This proposal is aimed at understanding how p53 restricts cellular plasticity, and how the loss of this restriction might be targeted in tumors wit compromised p53 function. p53 is best known for its role in eliminating cells that have sustained mutations, however p53 has also been shown to play a role in many other processes, suggesting p53 can also prevent tumor formation through alternative mechanisms. Multiple studies have implicated p53's capacity in regulating cell fate, however, the mechanisms have remained elusive and their relationship to p53's action in cancer unknown. Recently, the Lowe laboratory provided insight in discerning the mechanisms by which p53 regulates cell fate and how this mediates its anti-oncogenic role. They demonstrated that p53 deficiency in hepatocytes permits loss of terminal differentiation leading to the establishment of a nestin positive, dedifferentiated state that is sensitive to transformation by drivers of distinct liver cancer lineages and the emergence of nestin positive progenitor cell tumors. I propose to utilize this model to characterize the gene expression changes influenced by p53 during the dedifferentiation of hepatocytes, and examine p53's role in restricting liver plasticity and carcinogenesis through the use of antisense oligo technology to repress nestin and other effectors identified in my transcriptional profiling. This study will further our understanding of he molecular mechanisms underlying p53's restriction of plasticity and identify potential therapeutic targets for p53-mutant tumors.
Statement p53 is best known as a tumor suppressor for its translation of diverse stress signals into downstream responses including cell cycle arrest, DNA damage response, senescence, and apoptosis, however p53 has also been shown to play a role in many other processes, including stabilizing cell fate. By following up recent findings from the Lowe Lab which demonstrated how p53's role in restricting cellular plasticity is important for its action in tumor suppression, I will increase our understanding of how p53 restricts pro- tumorigenic de-differentiation and how its loss may be targeted therapeutically. Furthermore this work will identify effectors of de-differentiation downstream of p53 loss and determine their functional role, an essential step in determining if they represent candidate clinical targets
