Role of p53 in Mammary Epithelial Cell Senescence
Annual summary rept. 1 May 2002-30 Apr 2009
EVANSTON NORTHWESTERN HEALTHCARE RESEARCH INST IL
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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, senescence or autophagy. In this career development award, we studied the role of p53 in human mammary epithelial cell HMEC senescence and the requirement of p53 inactivation in transformation of HMECs. First, we determined that p53 binding activity increases with senescence in post-selection HMECs, and expression of its targets such as p21 is increased in post-selection senescent cells. We also found that there were no major differences in acetylation or phosphorylation of p53 in pre-selection and post-selection HMECs. However, there is a modest increase in acetylated p53 in post-selection senescent HMECs. Next, we studied the role of p53 in HMEC senescence using RNAi approach. Our studies suggested that p53 or p21 knockdown results in bypass of senescence in HMECs. We also carried out an array analysis of p53 targets in early passage proliferating and late passage senescent post-selection HMECs. Next, we studied the role of additional targets of p53 in HMEC senescence using RT-PCR analysis and identified additional targets of p53 using ChIP assay. Finally, we studied p53p21 pathway in BMI1H-RAS transformed HMECs, and the role of p53 in oncogene-induced senescence OIS in HMECs.
- Genetic Engineering and Molecular Biology
- Anatomy and Physiology
- Medicine and Medical Research