Research interests in my laboratory span from cell cycle control to genomic integrity with a particular focus on the role of ubiquitin-proteasome system (UPS) in the individual cellular system. We are particularly interested in how defects in the proteolytic machinery contribute to genomic instability and cancer formation. To achieve our research goals, we have developed a mutidisciplinary approach that includes biochemical, cell biological and genetic analyses as well as the use of animal models.
The Role of UPS in Genomic Integrity
Genotoxic stress, such as environmental radiation and chemical mutagens, results in genomic instability and cancer. Both the DNA-damage response and DNA repair are tightly regulated by UPS. To systematically search for proteins that are degraded in response to genotoxic stress and to further examine their impact on genomic integrity and carcinogenesis, we have performed high throughput screening as well as large-scale immunoblotting analyses. One interesting candidate that we identified is Rad17. We are currently investigating the mechanism by which Rad17 is ubiquitylated and degraded after cellular exposure to UV. We are also determining how failure in Rad17 proteolytic regulation would affect genomic integrity and tumorigenesis, especially melanomagenesis. We further hope to establish a new strategy to sensitize tumor cells to cancer treatments by exploiting our knowledge of the ubiquitin pathway.
The Role of UPS in Breast Carcinogenesis
Defective regulation of transforming growth factor beta (TGF-β) and estrogen receptor (ER) signaling pathways can predispose breast cells towards carcinogenesis. Our recent findings have revealed a previously unknown mechanism that centers on the interplay between KLF4, an oncogenic transcriptional factor, and Cdh1/APC, a critical E3 ligase in cell cycle control. Their functional interaction is critical in orchestrating the crosstalk between TGF-β and ER signaling pathways, which in turn determines whether breast cells retain their homeostasis or are transformed to initiate oncogenic growth. Our observations have provided insight into the pathological mystery previously observed by us and others that over 70% of human mammary cancers exhibited cellular accumulation of KLF4 and that disruption in Cdh1 function in mice often results in the genesis of breast tumor or its enhanced progression. We are currently studying the molecular basis of the interplay between KLF4 and Cdh1/APC in their regulation of ER and TGF-β signal transduction and determining how impaired KLF4 proteolytic regulation due to dysregulated Cdh1/APC would impact breast tumorigenesis. Outcomes from this project could provide a more effective strategy to modulate the ER signaling pathway by exploiting components of the Cdh1/APC-KLF4 cascade. Controlling the ER signaling pathway has long been a key focus in the field to develop new methods for chemoprevention and endocrine therapy for breast cancer.
The Role of APC Pathway in Cell Cycle Control and Cellular Differentiation
Anaphase-promoting complex (APC/C), a large multi-subunit enzyme, is a master regulator of cell cycle progression that functions as an ubiquitin E3 ligase for protein destruction. The activity of APC is controlled by Cdc20 and Cdh1. While recent biochemical and mouse genetic studies have implicated the function of Cdh1/APC in both cell cycle control and development, the exact mechanism of Cdh1 regulation remains unknown. We are currently investigating the upstream mechanism by which Cdh1 is regulated in the cell cycle and cellular differentiation. We are also studying the role of Cdh1/APC in the division and differentiation of stem cells.