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Expression of endogenous oncogenic V600EB-raf induces proliferation and developmental defects in mice and transformation of primary fibroblasts.

Mutations of the human B-RAF gene are detected in approximately 8% of cancer samples, primarily in cutaneous melanomas (70%). The most common mutation (90%) is a valine-to-glutamic acid mutation at residue 600 (V600E; formerly V599E according to previous nomenclature). Using a Cre/Lox approach, we have generated a conditional knock-in allele of (V600E)B-raf in mice. We show that widespread expression of (V600E)B-Raf cannot be tolerated in embryonic development, with embryos dying approximately 7.5 dpc. Directed expression of mutant (V600E)B-Raf to somatic tissues using the IFN-inducible Mx1-Cre mouse strain induces a proliferative disorder and bone marrow failure with evidence of nonlymphoid neoplasia of the histiocytic type leading to death within 4 weeks of age. However, expression of mutant B-Raf does not alter the proliferation profile of all somatic tissues. In primary mouse embryonic fibroblasts, expression of endogenous (V600E)B-Raf induces morphologic transformation, increased cell proliferation, and loss of contact inhibition. Thus, (V600E)B-Raf is able to induce several hallmarks of transformation in some primary mouse cells without evidence for the involvement of a cooperating oncogene or tumor suppressor gene.

Pubmed ID: 16357158

Authors

  • Mercer K
  • Giblett S
  • Green S
  • Lloyd D
  • DaRocha Dias S
  • Plumb M
  • Marais R
  • Pritchard C

Journal

Cancer research

Publication Data

December 15, 2005

Associated Grants

  • Agency: Cancer Research UK, Id: A6969

Mesh Terms

  • Animals
  • Apoptosis
  • Bone Marrow
  • Cell Adhesion
  • Cell Proliferation
  • Congenital Abnormalities
  • Embryo, Mammalian
  • Female
  • Fibroblasts
  • Integrases
  • MAP Kinase Signaling System
  • Male
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase Kinases
  • Mutation
  • Pregnancy
  • Proto-Oncogene Proteins B-raf
  • Signal Transduction