first year of this study we have largely accomplished the first of these objectives. We found that Src activated the first 100 amino acids in the estrogen receptor AF-1 function as its main target, that to do so Src worked primarily through the JNK family of MAP kinases, and that the JNk target appears to be the CBPp160 coactivators coactivators that mediate AF-1 action, and not the estrogen receptor itself. These results suggest potential new targets for anticancer therapy.
- Anatomy and Physiology
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