Dr. Wei Gu Research

Biography
Research Summary
Publications
Lab Members

Research Summary

The focus of our laboratory is to understand molecular mechanisms underlying p53 stabilization and activation in tumor suppression. Since p53 mutations are the most common genetic lesions associated with human cancer, a major objective of molecular oncology is to elucidate the mechanisms by which p53 is regulated. My laboratory has identified most of the molecules and pathways that regulate p53 activity. First, we discovered that p53 activity is controlled in large part by acetylation and deacetylation of the p53 polypeptide. In particular, we established that acetylation of specific p53 residues is required for its transcriptional function and acts as the primary signal to differentially induce its canonical functions in apoptosis, cell growth arrest and senescence. Second, we identified “dynamic ubiquitination” (polyubiquitination, monoubiquitination and deubiquitination) as the major mechanism by which the stability and subcellular localization of p53 protein are determined. More recently, we found that the three canonical functions of p53 in apoptosis, cell growth arrest and senescence are dispensable for its in vivo activity as a tumor suppressor. We further demonstrated that p53-mediated ferroptosis is critically involved in tumor suppression, representing the first evidence that p53 can suppress tumor growth in the absence of its canonical functions.

Notably, several of our findings have had important implications well beyond p53 biology. For example, our studies of p53 acetylation laid the foundation for the current view that reversible acetylation is a general mechanism for regulation of non-histone proteins. Likewise, following our initial discovery of a deubiquitinase HAUSP-mediated stabilization of the p53 and Mdm2 polypeptides, deubiquitination has come to be accepted as a common mechanism of protein stabilization. Other accomplishments include identification and characterization of key cofactors in the p53/ARF tumor suppression pathway. We have also established important mouse models dissecting these key factors in p53 regulation such as HAUSP-mutant mice, ARF-BP1-mutant mice, ULF-mutant mice and Sirt1 transgenic mice, which lead to significant implications in cancer therapy. Our lab has extensive experience in studying cell cycle regulation and tumor suppressors/oncogenic pathways using approaches ranging from molecular biology, biochemistry, cell biology to mouse genetics. The research in my laboratory has a significant impact in elucidating mechanisms of p53-mediated tumor suppression and uncovering novel strategies to target this critical pathway therapeutically. Specific lines of investigation include:

  1. Elucidating the acetylation code in p53 regulation and beyond
  2. Dissecting the roles of cell metabolism in tumor suppression
  3. Exploring the ubiquitination pathway in cancer therapy
  4. Investigating the roles of oxidative stress responses in aging