Oncogenic BRAF(V600E) inhibits BIM expression to promote melanoma cell survival

Robert A Cartlidge, G R Thomas, Sebastien Cagnol, Kimberly A Jong, Sarah A Molton, Andrew J Finch, Martin McMahon

Research output: Contribution to journalArticlepeer-review

Abstract

Somatic activating mutations of BRAF are the earliest and most common genetic abnormality detected in the genesis of human melanoma. However, the mechanism(s) by which activated BRAF promotes melanoma cell cycle progression and/or survival remain unclear. Here we demonstrate that expression of BIM, a pro-apoptotic member of the BCL-2 family, is inhibited by BRAF-->MEK-->ERK signaling in mouse and human melanocytes and in human melanoma cells. Trophic factor deprivation of melanocytes leads to elevated BIM expression. However, re-addition of trophic factors or activation of a conditional form of BRAF(V600E) leads to rapid inhibition of BIM expression. In both cases, inhibition of BIM expression was dependent on the activity of MEK1/2 and the proteasome. Consistent with these observations, pharmacological inhibition of BRAF(V600E) or MEK1/2 in human melanoma cells (using PLX4720 and CI-1040 respectively) led to a striking elevation of BIM expression. Re-activation of BRAF-->MEK-->ERK signaling led to phosphorylation of BIM-EL on serine 69 and its subsequent degradation. Interestingly, endogenous expression of BIM in melanoma cells was insufficient to induce apoptosis unless combined with serum deprivation. Under these circumstances, inhibition of BIM expression by RNA interference provided partial protection from apoptosis. These data suggest that regulation of BIM expression by BRAF-->MEK-->ERK signaling is one mechanism by which oncogenic BRAF(V600E) can influence the aberrant physiology of melanoma cells.
Original languageEnglish
Pages (from-to)534-44
Number of pages11
JournalPigment Cell and Melanoma Research
Volume21
Issue number5
DOIs
Publication statusPublished - Oct 2008

Keywords

  • Proto-Oncogene Proteins B-raf
  • Animals
  • Apoptosis
  • Humans
  • Apoptosis Regulatory Proteins
  • MAP Kinase Kinase 1
  • Mitochondria
  • Mice
  • Cell Line, Tumor
  • MAP Kinase Kinase 2
  • Melanocytes
  • Skin Neoplasms
  • Membrane Proteins
  • Cell Survival
  • Melanoma
  • Culture Media, Serum-Free
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins
  • Point Mutation
  • Intercellular Signaling Peptides and Proteins
  • RNA Interference
  • Signal Transduction

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