Mechanisms and Function of Programmed Cell Death
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:
- 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 intrinsic mitochondrial pathway. Critical for various biological events, this pathway is under close regulation in cells. Currently the lab is studying the mechanisms of such regulation. Further, using high throughput screening approach, we have identified a series of artificial small molecule modulators of this pathway, and are exploring their therapeutic potential.
- Molecular mechanisms of autophagy in mammals
Autophagy, a lysosome-dependent intracellular catabolic process, has emerged as a crucial component for regulating both apoptotic and non-apoptotic cell death. As such, autophagy is involved in various human diseases ranging from immune disorders, neurodegeneration, to cancer. Currently, we are investigating the molecular mechanisms of this complicated cellular process. Our mechanistic studies mainly focus on an autophagy-specific protein kinase complex known as ULK1-ATG13-FIP200 complex. This complex directly mediates the signaling of the nutrient-sensing kinase, mTOR, thus functioning as an interface linking autophagy with metabolism, cell growth, and cancer. We are also exploring the roles of autophagy in programmed cell death and cancer treatment.
- 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. Our study indicates that (1) PTEN is regulated in a highly context-specific manner, and (2) different subcellular populations of PTEN can perform distinct biological function. Currently, we are investigating the regulatory mechanisms and therapeutic implication of PTEN under two specific, cancer-relevant contexts: hypoxia and IGF signaling.