Regulation of p53 and its family members
As a guardian of the genome, p53 regulates many cellular functions including cell death, cell-cycle arrest, and DNA repair. To prevent unwanted cell death and cell-cycle arrest, p53 activity must be tightly regulated by changes in protein stability, physical interaction with various inhibitors, and post-translational modification. Conversely, p53 is functionally or genetically disabled in the majority of human cancers. Importantly, although p53 was initially discovered as a critical tumor suppressor, now it is known that it also plays a variety of roles in maintaining cellular homeostasis. We are investigating what kind of “day job” p53 has and how it is regulated. We are also interested in what unique roles p63 and p73, the other p53 family members, play in human disease and development and how they are regulated.
Role of protein degradation pathways in disease and development
The ubiquitin E3 ligase family plays a central role in the control of protein stabilities and cellular homeostasis. HUWE1 was initially discovered as an E3 ligase for the tumor suppressor p53 and the anti-apoptotic protein MCL1. One of the major interests in our lab is to elucidate what role HUWE1 plays in different tissues/organs under various physiological conditions. We discovered several novel substrates of HUWE1, including Protein Phosphatase 5 (PP5) and CHK1 kinase. We also discovered that HUWE1 protein stability is regulated by another p53-targeting E3 ligase MDM2, which, in turn, impacts the abundance of substrates of HUWE1. Currently, we are investigating an in vivo role of HUWE1 using conditional Huwe1 knockout mice.
Lipid metabolism and drug resistance in cancer
Fatty acids are lipids essential for cell survival and play a key role in cancer metabolism. In general, cells acquire fatty acids from exogenous sources via CD36-mediated uptake and/or endogenously through de novo lipogenesis involving an enzyme, fatty acid synthase (FASN). Although FASN is normally expressed at low levels in tissues (except liver and adipose tissues), it is highly expressed in many cancer cells. Consequently, much of the work on lipid metabolism in cancer has been focused on FASN. However, the capacity of cancer cells to utilize lipids of exogenous origin through CD36 is poorly understood. We have shown that when breast cancer cells acquire resistance to FDA-approved drugs, lapatinib and trastuzumab, there is a metabolic shift in cells toward reliance on CD36-mediated fatty acid uptake over de novo fatty acid synthesis for maintaining the cellular fatty acid pool. We also demonstrated that inhibition of CD36 kills resistant cells, but not drug-sensitive cells or normal healthy cells, suggesting that CD36 plays a critical role in breast cancer drug resistance and that CD36 can be a therapeutic target.
Eureka!
