Area of Interest
The ribosomal protein-Mdm2-p53 pathway and energy metabolism
Cellular growth and division are two fundamental processes that are exquisitely sensitive and responsive to environmental fluctuations. One of the most energetically demanding functions of these processes is ribosome biogenesis, the key component to regulating overall protein synthesis and cell growth. Perturbations to ribosome biogenesis have been demonstrated to induce an acute stress response leading to p53 activation through the inhibition of Mdm2 by a number of ribosomal proteins (RPs). The energy status of a cell is a highly dynamic variable that naturally contributes to metabolic fluctuations, which can impact both the rates of ribosome biogenesis and p53 function. This, in turn, determines whether a cell is in an anabolic, growth promoting state or a catabolic, growth suppressing state.
Our previous studies have shown that inhibition of ribosomal biogenesis can activate p53 through RP-mediated suppression of Mdm2 E3 ligase activity. To study the RP-Mdm2-p53 pathway, we generated mice carrying a single cysteine-to-phenylalanine substitution in the central zinc finger of Mdm2 (Mdm2C305F), disrupting Mdm2’s binding to RPL11 and RPL5 [Cancer Cell]. Despite developmentally normal and maintaining an intact p53 response to DNA damage the Mdm2C305F mice demonstrate a diminished p53 response to perturbations in ribosomal biogenesis.
Recently, our studies further indicate that the RP-Mdm2-p53 pathway is in fact an essential sensor of nutrient stress and regulator of energy output. Our results demonstrate, for the first time in an animal model, that p53 is indeed critically involved in regulating metabolism. Recent study using the Mdm2C305F mouse model further demonstrate that the RP-Mdm2-p53 pathway regulates glucose tolerance and energy homeostasis, and suggests that functional modulation of this pathway might have significant effect on both development and treatment of obesity and diabetes.
Awards and Honors
2000 Howard Temin Award.
2000 Burroughs Wellcome Career Award in Biomedical Sciences.
2001 M. D. Anderson Research Trust Award.
2005 Junior Research Fellow, UNC Chapel Hill.
2007 Leukemia & Lymphoma Society Scholar Award.
2008 American Cancer Society Scholar Award.
2008 UNC Jefferson-Pilot Award.
2010 The Battle Distinguished Cancer Research Award.