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Stress response gene ATF3 encodes a bZip-type transcription factor that is expressed at very low level but is induced by stimuli such as DNA damage, hypoxia, oxido-reductive stress, and is implicated in cell death.At the same time,however, some cancer cells, especially circulating tumor cells, express high level of ATF3 that is one of hallmarks of aggressive growth and metastasis of cancer.Previously, several laboratories including ours showed ATF3 is a direct target gene of tumor suppressor p53 (Zhang et al., BBRC, 2002).Of intrigue, our lab clearly demonstrated that high level of ATF3 expression negatively regulates the transcription of p53, providing a possible feedback loop between p53 and ATF3 (Kawauchi et al., JBC, 2002).In order to further understand biological role of the p53-ATF3 loop, we employed systems biology approach for identifying ATF3-binding target genes in DNA damage response of human colon cancer cells HCT 116 (PLosOne, 2011).ChIP-chip analysis identified ~6000 target genes in DNA response.The ATF3 target genes clearly contain ATF3/CRE sites on their promoter and also other binding sites for CHOP, HIF 1,E2F, YY 1, EGR 1, NRF2, or SP 1 that are closely located with ATF/CRE.By contrast, in human prostate cancer cells LNCaP overexpressing ATF3, much less target genes (~1400) were identified, 154 genes of which are unique to LNCaR Further, p53 target gene expression of ATF3 knocked-down cells was studied by expression microarray.Notably, stressinduced ATF3 binds to 40% of p53 targets and activates pro-apoptotic genes such as TNFRSF 10B/DR5 and BBC3/PUMA.Cancer-associated ATF3, by contrast, represses these pro-apoptotic genes in addition to CDKN1A/p21.These data clearly reveal different target genes of ATF3 between DNA damage response and cancer cells with ATF3 overexpression,demonstrating that ATF3 functions as tumor suppressor in stress response but it plays as cell survival or oncogenic factor.Among target genes in our ChIP-chip analysis, pro-apoptotic gene death receptor 5(DR5) was further studied.Upon DNA damage of HCT 116 cells with camptothecin (CPT), p53-ATF3-DR5 pathway was responsible for effective combined therapy of CPT and TRAIL, providing molecular mechanism that ATF3 is a transcriptional co-activator with p53 for inducing DR5 (Taketani et al., Oncogene, 2011).