IKK and (Beta)-Catenin in Breast Cancer
Annual summary rept. 1 Jul 2002-30 Jun 2003
GEORGETOWN UNIV WASHINGTON DC
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The Wnt pathway is involved in many differentiation events. Mutations involving downstream components like APC or b-catenin result in nuclear accumulation of b-catenin, which results in cancer. This project has discovered that cytokine, TNFa and ectodysplasin Eda and its receptor, Edar regulate b-catenin signaling activity. A conserved sequence, DSGXXS, within the N-terminus of b-catenin and IkappaB, allows for targeted phosphorylation by upstream kinases such as IkappaB kinase. Evidence show that TNFa is able to regulate b-catenin through IkappaB kinase complex. This complex is normally involved in inactivating inhibitor, IkappaB which sequesters NFkappaB in the cytoplasm. The second part of this project shows that NEkappaB signaling is independent of TKK regulation of b-catenin. Wnt signaling is not the only way b-catenin is regulated. Cytokine induced decrease in b-catenin signaling activity is not due to b-catenin degradation but rather, to its re-distribution. This study confirms that there is an active fraction of b-catenin present within the nucleus is responsible for its signaling activity and both TNFa and ectodysplasin reduce or redistribute that fraction.
- Anatomy and Physiology
- Medicine and Medical Research