Role of p53 in Mammary Epithelial Cell Senescence
Annual rept. 1 May 2003-30 Apr 2004
NEW ENGLAND MEDICAL CENTER HOSPITAL BOSTON MA
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The tumor suppressor p53 plays an important role in a variety of cancers including breast cancer. It inhibits the growth of malignant cells either by inducing G1 arrest, apoptosis or senescence. We previously showed that p53 protein level do not change in senescence of pre-selection HMECs, however p53 and its target gene p21 are significantly upregulated during senescence in post-selection HMECs. Do further study the role of p53 in senescence of postselection HMECs, we used knockdown approach using RNA interference RNAi technology. We generated post-selection HMECs stably expressing p53 and p21 RNAi. Here we show that cells with reduced p53 or p21 proteins have extended replicative life span. At the end of life span cells expressing p53 or p21 RNAi entered a crisis like stage without any emergence of immortal clones. Furthermore, we show that compared to p21 RNAi, p53 RNAi expressing cells proliferates for four more population doublings. Our data suggest that other transcriptional targets of p53 may also be involved in replicative senescence of post-selection HMECs. We are using chromatin immunoprecipitation linked PCR, ChIPassay to identify these additional targets of p53 involved in replicative senescence of HMECs.
- Anatomy and Physiology
- Medicine and Medical Research