title: Involvement of transcriptional repressor ATF3 in acceleration of caspase protease activation during DNA damaging agent-induced apoptosis.
abstract: DNA topoisomerase inhibitors are effective chemotherapeutic agents on several solid tumor cells. They induce a specific signaling cascade that executes an active cell death process (apoptosis), including caspase activation, and the blockage of the signaling is associated with drug-resistance of tumor cells. However, little is known about the initial signal transduction induced by the agents. In the present study, we screened genes that are initially upregulated in caspase-independent manner. We found that the activating transcription factor 3 (ATF3) protein, a repressor of cyclic-AMP responsive element (CRE)-dependent transcription, was strongly induced among CRE-BP/ATF members and subsequently accumulated in nuclei following camptothecin or etoposide treatment. During induction of apoptosis, the accumulation and the nuclear translocation of ATF3 coincided with the activation of caspase protease and were not inhibited by the broad caspase inhibitor Z-VAD-fmk, indicating that ATF3 induction is not a downstream event of caspase activation. When stably or transiently overexpressed, ATF3 markedly accelerated the drug-induced apoptosis and enhanced caspase protease activation. ATF3 strongly downregulated CRE-dependent transcription, while ATF3 did not affect the expression levels of Bcl-2, Bcl-x, or Bax. Our present results indicate that ATF3 plays a critical role in accelerating caspase protease activation and apoptosis. Since CRE-dependent transcription functions as cell survival signaling, ATF3 could control the upstream signaling of apoptosis by repressing CRE-dependent gene expression of cell survival factors.
authors.affiliation: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Kami-Ikebukuro, Toshima-ku, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Mashima
authors.forename: S
authors.initials: S
authors.lastname: Udagawa
authors.forename: T
authors.initials: T
authors.lastname: Tsuruo
mesh_terms: D051700:Activating Transcription Factor 3; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002166:Camptothecin / Q000494:pharmacology; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D005354:Fibrosarcoma / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006367:HeLa Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D059004:Topoisomerase I Inhibitors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
chemical_list: D051700:Activating Transcription Factor 3; D000590:Amino Acid Chloromethyl Ketones; C494826:BAX protein, human; C494811:BCL2L1 protein, human; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012097:Repressor Proteins; D059004:Topoisomerase I Inhibitors; D014157:Transcription Factors; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D005047:Etoposide; D020169:Caspases; D002166:Camptothecin