Crossregulation of NF-kappaB by the APC/GSK-3beta/beta-catenin pathway.
Glycogen synthase kinase-3beta (GSK-3beta) and adenomatous polyposis coli (APC) play an important role in the regulation of beta-catenin. Inhibition of or defects in their functions can lead to activation of beta-catenin. beta-catenin has been recently found to interact with and inhibit nuclear factor kappa B (NF-kappaB). However, the regulatory roles of GSK-3beta/APC on the NF-kappaB signaling pathway are unknown because of their diverse effects. In this study, we investigated whether GSK-3beta/APC might regulate NF-kappaB activity through beta-catenin. We found that inhibition of GSK-3beta suppressed NF-kappaB activity, whereas reexpression of APC restored NF-kappaB activity in APC mutated cells. The regulatory effects were through beta-catenin because depletion of beta-catenin with small interfering RNA (siRNA) in the same systems reversed the effects. The regulatory relationship was further supported by the analysis of primary breast tumor tissues in vivo in which NF-kappaB target TRAF1 was inversely correlated with activated beta-catenin. Thus, APC/GSK-3beta, through beta-catenin, may crossregulate NF-kappaB signaling pathway.
Deng
Jiong
J
Department of Molecular and Cellular Oncology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA.
Xia
Weiya
W
Miller
Stephanie A
SA
Wen
Yong
Y
Wang
Hong-Ying
HY
Hung
Mien-Chie
MC
D025601:Adenomatous Polyposis Coli Protein / Q000502:physiology*; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007150:Immunohistochemistry; D016328:NF-kappa B / Q000502:physiology*; D015534:Trans-Activators / Q000502:physiology*; D051176:beta Catenin
D025601:Adenomatous Polyposis Coli Protein; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D016328:NF-kappa B; D015534:Trans-Activators; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3