The tumour suppressor p53 is a transcription factor that can be activated by diverse stress stimuli, including DNA damage, hypoxia, and induction of certain oncogene. Activated p53 can trigger several cellular responses, of which cell cycle arrest, cell senescence and apoptotic cell death are thought to be indispensable for tumour suppression. The cyclin dependent kinase (CDK) inhibitor p21 is critical for p53-mediated induction of cell cycle arrest and senescence, whereas the pro-apoptotic BH3-only BCL-2 family members PUMA and NOXA are essential for p53-mediated apoptosis. Surprisingly, mice lacking PUMA, NOXA, and p21 are not cancer prone, despite the failure of cells derived from these mice to undergo p53 mediated apoptosis, cell cycle arrest and senescence. In contrast, all p53-deficient mice succumbed to lymphoma or other tumours between 120-250 days.
It will greatly improve our understanding of how p53 suppresses tumour development to identify genes that are induced or repressed by p53 in response to the activation of oncogenes. In this project, c-Myc or mutant N-Ras oncogenes are inducibly expressed in both wild-type and p53-deficient haematopoietic stem/ progenitor cells in vivo. RNA sequence analysis will be performed to identify genes that are specifically induced or repressed in response to oncogene activation in a p53-dependent manner. Subsequently, chromatin immunoprecipitation (CHIP) will be performed to analyse the interaction between p53 and the genes of interest. Finally, we will use transgenic or genome editing methods to identify the function of these genes with the intent to thereby reveal the mechanism(s) by which p53 prevents tumour development.