College of Physicians and Surgeons
Genotoxic stress triggers two major biological responses in mammalian cells. The first is cell cycle arrest that allows DNA repair and cell survival. The second is induction of cell suicide through apoptosis as a means of eliminating irreparably damaged cells. Tumor suppressor p53 plays essential roles in both cell cycle control and apoptosis. A fundamental challenge is to demonstrate how p53 distinguishes damage signals and determines cell fates. Our hypothesis is that p53 protein differentially is modified in response to distinct stresses, which leads to the activation of different target genes and ultimately different cell fates. Our studies of p53 functions include two aspects: one is to identify key elements of p53 function in signaling apoptosis and another is to reveal a link between posttranscriptional modifications of p53 and its biological functions. Our goals are to elucidate the mechanisms by which p53 induces apoptosis and to reveal essential targets for chemotherapeutic applications.
We have previously shown that PAC1, a phosphatase of MAP kinases, is a direct transcriptional target of p53 and it is essential for p53-dependent apoptosis.
We have demonstrated a novel mechanism for p53 to regulate its target genes. p53 binds to palindromic motifs in the promoters of its target genes and induces gene expression under specific genotoxic stress that leads to apoptosis. Using this information, we plan to conduct a genome-wide search to identify more target genes in the p53 pathway. We will then characterize these potential targets using a variety of molecular and cellular approaches. We will elucidate the mechanisms by which these genes are regulated, and the roles of these genes in signaling the cellular response to genotoxic stress.
An important question is how p53 determines the type of cellular responses to different damage. As we described above, p53 only regulates a specific subset of its target genes under the conditions that cause cell death rather than cell cycle arrest. We speculate that p53 protein is modified following specific damage signals, such as oxidative stress, and that this modified p53 binds to palindromic sites in the promoters of its downstream genes that function in the apoptotic pathway. We have developed two p53-inducible systems and several other cellular systems to investigate the mechanisms that mediate p53 modifications. Our goal is to reveal a link between p53 modifications and its choices of binding to different binding sites, resulting in different consequences, either cell cycle arrest or cell death. We will focus on phosphorylation, acetylation and ubiquitination of p53 protein. We have recently observed that p53 is phosphorylated at several serine sites under some treatments that induce apoptosis. We plan to pinpoint the phosphorylation sites critical for p53 function. We will also determine the status of p53 acetylation and try to find a link between p53 function and its acetylation.
Project Leader/Principal Investigator
United States of America
Department of Radiation Oncology