ATF1 phosphorylation by the ERK MAPK pathway is required for epidermal growth factor-induced c-jun expression

J Biol Chem. 2002 Dec 27;277(52):50550-6. doi: 10.1074/jbc.M209799200. Epub 2002 Oct 31.

Abstract

Epidermal growth factor induction of c-jun expression requires ATF1 and MEF2 sites in the c-jun promoter. We find that activation of the c-jun promoter through the ATF1 site requires phosphorylation of ATF1 at serine 63. A serine 63 to alanine mutation of ATF1 acts to block epidermal growth factor (EGF) induction of a transfected c-jun gene. ATF1 can be phosphorylated by mitogen- and stress-activated protein kinase 1 (MSK1), which is activated by EGF and ERK1/2. Kinase-dead MSK1 mutants blocked EGF induction of a transfected c-jun gene suggesting that MSK1 or a similar family member is required for induced c-jun expression. Use of the MEK1 inhibitor U0126 and dominant negative MEK1 further showed that MSK1 activation and c-jun induction require the ERK pathway. In contrast, a JNK inhibitor blocked EGF induction of c-jun expression but not ATF1 phosphorylation. These results show that the two MAPK pathways, ERK and JNK, are required for EGF-induced c-jun expression and that the ERK pathway acts through downstream phosphorylation of ATF1.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Activating Transcription Factor 1
  • Animals
  • DNA-Binding Proteins*
  • Enzyme Inhibitors / pharmacology
  • Epidermal Growth Factor / pharmacology*
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology*
  • Genes, jun / drug effects
  • Genes, jun / physiology*
  • HeLa Cells
  • Humans
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology*
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism*
  • Phosphorylation
  • Promoter Regions, Genetic / drug effects
  • Recombinant Proteins / pharmacology
  • Ribosomal Protein S6 Kinases, 90-kDa / antagonists & inhibitors
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / metabolism*
  • Transfection

Substances

  • Activating Transcription Factor 1
  • Atf1 protein, mouse
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Recombinant Proteins
  • Transcription Factors
  • Epidermal Growth Factor
  • Ribosomal Protein S6 Kinases, 90-kDa
  • mitogen and stress-activated protein kinase 1
  • Mitogen-Activated Protein Kinases