title: ATF3 and Fra1 have opposite functions in JNK- and ERK-dependent DNA damage responses.
abstract: JNK and ERK MAP kinases regulate cellular responses to genotoxic stress in a cell type and cell context-dependent manner. However, the factors that determine and execute JNK- and ERK-controlled stress responses are only partly known. In this study, we investigate the roles of the AP-1 components ATF3 and Fra1 in JNK- and ERK-dependent cell cycle arrest and apoptosis. We show that the anti-cancer drug cisplatin or UV light activates both JNK and ERK in human glioblastoma cells lacking functional p53. Inhibition experiments of JNK or ERK activities revealed that the ERK pathway strongly promotes cisplatin- and UV-induced apoptosis in these glioblastoma cells. Furthermore, JNK but not ERK is required for ATF3 induction, and both ERK and JNK are necessary for post-transcriptional induction of Fra1 in response to cisplatin or UV. Knock-down of ATF3 and Fra1 results in increased and decreased cisplatin-induced apoptosis, respectively, indicating that ATF3 is an anti-apoptotic JNK effector and Fra1 is a pro-apoptotic ERK/JNK effector. Knock-down experiments also revealed that ATF3 and Fra1, respectively, enhance and reduce S-phase arrest through differential modulation of the Chk1-Cdk2 pathway. Thus, we identify novel reciprocal functions of ATF3 and Fra1 in JNK- and ERK-dependent DNA damage responses.
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Hamdi
authors.forename: Herman E
authors.initials: HE
authors.lastname: Popeijus
authors.forename: Françoise
authors.initials: F
authors.lastname: Carlotti
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Janssen
authors.forename: Corina
authors.initials: C
authors.lastname: van der Burgt
authors.forename: Paulien
authors.initials: P
authors.lastname: Cornelissen-Steijger
authors.forename: Bob
authors.initials: B
authors.lastname: van de Water
authors.forename: Rob C
authors.initials: RC
authors.lastname: Hoeben
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsuo
authors.forename: Hans
authors.initials: H
authors.lastname: van Dam
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D015152:Blotting, Northern; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism; D000071877:Checkpoint Kinase 1; D002945:Cisplatin / Q000494:pharmacology; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D016196:S Phase / Q000187:drug effects / Q000528:radiation effects; D018808:Transcription Factor AP-1; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays; D000099169:Fos-Related Antigen 1
chemical_list: D051700:Activating Transcription Factor 3; D000071877:Checkpoint Kinase 1; D002945:Cisplatin; D051357:Cyclin-Dependent Kinase 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8; D011494:Protein Kinases; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; D000099169:Fos-Related Antigen 1; C490449:ATF3 protein, human; C000605867:CHEK1 protein, human; C495894:CDK2 protein, human