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.

IL-15 enhances the antitumor effect of human antigen-specific CD8+T cells by cellular senescence delay

“…S1). [27][28][29] Taken together, we found IL-15-expanded, Lchain-specific T cells have a higher percentage of S/G2 phase cells after stimulation, lower expression of cell cycle inhibitors, less production of senescence-associated proinflammatory cytokines, higher expression of CD27 and CD28, and downregulation of cellular senescence biomarker genes, suggesting that IL-15-expanded, L-chain-specific T cells exhibit senescence delay. 24,26,30,31 IL-15 regulates senescence delay in antigen-specific T cells through the JAK3-STAT5 signaling pathway…”

Status of RASSF1A in Uveal Melanocytes and Melanoma Cells

“…The microsatellite markers, D3S1478 and D3S1578, located on chromosome 3p21.3 and flanking the RASSF1A locus, were used to analyze the LOH on 9 uveal melanoma tumors (13)(14)(15)(16)(17)(18)(19)(20)(21). The methylation of RASSF1A promoter was analyzed by MSP on PCR products with specific primers from bisulfite-treated genomic DNA.…”

AIM2, an IFN-Inducible Cytosolic DNA Sensor, in the Development of Benign Prostate Hyperplasia and Prostate Cancer

“…13,14), reduce telomere length (15), resulting in an accumulation of senescent prostate epithelial cells (PrEC) in BPH (16). Accordingly, expression of a set of ISGs is upregulated during the onset of prostate epithelial cellular senescence (17)(18)(19). Furthermore, levels of the IFNb increase in human diploid fibroblasts (HDF) when HDFs approach cellular senescence (20) and the expression of IFNinducible proteins is upregulated in senescent PrECs (21) and HDFs (22).…”