Identification of promoters bound by c-Jun/ATF2 during rapid large-scale gene activation following genotoxic stress.
The NH2-terminal Jun kinases (JNKs) function in diverse roles through phosphorylation and activation of AP-1 components including ATF2 and c-Jun. However, the genes that mediate these processes are poorly understood. A model phenotype characterized by rapid activation of Jun kinase and enhanced DNA repair following cisplatin treatment was examined using chromatin immunoprecipitation with antibodies against ATF2 and c-Jun or their phosphorylated forms and hybridization to promoter arrays. Following genotoxic stress, we identified 269 genes whose promoters are bound upon phosphorylation of ATF2 and c-Jun. Binding did not occur following treatment with transplatin or the JNK inhibitor SP600125 or JNK-specific siRNA. Of 89 known DNA repair genes represented on the array, 23 are specifically activated by cisplatin treatment within 3-6 hr. Thus, the genotoxic stress response occurs at least partly via activation of ATF2 and c-Jun, leading to large-scale coordinate gene expression dominated by genes of DNA repair.
Hayakawa
Jun
J
Sidney Kimmel Cancer Center, 10835 Altman Row, San Diego, California 92121, USA.
Mittal
Shalu
S
Wang
Yipeng
Y
Korkmaz
Kemal S
KS
Adamson
Eileen
E
English
Christopher
C
Ohmichi
Masahide
M
Omichi
Masahide
M
McClelland
Michael
M
Mercola
Dan
D
D051698:Activating Transcription Factor 2; D000873:Anthracenes / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000633:toxicity; D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D002945:Cisplatin / Q000633:toxicity; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects / Q000378:metabolism*; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D000873:Anthracenes; D000970:Antineoplastic Agents; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; D014157:Transcription Factors; C432165:pyrazolanthrone; D002945:Cisplatin