Accession Number : ADA431638


Title :   IKK and (Beta) - Catenin in Breast Cancer


Descriptive Note : Annual summary rept. 1 Jul 2001-30 Jun 2004


Corporate Author : GEORGETOWN UNIV WASHINGTON DC


Personal Author(s) : Teo, Marissa ; Attiga, Fadwa ; Jarrett, Christy ; Zipper, Laurie ; Byers, Stephen


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a431638.pdf


Report Date : Jul 2004


Pagination or Media Count : 107


Abstract : The Wnt/beta-catenin and TNF/IkB/NF-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 APC/beta-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.


Descriptors :   *CELLS(BIOLOGY) , *BREAST CANCER , *CYTOKINES , MUTATIONS , TARGETING , GENES , MICE , INFLAMMATION , AMINO ACIDS , ABNORMALITIES , EPIDERMIS , SUPPRESSORS , SERINE , PHOSPHORYLATION , PHOSPHORUS TRANSFERASES


Subject Categories : Anatomy and Physiology
      Medicine and Medical Research


Distribution Statement : APPROVED FOR PUBLIC RELEASE