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A comparison of oncogene-induced senescence and replicative senescence: implications for tumor suppression and aging

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Abstract

Cellular senescence is a stable proliferation arrest associated with an altered secretory pathway, the senescence-associated secretory phenotype. However, cellular senescence is initiated by diverse molecular triggers, such as activated oncogenes and shortened telomeres, and is associated with varied and complex physiological endpoints, such as tumor suppression and tissue aging. The extent to which distinct triggers activate divergent modes of senescence that might be associated with different physiological endpoints is largely unknown. To begin to address this, we performed gene expression profiling to compare the senescence programs associated with two different modes of senescence, oncogene-induced senescence (OIS) and replicative senescence (RS [in part caused by shortened telomeres]). While both OIS and RS are associated with many common changes in gene expression compared to control proliferating cells, they also exhibit substantial differences. These results are discussed in light of potential physiological consequences, tumor suppression and aging.

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Acknowledgments

Microarray sample preparation and Affymetrix GeneChip Human Genome U133 Plus 2.0 microarray hybridization and scanning were conducted by the Paterson Institute for Cancer Research Microarray Service (Manchester, UK). Work in the lab of PDA was funded by BBSRC, and work in the lab of JMS was funded by NIA, as part of a joint-funding NIA/BBSRC partnership.

Data files

Accession number for RS array GSE36640 (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE36640)

Accession number for OIS array GSE54402 (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE54402)

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Authors and Affiliations

  1. Institute of Cancer Sciences, University of Glasgow, Glasgow, UK

    David M. Nelson, Tony McBryan & Peter D. Adams

  2. Beatson Institute for Cancer Research, Glasgow, UK

    David M. Nelson, Tony McBryan & Peter D. Adams

  3. Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, 02912, USA

    Jessie C. Jeyapalan & John M. Sedivy

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  1. David M. Nelson
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  2. Tony McBryan
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  3. Jessie C. Jeyapalan
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  5. Peter D. Adams
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Correspondence to Peter D. Adams.

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Supplementary Figure 1

Confirmation of RS and OIS. (A) Proliferation curve for IMR90 cells cultured to RS. (B) SA β-gal staining of proliferating and RS IMR90 cells. (C) Whole cell lysates from proliferating and RS IMR90 cells were fractionated by SDS-PAGE and Western blotted for markers of proliferation and senescence. GAPDH serves as a loading control. (D) SA β-gal staining of control and H-RASG12V-infected IMR90 cells. (E) Whole cell lysates from control and H-RASG12V-infected IMR90 cells were fractionated by SDS-PAGE and Western blotted for markers of proliferation and senescence. GAPDH serves as a loading control. (PDF 757 kb)

Supplementary Figure 2

Principal component analysis (PCA) of microarray expression datasets. (A) PCA shows that major separation of array datasets is according to proliferating (PD28) versus RS (PD90). (B) PCA shows that major separation of array datasets is according to control infection versus H-RAS infection (OIS). (PDF 49 kb)

Supplementary Figure 3

Unsupervised clustering of microarray expression datasets. (A) Unsupervised clustering shows that major separation of array datasets is according to control infection versus H-RAS infection (OIS). (B) Unsupervised clustering shows that major separation of array datasets is according to proliferating (PD28) versus RS (PD90). (PDF 1784 kb)

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Nelson, D.M., McBryan, T., Jeyapalan, J.C. et al. A comparison of oncogene-induced senescence and replicative senescence: implications for tumor suppression and aging. AGE 36, 9637 (2014). https://doi.org/10.1007/s11357-014-9637-0

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