title: JNK suppresses tumor formation via a gene-expression program mediated by ATF2.
abstract: JNK and p38 phosphorylate a diverse set of substrates and, consequently, can act in a context-dependent manner to either promote or inhibit tumor growth. Elucidating the functions of specific substrates of JNK and p38 is therefore critical for our understanding of these kinases in cancer. ATF2 is a phosphorylation-dependent transcription factor and substrate of both JNK and p38. Here, we show ATF2 suppresses tumor formation in an orthotopic model of liver cancer and cellular transformation in vitro. Furthermore, we find that suppression of tumorigenesis by JNK requires ATF2. We identify a transcriptional program activated by JNK via ATF2 and provide examples of JNK- and ATF2-dependent genes that block cellular transformation. Significantly, we also show that ATF2-dependent gene expression is frequently downregulated in human cancers, indicating that amelioration of JNK-ATF2-mediated suppression may be a common event during tumor development.
authors.affiliation: Department of Cell Regulation, CRUK Manchester Institute, Paterson Building, University of Manchester, Manchester M20 4BX, UK; Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Gozdecka
authors.affiliation: Department of Cell Regulation, CRUK Manchester Institute, Paterson Building, University of Manchester, Manchester M20 4BX, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Lyons
authors.affiliation: Department of Cell Regulation, CRUK Manchester Institute, Paterson Building, University of Manchester, Manchester M20 4BX, UK; Laboratory of Molecular Genetics, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Saki
authors.initials: S
authors.lastname: Kondo
authors.affiliation: Central Manchester NHS Trust and University of Manchester, the Nowgen Centre, 29 Grafton Street, Manchester M13 9WU, UK; Applied Computational Biology and Bioinformatics Group, CRUK Manchester Institute, Paterson Building, University of Manchester, Manchester M20 4BX, UK.
authors.forename: Janet
authors.initials: J
authors.lastname: Taylor
authors.affiliation: Applied Computational Biology and Bioinformatics Group, CRUK Manchester Institute, Paterson Building, University of Manchester, Manchester M20 4BX, UK.
authors.forename: Yaoyong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Cell Regulation, CRUK Manchester Institute, Paterson Building, University of Manchester, Manchester M20 4BX, UK.
authors.forename: Jacek
authors.initials: J
authors.lastname: Walczynski
authors.affiliation: Department of Medical Biochemistry and Molecular Biology, University of Saarland Medical Center, Building 44, 66421 Homburg, Germany.
authors.forename: Gerald
authors.initials: G
authors.lastname: Thiel
authors.affiliation: Department of Cell Regulation, CRUK Manchester Institute, Paterson Building, University of Manchester, Manchester M20 4BX, UK.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Breitwieser
authors.affiliation: Department of Cell Regulation, CRUK Manchester Institute, Paterson Building, University of Manchester, Manchester M20 4BX, UK. Electronic address: nic.jones@cruk.manchester.ac.uk.
authors.forename: Nic
authors.initials: N
authors.lastname: Jones
mesh_terms: D051698:Activating Transcription Factor 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D051698:Activating Transcription Factor 2; D012333:RNA, Messenger; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins