Regulation of the Activity and Stability of the Tumor Suppressor p53 In Vivo

Abstract

Abstract : Following DNA damage, p53 protein level is increased and its activity induced, leading to cell-cycle G1 arrest or apoptosis depending on cell type. Our research is focused on two aspects of p53 biology: (1) Elucidation of signaling pathways activating p53 following DNA damage; and (2) Understanding the importance of p53 transcriptional activity in the p53-dependent apoptosis and tumor suppression. During the past year, we have completed the analysis of p53 responses to DNA damage in p53Ser18Ala mutant ES cells, indicating that phosphorylation of mouse p53 at Ser 18 by is required for a full p53 responses to DNA damage. In addition, we have introduced this mutation into mouse germline for further in vivo analysis. We have also introduced Ser/Thr to Ala mutations at the JNK/MAP kinase phosphorylation sites and preliminary analysis of the mutant indicates that these phosphorylation events are not required for p53 responses to DNA damage but might be involved in cellular proliferation. We have also demonstrated that p53 transcriptional activity is required for p53-dependent apoptosis in both ES cells and thymocytes following DNA damage. We have introduced the p53G1n25Ser26 mutation into mouse germline to test the importance of p53 transcriptional activity in p53-dependent tumor suppression.