ATF1 phosphorylation by the ERK MAPK pathway is required for epidermal growth factor-induced c-jun expression.
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.
Gupta
Pankaj
P
Department of Biological Sciences, Columbia University, New York, New York 10027, USA.
Prywes
Ron
R
D051697:Activating Transcription Factor 1; D000818:Animals; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D016758:Genes, jun / Q000187:drug effects / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014162:Transfection
D051697:Activating Transcription Factor 1; C497100:Atf1 protein, mouse; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D014157:Transcription Factors; D004815:Epidermal Growth Factor; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D020928:Mitogen-Activated Protein Kinases