Phosphorylation of elk-1 by MEK/ERK pathway is necessary for c-fos gene activation during cardiac myocyte hypertrophy

J Mol Cell Cardiol. 2000 Aug;32(8):1447-57. doi: 10.1006/jmcc.2000.1185.

Abstract

Cardiac hypertrophy is associated with specific alterations in myocardial gene expression; however, the exact mechanisms responsible for altered gene expression are poorly defined. The goal of this study was to investigate whether signaling kinases that are activated during cardiac hypertrophy directly modulate transcription factor activity and regulate gene expression. In an effort to understand this process, we focused our studies on the transcriptional activation of c-fos gene through the serum response element (SRE)/ternary complex factor (TCF) element, during phenylephrine-induced myocyte hypertrophy. In this study, we show that phosphorylated Elk-1, a TCF, binds to c-fos SRE and its binding to SRE is increased upon phenylephrine stimulation. Phenylephrine treatment activates phosphorylation of Elk-1 in the nucleus within five minutes and Elk-1-dependent transcriptional activation is abolished by inhibitors selective for MEK/ERK kinases. These studies implicate that phosphorylation of Elk-1 by ERK kinase pathway is important for early gene activation during phenylephrine-induced myocyte hypertrophy.

Publication types

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

MeSH terms

  • Adrenergic alpha-Agonists / pharmacology
  • Animals
  • Animals, Newborn
  • Blotting, Western
  • Cardiomegaly / pathology*
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Cytosol / metabolism
  • DNA-Binding Proteins / metabolism
  • Dose-Response Relationship, Drug
  • Electrophoresis, Polyacrylamide Gel
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / pharmacology
  • Genes, Reporter
  • Imidazoles / pharmacology
  • MAP Kinase Kinase 1
  • Microscopy, Confocal
  • Mitogen-Activated Protein Kinase Kinases / metabolism*
  • Mitogen-Activated Protein Kinases / metabolism*
  • Myocardium / cytology
  • Myocardium / metabolism*
  • Nuclear Proteins / metabolism
  • Phenylephrine / pharmacology
  • Phosphorylation
  • Plasmids / metabolism
  • Promoter Regions, Genetic
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-fos / genetics*
  • Pyridines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Serum Response Factor
  • Time Factors
  • Transcription Factors*
  • Transfection
  • ets-Domain Protein Elk-1

Substances

  • Adrenergic alpha-Agonists
  • DNA-Binding Proteins
  • Elk1 protein, rat
  • Enzyme Inhibitors
  • Flavonoids
  • Imidazoles
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-fos
  • Pyridines
  • Serum Response Factor
  • Transcription Factors
  • ets-Domain Protein Elk-1
  • Phenylephrine
  • Protein-Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 1
  • MAP2K1 protein, human
  • Mitogen-Activated Protein Kinase Kinases
  • SB 203580
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one