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- Title
ATM-dependent nuclear accumulation of IKK-α plays an important role in the regulation of p73-mediated apoptosis in response to cisplatin.
- Authors
Yoshida, K.; Ozaki, T.; Furuya, K.; Nakanishi, M.; Kikuchi, H.; Yamamoto, H.; Ono, S.; Koda, T.; Omura, K.; Nakagawara, A.
- Abstract
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.Oncogene (2008) 27, 1183–1188; doi:10.1038/sj.onc.1210722; published online 13 August 2007
- Subjects
ATAXIA telangiectasia; PROTEIN kinases; APOPTOSIS; CISPLATIN; IMMUNOFLUORESCENCE; PHOSPHORYLATION
- Publication
Oncogene, 2008, Vol 27, Issue 8, p1183
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1210722