Our research is focused on the pathways that are critical to maintain genetic stability in mammalian cells, particularly embryonic stem cells (ESCs). To achieve our goals, we will continue to develop the most physiologically relevant genetic models, including the disease-specific human ESCs, to elucidate the roles of tumor suppressors in maintaining genetic stability and suppressing tumorigenesis.
Tumor suppressor p53 is the “guardian of the genome”. Loss of wild-type p53 function is required for the progression of most human cancers. In this context, the p53 gene is somatically mutated in over 50% of all human cancers. p53 cancer mutants gain novel oncogenic activities to promote tumorigenesis and drug resistance, leading to the poor prognosis of cancer patients who express p53 mutants. In the human cancers that harbor wild-type p53, p53 is mostly dysfunctional due to the disruption of pathways important for its activation. Therefore, we will continue to elucidate the pathways involved in activating p53 tumor suppression activity and to reveal the gain of functions of p53 cancer mutants.
Embryonic stem cells (ESCs) are capable of unlimited self-renewal and differentiation into all cell lineages in the body. Since DNA damage occurs during normal cellular proliferation, it is critical for ESCs to possess stringent mechanisms to maintain genetic stability to prevent the passage of DNA damage to the progeny. One goal of our research is to elucidate the pathways involved in maintaining the self-renewal and genetic stability in both mouse and human ESCs. In the course of these studies, we will establish a panel of disease-specific human ESCs that will be used to study the mechanisms of tumorigenesis in human cancers.