ATM activation by a sulfhydryl-reactive inflammatory cyclopentenone prostaglandin.
ATM (ataxia-telangiectasia mutated) is activated by a variety of noxious agent, including oxidative stress, and ATM deficiency results in an anomalous cellular response to oxidative stress. However, the mechanisms for ATM activation by oxidative stress remain to be established. Furthermore, it is not clear whether ATM responds to oxidative DNA damage or to a change in the intracellular redox state, independent of DNA damage. We found that ATM is activated by N-methyl-N'-nitro-nitrosoguanidine (MNNG) and 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), in NBS1- or MSH6-deficient cells. We further found that ATM is activated by treating chromatin-free immunoprecipitated ATM with MNNG or 15d-PGJ(2), which modifies free sulfhydryl (SH) groups, and that 15d-PGJ(2) binds covalently to ATM. Interestingly, 15d-PGJ(2)-induced ATM activation leads to p53 activation and apoptosis, but not to Chk2 or H2AX phosphorylation. These results indicate that ATM is activated through the direct modification of its SH groups, independent of DNA damage, and this activation leads, downstream, to apoptosis.
Kobayashi
Masahiko
M
Department of Molecular Pathology, Cancer Research Institute, Kanazawa University, Kanazawa, 13-1 Takaramachi, Ishikawa 920-0934, Japan.
Ono
Hirohito
H
Mihara
Keiko
K
Tauchi
Hiroshi
H
Komatsu
Kenshi
K
Shibata
Takashi
T
Shimizu
Hiroko
H
Uchida
Koji
K
Yamamoto
Ken-ichi
K
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002645:Chickens; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D009687:Nuclear Proteins / Q000172:deficiency / Q000378:metabolism; D010766:Phosphorylation; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
C477819:15-deoxyprostaglandin J2; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C112156:NBN protein, human; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D008769:Methylnitronitrosoguanidine; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D015230:Prostaglandin D2