Inhibitor of apoptosis protein (IAP) survivin is upregulated by oncogenic c-H-Ras

Oncogene. 2003 Jul 3;22(27):4266-80. doi: 10.1038/sj.onc.1206509.

Abstract

Among the inhibitors of apoptosis proteins (IAPs), survivin has attracted special attention through its involvement in human cancer. The mechanism underlying tumour-associated survivin re-expression is not known. We found a correlation between exogenous c-H-Ras oncoprotein and endogenous survivin in a series of rat cell lines, which expressed defined oncogenes. Moreover, human HaCat cells, transfected with a constitutively activated c-H-ras gene, had significantly increased survivin levels. To study the interdependence of the two proteins, we generated a rat cell line that expressed a dexamethasone-inducible c-H-ras construct. Induction of c-H-Ras expression was followed by rapid upregulation of survivin. Conversely, downregulation of the oncoprotein resulted in prompt reduction of survivin to baseline value. c-H-Ras-induced survivin was expressed constitutively and independent of cell cycle progression or proliferation. Compromising Ras-stimulated PI3-K activity and MEK1 by chemicals abolished survivin expression and was associated with apoptotic cell death. Upregulation of survivin appeared to be an important activity of c-H-Ras oncoprotein, since cotransfection of a survivin-antisense construct into c-myc/c-H-ras-transfected primary rat embryo cells resulted in profound reduction of transformed clones. It is tempted to speculate that the frequent presence of survivin in human cancer cells might be a consequence of activated Ras-signalling pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cell Cycle
  • Cell Division
  • Cell Line, Transformed
  • Cell Separation
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Flow Cytometry
  • Genes, ras / genetics*
  • Humans
  • Immunoblotting
  • Inhibitor of Apoptosis Proteins
  • Luciferases / metabolism
  • MAP Kinase Kinase 1
  • Microscopy, Fluorescence
  • Microtubule-Associated Proteins / biosynthesis*
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mitosis
  • Neoplasm Proteins
  • Oligonucleotides, Antisense / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Plasmids / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Rats
  • Signal Transduction
  • Survivin
  • Time Factors
  • Transfection
  • Tumor Cells, Cultured
  • Up-Regulation*
  • ras Proteins / metabolism*

Substances

  • BIRC5 protein, human
  • Inhibitor of Apoptosis Proteins
  • Microtubule-Associated Proteins
  • Neoplasm Proteins
  • Oligonucleotides, Antisense
  • Survivin
  • Luciferases
  • Phosphatidylinositol 3-Kinases
  • Protein-Serine-Threonine Kinases
  • MAP Kinase Kinase 1
  • MAP2K1 protein, human
  • Mitogen-Activated Protein Kinase Kinases
  • ras Proteins