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Critical pathways in cellular senescence and immortalization revealed by gene expression profiling

Oncogene volume 27, pages 5975–5987 (2008)Cite this article

Abstract

Bypassing cellular senescence and becoming immortal is a prerequisite step in the tumorigenic transformation of a cell. It has long been known that loss of a key tumor suppressor gene, such as p53, is necessary, but not sufficient, for spontaneous cellular immortalization. Therefore, there must be additional mutations and/or epigenetic alterations required for immortalization to occur. Early work on these processes included somatic cell genetic studies to estimate the number of senescence genes, and microcell-mediated transfer of chromosomes into immortalized cells to identify putative senescence-inducing genetic loci. These principal studies laid the foundation for the field of senescence/immortalization, but were labor intensive and the results were somewhat limited. The advent of gene expression profiling and bioinformatics analysis greatly facilitated the identification of genes and pathways that regulate cellular senescence/immortalization. In this review, we present the findings of several gene expression profiling studies and supporting functional data, where available. We identified universal genes regulating senescence/immortalization and found that the key regulator genes represented six pathways: the cell cycle pRB/p53, cytoskeletal, interferon-related, insulin growth factor-related, MAP kinase and oxidative stress pathway. The identification of the genes and pathways regulating senescence/immortalization could provide novel molecular targets for the treatment and/or prevention of cancer.

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Acknowledgements

This study was supported by the Barbara and Fred Erb Endowed Chair in Cancer Genetics (to MAT), and by funds from the Barbara Ann Karmanos Cancer Institute, the State of Michigan Life Sciences Corridor, Wayne State University and Michigan Center for Genomic Technologies Applied Genomics Technology Center (MEDC 085P10009816), and the Genomics and Biostatistics Cores of the Barbara Ann Karmanos Cancer Institute (P30CA022453). We thank the numerous members of the Tainsky lab who over the past 20 years have contributed to the studies of the immortalization of Li-Fraumeni cells, including Sun Yim, Farideh Bischoff, Tian-Ai Wu, Eliayhu Kraus, Sylvia Dryden, Olga Kulaeva, Lin Tang, Rita Rosati, Janice Kraniak and Qunfang Li. We acknowledge Louise C Strong whose insight into human cancer genetics led to the establishment of cell lines from Li-Fraumeni patients. We thank Dr Janice Kraniak for critical reading of the manuscript.

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  1. Department of Pathology, Program in Molecular Biology and Genetics, Barbara Ann Karmanos Cancer Institute, and Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA

    A L Fridman & M A Tainsky

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  1. A L Fridman
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  2. M A Tainsky
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Correspondence to M A Tainsky.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Fridman, A., Tainsky, M. Critical pathways in cellular senescence and immortalization revealed by gene expression profiling. Oncogene 27, 5975–5987 (2008). https://doi.org/10.1038/onc.2008.213

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