p53; Mdm2; MdmX; Ribosomal protein-Mdm2-p53 pathway; p32
In vivo function of Mdm2 E3 ubiquitin ligase in p53 regulation
The tumor suppressor p53 is a critical mediator of the cellular stress response, maintaining genomic integrity and preventing oncogenic transformation. Mdm2, the primary negative regulator for p53, controls p53 through functioning as an E3 ubiquitin ligase targeting p53 for proteasomal degradation. Our recent studies with mouse models expressing knock-in mutant Mdm2 have revealed a surprisingly dispensable nature for the Mdm2 E3 ligase under unstressed conditions. We are interested in defining the function of Mdm2 in p53 regulation, thereby providing insight into the Mdm2-p53 regulatory loop and solutions to the current problems surrounding the development of effective cancer therapeutics targeting the p53 pathway.
The ribosomal protein-Mdm2-p53 signaling pathway in energy metabolism and cancer prevention
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, a key component to regulating overall protein synthesis and cell growth. Our previous studies have established the RP-Mdm2-p53 signaling pathway that is critical in glucose tolerance and energy homeostasis. We are interested in delineating the function and mechanism of this pathway in preventing oncogenic induced tumorigenesis and dietary induced obesity and diabetes.
Multifaceted mitochondrial p32 in the regulation of apoptotic cell death
Apoptosis is a tightly regulated form of programmed cell death that is critical for proper embryonic development, tissue homeostasis and immune response, and aberrant regulation of this process contributes to autoimmune disorders, neurodegenerative disease and cancer. We have previously identified mitochondrial protein p32 as a critical mediator of p53’s apoptotic function. We are interested in characterizing the role of p32 in coordinating mitochondrial metabolism with apoptotic cell death, and exploring the potential of p32 as a therapeutic target for the treatment of cancers.