Ras-GTPase activating protein inhibition specifically induces apoptosis of tumour cells

Oncogene. 1999 Aug 26;18(34):4884-9. doi: 10.1038/sj.onc.1202855.


Oncogenes and tumour suppressor genes control the balance between apoptotic death and anti-apoptotic survival signals determining whether a cell proliferates or dies. Through which effectors might oncoproteins generate sensitivity to apoptosis remains to be determined. Ras GTPase activating protein (Ras-GAP) is a key element in the Ras signalling pathway, being both a negative regulator and possibly an effector of Ras. Ras-GAP acts as a regulator of transcription, and possibly connects Ras to stress-activated protein kinases. A role for Ras-GAP in cell survival has been suspected from the study of knock-out mouse embryos. In search for selective killing of tumour cells, we asked whether Ras-GAP inhibition by other means would lead to apoptosis in established cell lines. We injected a monoclonal antibody directed against the SH3 domain of Ras-GAP (mAb200) that has been shown to block Ras-GAP downstream signalling into various human normal and tumour cell lines. We show that inhibition of Ras-GAP induces apoptosis specifically in tumour, but not in normal cells, therefore pointing at a specific role for Ras-GAP in tumour cell survival. MAb200-induced apoptosis is largely prevented by coinjection of activated RhoA or Cdc42 proteins, by injection of a constitutively activated mutant of phosphoinositide 3-OH kinase (PI3-K), but not by injection of v-Raf. These results show that targeting of Ras-GAP could represent a novel anticancer approach.

MeSH terms

  • Antibodies, Monoclonal / pharmacology
  • Apoptosis / physiology*
  • Breast Neoplasms / pathology
  • Breast Neoplasms / physiopathology*
  • Cell Cycle Proteins / metabolism
  • Cell Survival
  • Colonic Neoplasms / pathology
  • Colonic Neoplasms / physiopathology*
  • Female
  • Fibroblasts
  • GTP-Binding Proteins / genetics*
  • GTP-Binding Proteins / metabolism
  • GTPase-Activating Proteins
  • HeLa Cells
  • Humans
  • Lung Neoplasms / pathology
  • Lung Neoplasms / physiopathology*
  • Microinjections
  • Microscopy, Video
  • Oncogene Proteins v-raf
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Proteins / antagonists & inhibitors*
  • Proteins / immunology
  • Retroviridae Proteins, Oncogenic / genetics
  • Tumor Cells, Cultured / metabolism
  • Tumor Cells, Cultured / pathology
  • cdc42 GTP-Binding Protein
  • ras GTPase-Activating Proteins
  • rhoA GTP-Binding Protein
  • src Homology Domains / immunology


  • Antibodies, Monoclonal
  • Cell Cycle Proteins
  • GTPase-Activating Proteins
  • Proteins
  • Retroviridae Proteins, Oncogenic
  • ras GTPase-Activating Proteins
  • Phosphatidylinositol 3-Kinases
  • Oncogene Proteins v-raf
  • GTP-Binding Proteins
  • cdc42 GTP-Binding Protein
  • rhoA GTP-Binding Protein