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

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.

Figure 1

Senescence/immortalization pathways. This figure was drawn using GenMAPP version 2 (http://www.genmapp.org/; Salomonis et al. (2007)). Pathway and gene interactions were derived from literature referenced in this paper and the supplemental section of this paper, GenMAPP, KEGG Pathway (Kanehisa and Goto, 2000), NCBI Entrez Gene (http://www.ncbi.nlm.nih.gov/sites/entrez), InvivoGen (http://www.invivogen.com/docs/Insight200509.pdf), Schroder et al. (2004), and Takaoka and Yanai (2006).