Abstract
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.
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Acknowledgements
We are grateful to Pr Alan Hall for supplying the expression vectors for RhoAV14 and Cdc42V12, and Dr Julian Downward for providing the expression vector encoding p110K227E. We thank Mireille Kenigsberg for helpful advice concerning microinjection experiments.
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Leblanc, V., Delumeau, I. & Tocqué, B. Ras-GTPase activating protein inhibition specifically induces apoptosis of tumour cells. Oncogene 18, 4884–4889 (1999). https://doi.org/10.1038/sj.onc.1202855
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DOI: https://doi.org/10.1038/sj.onc.1202855
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