The Activity of the Ets Transcription Factor PEA3 Is Regulated by Two Distinct MAPK Cascades

Oncogene. 1996 Sep 19;13(6):1323-33.

Abstract

PEA3, a member of the Ets family of transcriptional regulatory proteins, binds to the PEA3 promoter element and stimulates transcription through this site. The activity of the PEA3 element is regulated by mitogens, activated receptor tyrosine kinases, and oncogenic members of the Ras signal transduction pathway. However, it is not clear whether PEA3 mediates transcriptional regulation by these agents because a number of different Ets proteins can functionally interact with the PEA3 element. To specifically learn whether the activity of PEA3 is regulated, we investigated the ability of constitutively-activated Ras (Ha-RasV12) and signaling proteins downstream of Ras to alter PEA3-dependent reporter gene expression in COS cells. Ha-RasV12 and activated proteins in both the extra-cellular regulated kinase (ERK) and the stress-activated protein kinase (SAPK) or Jun N-terminal kinase (JNK) cascades independently stimulated PEA3-mediated gene expression. Ha-RasV12 stimulation of PEA3 activity was reduced by dominant-negative mutants in each of these protein kinase cascades, suggesting that Ras activates PEA3 through both pathways. Furthermore, the ability of unique activators of each kinase cascade to stimulate PEA3-dependent gene expression was selectively reduced by dominant-negative mutants within the homologous but not the heterologous pathway. Hence two distinct mitogen-activated protein kinase (MAPK) cascades regulate PEA3 activity. PEA3 was phosphorylated in vivo at serine residues consistent with the possibility that it may be a direct target of MAPKs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells / enzymology
  • COS Cells / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinases / physiology*
  • Enzyme Activation
  • Gene Expression
  • Genes, ras / physiology
  • JNK Mitogen-Activated Protein Kinases*
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 4
  • Mitogen-Activated Protein Kinase Kinases*
  • Phosphorylation
  • Protein Biosynthesis
  • Protein Kinases / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Serine-Threonine Kinases / physiology
  • Protein-Tyrosine Kinases / metabolism
  • Proteins / physiology
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins / physiology
  • Proto-Oncogene Proteins c-raf
  • Serine / metabolism
  • Signal Transduction / physiology
  • Transcription Factors / metabolism
  • Transcription Factors / physiology*
  • ras Proteins / physiology

Substances

  • Proteins
  • Proto-Oncogene Proteins
  • Transcription Factors
  • transcription factor PEA3
  • Serine
  • Protein Kinases
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-raf
  • Calcium-Calmodulin-Dependent Protein Kinases
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 4
  • Mitogen-Activated Protein Kinase Kinases
  • ras Proteins