Mechanism of p53-Dependent Apoptosis and its Role in Breast Cancer Therapy

摘要

p73, a member of the p53 family, can induce apoptosis and physically interact with p53. To determine whether p53 and p73 functionally interact, we generated several MCF7 cell lines that inducibly express p73. We found that p73- dependent apoptosis was enhanced by DNA damage (i.e., p53) in MCF7 cells that harbor wild-type p53, but not in MCF7E6 cells that ectopically express human papillomavirus E6 protein and are functionally p53-null. These results suggest that a functional interaction between p53 and p73 in MCF7 cells leads to enhanced induction of apoptosis. It has been shown by others that the proline- rich domain within residues 60-90 are necessary for growth suppression. Here, we showed that the proline-rich domain is required for inducing apoptosis but not cell cycle arrest. We also showed that this domain is necessary for induction of cellular target genes, e.g., p21, MDM2, but not for activation of transiently transfected promoters from such genes. These results suggest that the proline- rich domain plays a role in chromatin remodeling, which counteracts chromatin- mediated repression for the cellular genes.