Pathway profiling of replicative and induced senescence.

摘要

Senescence is a permanent withdrawal from cell cycle that occurs naturally in cells in response to the shortening of telomeres. This natural "clock" serves to limit the number of cell divisions and therefore protects the cell from potentially carcinogenic mutations. However, senescence also occurs in response to external stresses to the cell, which is known as induced senescence. This study compares the mechanisms of natural senescence, a response to the shortening of telomeres during replication, with induced senescence by using various drugs to induce senescence: 5-aza-2-deoxycytidine (a demethylating agent), Adriamycin (a chemotherapeutic drug), and H 2O2 (an agent causing oxidative stress).;MDAH041 cells, which are fibroblasts isolated from a patient with Li Fraumeni Syndrome, have heterozygous alleles of p53 and can therefore undergo natural senescence with serial cell culture or at a low frequency spontaneously immortalize once the wildtype copy of p53 is lost. Therefore, this cell model provides naturally senescent cells as well as immortal cells which can be treated with the aforementioned drugs resulting in induced senescence. Using these conditions, gene expression profiling was performed. Gene expression analysis revealed 48 genes differentially expressed in all 4 senescence types compared to the immortal control. Pathway analysis of these 48 genes from all types of cellular senescence revealed several pathways, each of which are involved in innate immunity, showing for the first time a common gene expression profile among different types of senescence, as well as a central role for the IFN pathway in both natural and induced senescence. Specifically, I have focused on the IL1 pathway which is up-regulated in all types of senescence compared to immortal proliferating cells and will be the basis for additional mechanistic studies.