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  • Original Paper
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Molecular signature of oncogenic ras-induced senescence

Oncogene volume 23, pages 9238–9246 (2004)Cite this article

Abstract

Senescence irreversibly arrests the proliferation of cells that have sustained significant cellular stress. Replicative senescence, due to the shortening and dysfunction of telomeres, appears to provide a barrier to the immortalization of cells and development of cancer. In normal human fibroblasts, senescence induced by oncogenic H-ras displays a nearly identical cellular phenotype to that of replicative senescence, suggesting the activation of a common senescence mechanism. In this study, we investigated the gene expression profile of oncogenic H-ras-induced senescent human diploid fibroblasts. We found altered gene expression of various cell cycle regulators in both oncogenic H-ras-induced senescent cells and replicative senescent cells. Similar to replicative senescent cells, H-ras-induced senescent cells exhibited specific downregulation of genes involved in G2/M checkpoint control and contained tetraploid cells that were arrested in a G1 state. This observation suggests that the inactivation of G2/M checkpoints may be involved in senescence and may play a role in the generation of senescent G1 tetraploid cells. Lastly, we have identified two genes, topoisomerase IIα and HDAC9, whose expression was specifically altered under several conditions associated with senescence, suggesting that these two molecules may be novel biomarkers for senescent human fibroblasts.

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Acknowledgements

We thank J Platt and L Stein of the Gene Expression Core Facility at Roswell Park Cancer Institute for their assistance with the microarray analysis. We are also grateful to Dr J Black and Dr A Black for generously providing antibodies, Dr M Kimura and Dr H Nagase for assistance with real-time PCR, Dr M McHugh and Dr T Beerman for reagents and assistance with the comet assay, Dr F Li and Dr I Roninson (Ordway Research Institute, Inc.) for PCR primer sequences. We also thank Dr M Brattain, Dr C Porter, Dr J Black, Dr T Beerman, Dr W Weebadda and T Bihani for critical reading and helpful comments of this manuscript. This work was supported by the Roswell Park Cancer Center Core Grant CA16056 and the Greater Buffalo Community Foundation contract Grant number 6234401.

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  1. Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, 14263, NY, USA

    Douglas X Mason, Tonya J Jackson & Athena W Lin

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  1. Douglas X Mason
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Correspondence to Athena W Lin.

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Mason, D., Jackson, T. & Lin, A. Molecular signature of oncogenic ras-induced senescence. Oncogene 23, 9238–9246 (2004). https://doi.org/10.1038/sj.onc.1208172

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