Inhibitor of apoptosis protein (IAP) survivin is upregulated by oncogenic c-H-Ras.
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.
Sommer
Klaus W
KW
Institute of Cancer Research, University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
Schamberger
Chantal J
CJ
Schmidt
Gerlinde E
GE
Sasgary
Soleman
S
Cerni
Christa
C
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002455:Cell Division; D002461:Cell Line, Transformed; D002469:Cell Separation; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005434:Flow Cytometry; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D015151:Immunoblotting; D051034:Inhibitor of Apoptosis Proteins; D008156:Luciferases / Q000378:metabolism; D048369:MAP Kinase Kinase 1; D008856:Microscopy, Fluorescence; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008938:Mitosis; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D000077022:Survivin; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D018631:ras Proteins / Q000378:metabolism*
D051034:Inhibitor of Apoptosis Proteins; D008156:Luciferases; D048369:MAP Kinase Kinase 1; D008869:Microtubule-Associated Proteins; D020929:Mitogen-Activated Protein Kinase Kinases; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D000077022:Survivin; D018631:ras Proteins; C107489:BIRC5 protein, human; C482125:MAP2K1 protein, human