Regulation of both apoptosis and cell survival by the v-Src oncoprotein

Cell Death Differ. 2000 Aug;7(8):685-96. doi: 10.1038/sj.cdd.4400700.

Abstract

A number of oncogenes alter the regulation of the cell cycle and cell death, contributing to the altered growth of tumours. Expression of the v-Src oncoprotein in Rat-1 fibroblasts prevented cell cycle exit in response to growth factor withdrawal. Here we investigated whether survival of v-Src transformed cells in low serum is dependent on v-Src activity. We used a temperature sensitive v-Src to study the effect inactivating v-Src on transformed cells growing under low serum conditions. We found when we switched off v-Src the cells died by apoptosis characterised by activation of caspases and the stress-activated kinases, JNK (Jun N-terminal kinase) and p38 MAP (mitogen activated protein) kinase. We were able to prevent cell death by addition of serum or overexpression of Bcl-2. Thus v-Src transformed Rat-1 cells can be protected from apoptosis by serum, v-Src, or Bcl-2. We investigated how v-Src protects from apoptosis under these conditions. Amongst other effects, v-Src activates two kinases which have been shown to protect cells from apoptosis, phosphatidylinositol 3-kinase (PI3-K) and extracellular signal-regulated kinase (ERK1/2). We found that switching off v-Src led to a decrease in the activity of both PI3-K and ERK1/2, however, we found that adding a specific inhibitor of PI3-K (LY294002) to v-Src transformed Rat-1 cells grown in low serum induced apoptosis while a specific ERK kinase (MEK1) inhibitor (PD98059) had no effect. This suggests that v-Src protects from apoptosis under low serum conditions by activating PI3-K.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Caspase Inhibitors
  • Caspases / physiology
  • Cell Line
  • Cell Line, Transformed
  • Cell Survival
  • Culture Media
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / physiology
  • Oncogene Protein pp60(v-src) / genetics
  • Oncogene Protein pp60(v-src) / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Rats
  • Serum Albumin, Bovine
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Caspase Inhibitors
  • Culture Media
  • Proto-Oncogene Proteins c-bcl-2
  • Serum Albumin, Bovine
  • Oncogene Protein pp60(v-src)
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Caspases