title: ATF-2 is preferentially activated by stress-activated protein kinases to mediate c-jun induction in response to genotoxic agents.
abstract: The major regulators of the c-jun promoter are ATF-2 and c-Jun. They act as pre-bound heterodimers on two 'AP-1-like' sites, and are preferentially addressed by different types of extracellular signals. The transactivating potential of ATF-2 is stimulated to a higher extent than that of c-Jun by a broad group of agents causing DNA damage and other types of cellular stress, such as short-wavelength UV, or the alkylating compounds N-methyl-N'-nitro-N-nitroso-guanidine (MNNG) or methylmethanesulphonate (MMS). In contrast, treatment with the phorbol ester TPA preferentially enhances c-Jun-dependent transactivation but does not affect ATF-2. Accordingly, UV and MMS but not TPA induce c-jun transcription in F9 cells, which express ATF-2, but not c-Jun. Stimulation of ATF-2-dependent transactivation by genotoxic agents requires the presence of threonines 69 and 71 located in the N-terminal transactivation domain. These sites are the target of p54 and p46 stress-activated protein kinases (SAPKs) which bind to, and phosphorylate ATF-2 in vitro. However, p46 and p54 kinase activity is not increased by phorbol ester, which strongly suggests that the protein kinase phosphorylating c-Jun in response to TPA is distinct from SAPKs and does not act on ATF-2. Our data demonstrate that distinct signal transduction pathways converge at c-Jun/ATF-2, whereby each subunit is individually addressed by a specific class of protein kinases. This allows fine tuned modulation of c-jun expression by a large spectrum of extracellular signals.
authors.affiliation: Forschungszentrum Karlsruhe, Institut für Genetik, Germany.
authors.forename: H
authors.initials: H
authors.lastname: van Dam
authors.forename: D
authors.initials: D
authors.lastname: Wilhelm
authors.forename: I
authors.initials: I
authors.lastname: Herr
authors.forename: A
authors.initials: A
authors.lastname: Steffen
authors.forename: P
authors.initials: P
authors.lastname: Herrlich
authors.forename: P
authors.initials: P
authors.lastname: Angel
mesh_terms: D051698:Activating Transcription Factor 2; D001483:Base Sequence; D002454:Cell Differentiation; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004249:DNA Damage; D005786:Gene Expression Regulation; D006801:Humans; D048670:MAP Kinase Kinase 4; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D020929:Mitogen-Activated Protein Kinase Kinases; D008957:Models, Genetic; D008969:Molecular Sequence Data; D010703:Phorbol Esters / Q000494:pharmacology; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis*; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D013912:Threonine / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014466:Ultraviolet Rays
chemical_list: C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D017362:Cyclic AMP Response Element-Binding Protein; D010703:Phorbol Esters; D016755:Proto-Oncogene Proteins c-jun; D014157:Transcription Factors; D008769:Methylnitronitrosoguanidine; D013912:Threonine; D008741:Methyl Methanesulfonate; D011494:Protein Kinases; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases