Employing a combination of quantitative proteomics technology and traditional molecular cell biology approaches, our laboratory studies 1) the ubiquitination substrates and interaction partners of a tumor-suppressing ubiquitin ligase, VHL, 2) the senescence-associated protein secretion patterns of normal as well as tumor cells, and 3) the serum biomarkers for VHL-mutated cancer.

 

1) Mutation of the VHL tumor suppressor plays a central role in the generation of both hereditary and non-hereditary kidney cancers. VHL is a ubiquitin ligase, an enzyme that attaches a small protein called ubiquitin to its substrate proteins. A major bottleneck in understanding the functions of ubiquitin ligases has been the difficulty in identifying their ubiquitination substrates. We are using quantitative proteomics approaches to identify the ubiquitination substrates of VHL. We are also analyzing the interaction partners of VHL by proteomics approach. (NIH R01CA125020)

 

2) Senescent cells accumulate with age at sites of age-related pathologies (e.g. atherosclerotic lesions). These senescent cells secrete proteins that could alter the architecture and function of the surrounding tissues, which may mediate the aging process. In addition to normal cells, cancer cells also undergo proliferative senescence upon treatment with chemotherapeutic drugs. Importantly, many genes that are induced in senescent tumor cells encode secreted proteins with both tumor-promoting and tumor-suppressing activities, which can affect the prognosis of tumor patients. Therefore, the emerging hypothesis is that cytokines secreted from senescent cells mediate in vivo aging process and age-related pathologies as well as tumor response to therapy. We are using quantitative proteomics to identify and characterize the cytokines secreted from senescent normal cells and senescent tumor cells. (NIH R21AG029587)

 

3) The serum cancer biomarkers that can be measured by a simple blood test have great potential for early diagnosis, disease monitoring, and assessment of therapeutic response. However, direct proteomic analysis of cancer patient serum is technically difficult. As an alternative, we are identifying candidate cancer biomarkers by analyzing proteins secreted from cancer cells in culture, which will be validated using serum samples from cancer patients and healthy controls. (NIH R21CA139170)