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

Oncogene volume 22, pages 4266–4280 (2003)Cite this article

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.

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Acknowledgements

The authors are thankful to H Grunicke (University of Innsbruck, Austria) for providing MMTV-ras plasmids and to the Resource Center/Primary Database of the Human Genome Project (Berlin, Germany) for providing the survivin clone. We thank J Gotzmann for valuable advice regarding immunofluorescence studies, and B Lüscher and G Krupitza for critical reading of the manuscript. The work was supported by grants of the Institute of Cancer Research of the University of Vienna (to KS), the Hochschuljubiläumsstiftung (Project 165/1) (to CS) and the Jubiläumsfond der Österreichischen Nationalbank (Project 8317) (to CC).

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  1. Institute of Cancer Research, University of Vienna, Borschkegasse 8a, Vienna, A-1090, Austria

    Klaus W Sommer, Chantal J Schamberger, Gerlinde E Schmidt, Soleman Sasgary & Christa Cerni

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  1. Klaus W Sommer
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Correspondence to Christa Cerni.

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Sommer, K., Schamberger, C., Schmidt, G. et al. Inhibitor of apoptosis protein (IAP) survivin is upregulated by oncogenic c-H-Ras. Oncogene 22, 4266–4280 (2003). https://doi.org/10.1038/sj.onc.1206509

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