Distinguished Professor; William R. Kenan Professor
Biochemistry & Biophysics
Cancer Cell Biology
Area of interest
I have had a long standing interest in understanding the mechanisms of cell proliferation and cancer development and have made significant contributions in three areas. (1) The discovery and regulation of mammalian G1 cyclins and CDK inhibitor genes. (2) The mechanism of E3 ubiquitin ligases and the control of cell cycle and p53 by the ubiquitin pathway. (3) How altered metabolic enzymes impact epigenetic control and contribute to tumorigenesis.
Since arriving at UNC-Chapel Hill in 1993, my lab has been studying the function and mechanism of both RB and p53 tumor suppression pathways. We isolated three new INK4 genes and were the first to demonstrate the functional dependency of INK4 genes on RB, leading to the establishment of the INK4-CDK4-RB pathway. We have also demonstrated, genetically, the function of INK4 genes in tumor suppression and stem cell control and, biochemically, the epigenetic control of p16 by polycomb. We discovered p53 regulation by tumor suppressor ARF, ribosomal proteins, nuclear-cytoplasmic shuttling, and very recently two cytoplasmic E3 ubiquitin ligases, CUL7 and CUL9.
These significant contributions helped to advance our understanding of the two major tumor suppression pathways. Late in the 1990s, I initiated a new line of research on cell regulation and tumor suppression by the ubiquitin pathway. My laboratory discovered two small RING proteins, ROC1 and ROC2, as the core of estimated 400 – 500 cullin-RING E3 ubiquitin ligases (CRLs), the mechanism for assembling a large number of CRL3 and CRL4 ligase complexes, a key regulator of the CRLs, CAND1, and several CRL substrates that regulate different cellular processes and are linked to human diseases. These accomplishments helped to establish CRL as the largest family of E3 ligases in the regulation of most cellular processes. Beginning in 2006, I started to study cancer metabolism. We discovered that acetylation plays broad roles in the regulation of many metabolic enzymes, establishing acetylation as a major posttranslational modification rivaling phosphorylation and ubiquitylation.
We have also demonstrated that tumor-derived mutant metabolic enzymes IDH lost its catalytic activity in producing Î±-ketoglutarate (Î±-KG) and that oncometabolite 2-hydroxygultarate (2-HG) produced by the mutants IDH and succinate and fumarate accumulated in tumors cells, is an antagonist of Î±-KG and inhibits Î±-KG-dependent dioxygenases, including both histone demethylases and TET DNA dioxygenases. These discoveries opened the field of epigenetic control by metabolites.
Awards and Honors
- 2012 Elected fellow, American Association for the Advancement of Science
- 1995: American Cancer Society Junior Faculty Research Award
- 1995: Pew Scholar in Biomedical Sciences
- 1999: UNC Hettleman Award for Scholarly Achievement
- 1999: AACR Gertrude B. Elion Cancer Research Award
- 1999: United States Department of Defense Breast Cancer Research Career Development Award
- 2005: William R. Kenan Distinguished Professor, UNC-Chapel Hill
- 2011: Battle Distinguished Cancer Research Award, UNC-Chapel Hill
- 2012: Elected Fellow, American Association for the Advancement of Science