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

摘要

The p53 protein contains several functional domains. We found that activation domain 2 and proline-rich domain are necessary for the apoptotic activity but not cell cycle arrest and form an activation domain for inducing pro-apoptotic genes. We also found that at least two of the three domains, that is, activation domain 1 and 2 and the proline-rich domain, are necessary for cell cycle arrest. Interestingly, we found that deletion of activation domain 1 alleviates the requirement of the C-terminal basic domain for apoptotic activity. Therefore, we generated a small but very potent apoptotic inducer of p53 n MCF7 Breast cancer cells. To determine the efficacy of chemotherapeutic agents in inducing apoptosis, we found that at a comparable expression level, p73, but not p53, cooperate DNA Damage agents to induce apoptosis in MCF7 cells in a p53-dependent manner. As an extension of our studies to determine how p53 functions as a tumor suppressor, we identified five novel p53 and p73 target genes, including Dickkopf-l (Dkk-i), an antagonist of the Wnt oncogenic pathway, and TAP 1, a transporter of major histocompatibility class I antigens. This suggests that p53 may suppress transformation by Wnt and play a role in immunosurveillance.