ATF-2 is preferentially activated by stress-activated protein kinases to mediate c-jun induction in response to genotoxic agents

EMBO J. 1995 Apr 18;14(8):1798-811.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 2
  • Base Sequence
  • Cell Differentiation
  • Cells, Cultured
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • DNA Damage
  • Gene Expression Regulation*
  • Humans
  • MAP Kinase Kinase 4*
  • Methyl Methanesulfonate / pharmacology
  • Methylnitronitrosoguanidine / pharmacology
  • Mitogen-Activated Protein Kinase Kinases*
  • Models, Genetic
  • Molecular Sequence Data
  • Phorbol Esters / pharmacology
  • Phosphorylation
  • Protein Kinases / metabolism*
  • Proto-Oncogene Proteins c-jun / biosynthesis*
  • Signal Transduction*
  • Structure-Activity Relationship
  • Threonine / metabolism
  • Transcription Factors*
  • Transcription, Genetic
  • Transcriptional Activation
  • Ultraviolet Rays


  • ATF2 protein, human
  • Activating Transcription Factor 2
  • Cyclic AMP Response Element-Binding Protein
  • Phorbol Esters
  • Proto-Oncogene Proteins c-jun
  • Transcription Factors
  • Methylnitronitrosoguanidine
  • Threonine
  • Methyl Methanesulfonate
  • Protein Kinases
  • MAP Kinase Kinase 4
  • MAP2K4 protein, human
  • Mitogen-Activated Protein Kinase Kinases