IKK and (Beta) - Catenin in Breast Cancer
Annual summary rept. 1 Jul 2001-30 Jun 2004
GEORGETOWN UNIV WASHINGTON DC
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The Wntbeta-catenin and TNFIkBNF-kB pathways are involved in cell cycle control, differentiation, and inflammation. Both IkB and beta-catenin are regulated by phosphorylation at similar consensus serines and targeted for ubiquitination and degradation by the same ubiquitin ligase complex. The IkB kinase complex IKK that phosphorylates IkB contains two kinases, IKKalpha and IKKbeta, which are activated in response to cytokines such as TNFalpha. We show that TNFalpha inhibits beta-catenin signaling activity independently of the tumor suppressor gene APC. Manipulation of APCbeta-catenin signaling does not affect NFkB activity. We show that IKKalpha and IKKbeta but not NFkB mediate the effects of TNFalpha inhibits beta-catenin signaling activity. Although neither TNFalpha nor constitutively active IKKs reduce total beta-catenin protein levels they markedly reduce the level of active de-phosphorylated beta-catenin in the nucleus by targeting serine and threonine residues in the N-terminal regulatory domain of beta-catenin. Levels of beta-catenin and the beta-catenin target gene cyclin D1 were elevated in the nuclei of epidermal cells in the abnormal skin of IKKalpha -- mice. These data point to a role for cytokines and the IKK complex, in the normal regulation of beta-catenin signaling activity.
- Anatomy and Physiology
- Medicine and Medical Research