Mutation of the TP53 gene is frequent in human cancer with wild-type p53 clearly being implicated as a tumor suppressor. A growing body of evidence now supports the notion that tumor-associated mutant p53 has not only lost tumor suppressing activity, but has also gained oncogenic roles. Thus, a central and significant challenge is to elucidate the molecular bases both for the tumor suppressing functions of wild-type p53 and the oncogenic activities of mutant p53 as well as deconvoluting the molecular relationship between these two. It is reasonable to expect that relevant detailed insights into wild-type-mediated tumor suppression will inform understanding of mutant-driven oncogenesis and vice versa. It is further hypothesized that by studying wild-type and mutant p53 in parallel, insights will be gained that would have been otherwise elusive. Further confounding this complex question, studies using mouse models in vivo indicate that p53-driven cell fate outcomes, be they tumor suppressing or oncogenic, can be tissue-specific. Although p53 has been shown to have cytoplasmic functions, its role in controlling gene expression is certainly central to both its wild-type tumor suppressing role and its mutant oncogenic function. The goal of the planned studies is to address this significant issue which carries important translational potential.
Specific aims are proposed to explore the tissue-specific transcriptional activity of either wild-type or mutant p53 in vivo and to identify lineage-specific determinants for p53-driven fate outcomes in a subset of tissues, namely, liver, thymus, and spleen.
The first aim i s focused on wild-type p53 in vivo and involves elucidating the molecular basis for cell lineage as a determinant for the wild-type p53-dependent response to DNA damage.
The second aim deals with tumor-associated mutant p53 and is to explore the molecular basis for the tissue-specific oncogenic activity of mutant p53. Given the essential role of transcriptional regulation in the activity of p53, it is postulated that downstream control of specific target genes are key determinants of cellular outcomes. Elucidating the molecular basis for the tumor suppressor activity of wild-type p53 is essential to be able to exploit such findings as a means to restore this function in tumor cells as a therapeutic approach. Likewise, the existence of gained oncogenic activity by tumor-associated mutant p53 provides the unexpected possibility for a targeted therapy involving a tumor suppressor. As a key difference between normal and tumor cells is their p53 status, it is anticipated that such approaches are likely to have a high therapeutic index. Given the tissue-specificity of responses to p53, it is essential that studies of p53-driven fate outcomes be addressed in a cell lineage-dependent manner, providing a central tenet for the proposed research.
The proposed research is focused on understanding the molecular basis of the tumor suppressor activity of wild-type p53 and the oncogenic functions of tumor-derived mutant p53. The long-term goal is to utilize this knowledge to improve diagnosis and design novel targeted therapies for a wide variety of human cancers.
