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ATM activation by a sulfhydryl‐reactive inflammatory cyclopentenone prostaglandin
Author(s) -
Kobayashi Masahiko,
Ono Hirohito,
Mihara Keiko,
Tauchi Hiroshi,
Komatsu Kenshi,
Shibata Takashi,
Shimizu Hiroko,
Uchida Koji,
Yamamoto Kenichi
Publication year - 2006
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/j.1365-2443.2006.00976.x
Subject(s) - oxidative stress , dna damage , biology , microbiology and biotechnology , prostaglandin d2 , oxidative phosphorylation , chromatin , histone , methylnitronitrosoguanidine , dna , biochemistry , prostaglandin , mutation , gene
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‐Δ 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.