Protein kinase C delta activates IkappaB-kinase alpha to induce the p53 tumor suppressor in response to oxidative stress.
Protein kinase C delta (PKCdelta) functions as a redox-sensitive kinase in various cell types. Upon exposure to reactive oxygen species (ROS), it is activated by tyrosine phosphorylation, nuclear translocation and caspase-3-mediated cleavage. Activated PKCdelta is associated with cell cycle arrest or apoptosis, although its precise mechanism of action is unclear. Previous studies have demonstrated that the transcription factor, nuclear factor kappaB (NF-kappaB), functions as a redox-sensitive factor. ROS induce NF-kappaB signaling pathways including upstream IkappaB kinases (IKKs), although the mechanisms of ROS-induced activation of IKKs are unknown. Here we show that both PKCdelta and IKKalpha, but not IKKbeta, translocate to the nucleus in response to oxidative stress. The results also demonstrate that PKCdelta interacts with and activates IKKalpha. Importantly, our data suggest that, upon exposure to oxidative stress, PKCdelta-mediated IKKalpha activation does not contribute to NF-kappaB activation; instead, nuclear IKKalpha regulates the transcription activity of the p53 tumor suppressor by phosphorylation at Ser20. These findings collectively support a novel mechanism in which the PKCdelta-->IKKalpha signaling pathway contributes to ROS-induced activation of the p53 tumor suppressor.
Yamaguchi
Tomoko
T
Department of Molecular Genetics, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Miki
Yoshio
Y
Yoshida
Kiyotsugu
K
D021581:Active Transport, Cell Nucleus; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000201:enzymology; D004789:Enzyme Activation; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress; D051745:Protein Kinase C-delta / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; D051550:I-kappa B Kinase; D051745:Protein Kinase C-delta