title: Systems analysis of ATF3 in stress response and cancer reveals opposing effects on pro-apoptotic genes in p53 pathway.
abstract: Stress-inducible transcription factors play a pivotal role in cellular adaptation to environment to maintain homeostasis and integrity of the genome. Activating transcription factor 3 (ATF3) is induced by a variety of stress and inflammatory conditions and is over-expressed in many kinds of cancer cells. However, molecular mechanisms underlying pleiotropic functions of ATF3 have remained elusive. Here we employed systems analysis to identify genome-wide targets of ATF3 that is either induced by an alkylating agent methyl methanesulfonate (MMS) or over-expressed in a prostate tumour cell line LNCaP. We show that stress-induced and cancer-associated ATF3 is recruited to 5,984 and 1,423 targets, respectively, in the human genome, 89% of which are common. Notably, ATF3 targets are highly enriched for not only ATF/CRE motifs but also binding sites of several other stress-inducible transcription factors indicating an extensive network of stress response factors in transcriptional regulation of target genes. Further analysis of effects of ATF3 knockdown on these targets revealed that stress-induced ATF3 regulates genes in metabolic pathways, cell cycle, apoptosis, cell adhesion, and signalling including insulin, p53, Wnt, and VEGF pathways. Cancer-associated ATF3 is involved in regulation of distinct sets of genes in processes such as calcium signalling, Wnt, p53 and diabetes pathways. Notably, stress-induced ATF3 binds to 40% of p53 targets and activates pro-apoptotic genes such as TNFRSF10B/DR5 and BBC3/PUMA. Cancer-associated ATF3, by contrast, represses these pro-apoptotic genes in addition to CDKN1A/p21. Taken together, our data reveal an extensive network of stress-inducible transcription factors and demonstrate that ATF3 has opposing, cell context-dependent effects on p53 target genes in DNA damage response and cancer development.
authors: Laboratory of Genome Structure and Regulation, School of Biomedical Science and Department of Biochemical Genetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan. ytanaka.bgen@mri.tmd.ac.jp
authors: Yujiro
authors: Y
authors: Tanaka
authors: Aya
authors: A
authors: Nakamura
authors: Masaki Suimye
authors: MS
authors: Morioka
authors: Shoko
authors: S
authors: Inoue
authors: Mimi
authors: M
authors: Tamamori-Adachi
authors: Kazuhiko
authors: K
authors: Yamada
authors: Kenji
authors: K
authors: Taketani
authors: Junya
authors: J
authors: Kawauchi
authors: Miki
authors: M
authors: Tanaka-Okamoto
authors: Jun
authors: J
authors: Miyoshi
authors: Hiroshi
authors: H
authors: Tanaka
authors: Shigetaka
authors: S
authors: Kitajima
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics*; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics*; D053263:Gene Regulatory Networks; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D051017:Apoptosis Regulatory Proteins; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53