A-Raf and Raf-1 work together to influence transient ERK phosphorylation and Gl/S cell cycle progression

Oncogene. 2005 Aug 4;24(33):5207-17. doi: 10.1038/sj.onc.1208707.


The Raf/MEK/ERK (extracellular regulated kinase) signal transduction pathway controls the ability of cells to respond to proliferative, apoptotic, migratory and differentiation signals. We have investigated the combined contribution of A-Raf and Raf-1 isotypes to signalling through this pathway by generating mice with knockout mutations of both A-raf and raf-1 genes. Double knockout (DKO) mice have a more severe phenotype than single null mutations of either gene, dying in embryogenesis at E10.5. The DKO embryos show no changes in apoptosis, but staining for Ki67 indicates a generalized reduction in proliferation. DKO mouse embryonic fibroblasts (MEFs) exhibit a delayed ability to enter S phase of the cell cycle. This is associated with a reduction in levels of transiently induced MEK and ERK phosphorylation and reduced expression of c-Fos and cyclin Dl. Levels of sustained ERK phosphorylation are not significantly altered. Thus, Raf-1 and A-Raf have a combined role in controlling physiological transient ERK activation and in maintenance of cell cycle progression at its usual rate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Embryo, Mammalian / cytology
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / physiology
  • Fibroblasts / cytology
  • G1 Phase / genetics
  • G1 Phase / physiology*
  • Gene Targeting
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Phenotype
  • Phosphorylation
  • Proto-Oncogene Proteins A-raf / physiology*
  • Proto-Oncogene Proteins c-fos / biosynthesis
  • Proto-Oncogene Proteins c-raf / physiology*
  • S Phase / genetics
  • S Phase / physiology*
  • Signal Transduction


  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins A-raf
  • Proto-Oncogene Proteins c-raf
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinase Kinases