ATM-dependent nuclear accumulation of IKK-α plays an important role in the regulation of p73-mediated apoptosis in response to cisplatin
ATM-dependent nuclear accumulation of IKK-α plays an important role in the regulation of p73-mediated apoptosis in response to cisplatin
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DOI：
10.1038/sj.onc.1210722
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发表时间：
2008-02
期刊：
影响因子：
8
通讯作者：
K. Yoshida;T. Ozaki;K. Furuya;M. Nakanishi;H. Kikuchi;H. Yamamoto;S. Ono;T. Koda;K. Omura;A. Nakagawara
中科院分区：
文献类型：
--
作者：
K. Yoshida;T. Ozaki;K. Furuya;M. Nakanishi;H. Kikuchi;H. Yamamoto;S. Ono;T. Koda;K. Omura;A. Nakagawara
I kappa B kinase (IKK) complex plays an important role in the regulation of signaling pathway that activates nuclear factor–kappa-B (NF-κB). Recently, we reported that cisplatin (CDDP) treatment causes a remarkable nuclear accumulation of IKK-α in association with stabilization and activation of p73. However, underlying mechanisms of CDDP-induced nuclear accumulation of IKK-α are elusive. Here, we found that ataxia–telangiectasia mutated (ATM) is one of upstream mediators of IKK-α during CDDP-induced apoptosis. In response to CDDP, ATM was phosphorylated at Ser-1981, which was accompanied with nuclear accumulation of IKK-α in HepG2 cells, whereas CDDP treatment had undetectable effects on IKK-α in ATM-deficient cells. Indirect immunofluorescence experiments demonstrated that phosphorylated form of ATM colocalizes with nuclear IKK-α in response to CDDP. In vitro kinase assay indicated that ATM phosphorylates IKK-α at Ser-473. Moreover, IKK-α-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-α, which stabilizes p73, is one of the main apoptotic pathways in response to CDDP.
