As a step towards understanding the mechanisms of p53 mediated apoptosis and carcinogenesis, we design to investigate the molecular events determining whether the cell enters growth arrest or undergoes apoptosis upon p53 induction. We propose that translocation of Bax protein from cytosol to mitochondria represents an important regulatory step in p53-mediated apoptosis and this process is regulated by a class of proteins named as modulators or co-activators of apoptosis. The research plan of this proposal is centered on testing this hypothesis. The first two specific aims are focused on investigating the role of Peg3/Pw1 on the regulation of cell death checkpoint, namely Bax and Bcl-2. In the first specific aim, we will set up both in vitro and in vivo assays to explore the molecular mechanisms for Peg3/Pw1 -induced Bax translocation from cytosol to mitochondria. In the second specific aim, we will investigate the molecular basis of Peg3/Pw1-induced Bcl-2 ubiquitination and degradation. The third specific aim concentrates on the identification and preliminary characterization of novel modulators of apoptosis in murine cells using a retroviral gene trapping system. Genetic alteration of p53 is frequently associated with human cancers and p53-mediated apoptosis plays a critical role in preventing carcinogenesis and malignancies. Thus, understanding the mechanisms of p53-induced apoptosis represents an important research avenue and may provide scientific basis for better treatment of human cancers.
| Ren, Xiaoyang; Xu, Zhengming; Myers, Jeffery N et al. (2007) Bypass NFkappaB-mediated survival pathways by TRAIL and Smac. Cancer Biol Ther 6:1031-5 |
| Johnson, Mark D; Wu, Xiangwei; Aithmitti, Nadia et al. (2002) Peg3/Pw1 is a mediator between p53 and Bax in DNA damage-induced neuronal death. J Biol Chem 277:23000-7 |
