Molecular signature of oncogenic ras-induced senescence.
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 IIalpha 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.
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Douglas X
DX
Mason
Tonya J
TJ
Jackson
Athena W
AW
Lin
D000951:Antigens, Neoplasm; D002453:Cell Cycle; D016922:Cellular Senescence / Q000502:physiology*; D020552:Comet Assay; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins; D015536:Down-Regulation; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D015689:Oncogene Protein p21(ras) / Q000502:physiology*; D012097:Repressor Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D012097:Repressor Proteins; C486544:HDAC9 protein, human; D006655:Histone Deacetylases; D015689:Oncogene Protein p21(ras); D004250:DNA Topoisomerases, Type II