Attardi Lab Research
Cancer is a disease of uncontrolled cellular proliferation driven by mutations of key proto-oncogenes and tumor suppressor genes. A particularly prevalent event in tumorigenesis, occurring in over half of all human cancers, is inactivation of the p53 tumor suppressor. p53’s critical role as a tumor suppressor is underscored further by the observation that p53-/- mice develop cancer at 100% frequency. p53 loss in tumors is associated with numerous phenotypes, including deregulated proliferation, enhanced cell survival, increased angiogenesis, augmented genomic instability and generally aggressive behavior. The pleiotropic effects of p53-deficiency suggest a broad spectrum of functions for p53.
p53 performs its tumor suppressor function at least in part by sensing cellular stress signals and restricting cellular proliferation in the face of such adverse conditions by inducing cell cycle arrest or apoptosis. Although p53’s ability to transcriptionally activate a host of target genes is thought to contribute to its function, p53 also possesses other activities, including regulating transcriptional repression, homologous recombination, and mitochrondrial membrane integrity. Additionally, there is functional overlap and interaction between p53 and its family members p63 and p73, also transcription factors that transactivate genes through the same response elements. Thus, p53 is a complex, multifaceted protein whose mechanism of action in vivo is not well understood. Studying the networks downstream of p53 will provide insight into various aspects of its function. p53 functions include not only tumor suppression but also roles in stress responses in other contexts, including aging, sensitivity to chemo and radiation therapies, pigmentation, cellular reprogramming, and both stroke and neuronal disease, amongst others.
Our goals involve dissecting the pathways downstream of p53 in apoptosis, tumor suppression, and other p53 functions in vivo using mouse genetics, with the specific aims of:
1) delineating the biochemical activities of p53 essential for its function in different settings through the generation of p53 knock-in mice, and using this information to define molecular components of p53 pathways.
2) defining the role of specific novel p53-inducible genes through the creation of p53 target gene knockout mice. These include Perp, an apoptosis-specific target gene with dual roles downstream of p53 in apoptosis and downstream of p63 in cell-cell adhesion, and other genes involved in apoptosis, such as Siva.
Studying p53 using genetically engineered mice, where in vivo phenotypes including tumor suppression can be examined, and from which a variety of different types of primary cells can be derived and analyzed, will yield important, physiologically relevant insight into p53 function. In addition to providing an understanding of p53, our work, in particular through the detailed analysis of p53 target gene products, will provide general insight into fundamental cell biological processes, including apoptosis and cell-cell adhesion, and their importance in tissue homeostasis and cancer.
Perp, a p53/p63 target gene | p53 targets in apoptosis | p53 knock-in mice