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.
Yoshida
K
K
Division of Biochemistry, Chiba Cancer Center Research Institute, Chiba, Japan.
Ozaki
T
T
Furuya
K
K
Nakanishi
M
M
Kikuchi
H
H
Yamamoto
H
H
Ono
S
S
Koda
T
T
Omura
K
K
Nakagawara
A
A
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000502:physiology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology*; D002945:Cisplatin / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000378:metabolism / Q000502:physiology*
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase; D002945:Cisplatin