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B-Raf inhibits programmed cell death downstream of cytochrome c release from mitochondria by activating the MEK/Erk

P Erhardt1, E J Schremser, G M Cooper

  • 1Department of Biology, Boston University, Boston, Massachusetts 02215, USA.

Molecular and Cellular Biology
|July 20, 1999
PubMed

Insights

Overexpressing B-Raf kinase activates the MEK/Erk pathway, conferring resistance to apoptosis. This pathway protects cells by inhibiting caspase activation downstream of mitochondrial cytochrome c release.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Growth factor-dependent kinases, including PI 3-kinase and Raf kinases, are involved in preventing programmed cell death (apoptosis).
  • The MEK/Erk mitogen-activated protein kinase pathway plays a crucial role in cellular signaling and survival.

Purpose of the Study:

  • To investigate the role of B-Raf overexpression and the subsequent MEK/Erk pathway activation in apoptosis suppression.
  • To determine the specific mechanism by which B-Raf confers resistance to apoptosis.

Main Methods:

  • Established Rat-1 fibroblast cell lines overexpressing B-Raf.
  • Utilized MEK inhibitors (PD98059) and dominant-negative MEK mutants.
  • Assessed apoptosis induction by growth factor withdrawal and PI 3-kinase inhibition.
  • Measured cytochrome c release from mitochondria and subsequent caspase activation.

Main Results:

  • B-Raf overexpression led to constitutive Erk activation and resistance to apoptosis.
  • MEK activity was essential and sufficient for the antiapoptotic effects of B-Raf.
  • The B-Raf/MEK/Erk pathway conferred resistance at the level of cytosolic caspase activation, downstream of cytochrome c release.

Conclusions:

  • The B-Raf/MEK/Erk signaling pathway is a key regulator of apoptosis.
  • This pathway protects cells by inhibiting caspase activation, independent of mitochondrial integrity.
  • Targeting the B-Raf/MEK/Erk pathway may offer therapeutic strategies for preventing apoptosis in certain conditions.

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