The laboratory investigates programmed cell death, a cellular process functioning to maintain tissue homeostasis and eliminate damaged or unwanted cells in multicellular organism. Programmed cell death plays crucial roles in development, immune responses, and many other physiological events. Malfunction of programmed cell death can lead to diseases such as cancer, immune disorders, and neurodegenerative diseases. We employ multiple approaches to study the molecular basis of programmed cell death. We also seek to translate our basic research findings into novel cancer therapies.
Currently, we are focusing on three topics:
1. Mitochondria-mediated apoptosis
Apoptosis is the major form of programmed cell death. It is executed by a subfamily of cysteine proteases known as caspases. During apoptosis, these "death executioners" are activated to attack a variety of cellular targets, and eventually lead to death of the host cells. A major caspase activation pathway in mammals is the mitochondrial pathway in which caspases are activated via cytochrome c released from mitochondria and subsequent assembly of the caspase activation machinery, the apoptosome complex. Recently, we discovered a novel regulatory pathway that controls apoptosome assembly and activity. Both oncoprotein prothymosin-alpha and tumor suppressor PHAP are involved in the pathway, indicating its close relationship with oncogenesis. We are further studying this new pathway in order to identify all the players involved, to understand its physiological functions, as well as its potential role in cancer development.
2. Regulation of the tumor suppressor PTEN
PTEN is a potent tumor suppressor whose gene is mutated or deleted in various human cancers with a frequency as high as that of p53. Although PTEN is a master regulator for multiple cellular functions including cell growth, migration, and programmed cell death, how PTEN itself is regulated is not well-defined. Therefore, we are studying regulation of PTEN in context of programmed cell death. We recently identified an ubiquitin ligase for PTEN that negatively regulates its tumor suppressive function.
3. Molecular mechanisms of autophagy in mammals
Recent advances indicate that there are apoptosis-independent programmed cell death mechanisms. Autophagy, a lysosome-dependent intracellular degradation process, has been implicated as such a mechanism. Multiple genes have been identified by yeast genetic screens as essential components for autophagy, and most of these components have homologs in mammals. To date, autophagy has been firmly established as a critical process for multiple physiological events, and is linked to diseases such as neurodegeneration. Currently, we are exploring the roles of autophagy in programmed cell death and whether it can be targeted for cancer treatment. We are also investigating the biochemical mechanisms of this complicated cellular process.
