ATM-dependent nuclear accumulation of IKK-alpha plays an important role in the regulation of p73-mediated apoptosis in response to cisplatin.

I kappa B kinase (IKK) complex plays an important role in the regulation of signaling pathway that activates nuclear factor-kappa-B (NF-kappaB). Recently, we reported that cisplatin (CDDP) treatment causes a remarkable nuclear accumulation of IKK-alpha in association with stabilization and activation of p73. However, underlying mechanisms of CDDP-induced nuclear accumulation of IKK-alpha are elusive. Here, we found that ataxia-telangiectasia mutated (ATM) is one of upstream mediators of IKK-alpha during CDDP-induced apoptosis. In response to CDDP, ATM was phosphorylated at Ser-1981, which was accompanied with nuclear accumulation of IKK-alpha in HepG2 cells, whereas CDDP treatment had undetectable effects on IKK-alpha in ATM-deficient cells. Indirect immunofluorescence experiments demonstrated that phosphorylated form of ATM colocalizes with nuclear IKK-alpha in response to CDDP. In vitro kinase assay indicated that ATM phosphorylates IKK-alpha at Ser-473. Moreover, IKK-alpha-deficient MEFs displayed CDDP-resistant phenotype as compared with wild-type MEFs. Taken together, our present results suggest that ATM-mediated phosphorylation of nuclear IKK-alpha, which stabilizes p73, is one of the main apoptotic pathways in response to CDDP.