Honglin Li, PhD Assistant Professor Pediatrics, CMIER Neurobiology Program The roles of caspase and Bcl-2 family members in regulation of apoptosis Curricula: Neurobiology Cancer Biology Cell Biology E-mail:   h-li2@northwestern.edu

Apoptosis, or programmed cell death, is a cell-intrinsic suicidal mechanism, which is essential for animal development, tissue homeostasis, and defense against infection. Improper apoptosis has been implicated in the pathogenesis of cancer, neurodegenerative diseases, or other pathological conditions such as AIDS and rheumatoid arthritis. For examples, cancer cells forget to die, while T cells in AIDS patients die too easily and too early. A novel class of cysteine proteases, named caspases, have been implicated in both the initiation and execution of apoptosis.

To further understand the role of caspases in apoptosis, I have systematically screened for caspase substrates with the use of in vitro expression cloning during my post-doctoral training. Screening of about 1700 small pools of cDNAs (100 clones per pool) has resulted in the detection of more than 60 in vitro substrates, 10 of which have been verified to be cleaved in vivo. Of these various proteins, 24 have not been previously identified or have no assigned function. One of the caspase substrates identified is BID, a BH3 (Bcl-2 homolog 3) domain-containing pro-apoptotic member of the Bcl-2 family. Whereas full-length BID is localized in the cytosol, the caspase-cleaved BID (the C-terminal fragment translocated to mitochondria and induces the mitochondrial damage and the release of cytochrome c.

One of the ongoing projects in my lab is to characterize novel caspase substrates that I found in my screening. Further characterization of these novel substrates will allow us to understand the intracellular signal transduction of apoptosis. Given that mitochondria play a critical role in apoptotic signal transduction, I are also interested in investigating the mechanism by which BID and other pro-apoptotic members of the Bcl-2 family induce mitochondrial damage.

Publications:

Chou, J. J., Li, H., Salvesen, G., Yuan, J. and Wagner, G. (1999) Solution structure of Bid, an intracellular amplifier of apoptotic signaling. Cell 96, 615-624

Li, H. and Yuan, J. (1999) Decipering the pathways of life and death. Current Opinion in Cell Biology 11, 261-266.

Li, H., Zhu, H., Xu, C., Yuan, J. (1998) Cleavage of BID by caspase-8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94, 491-501

Li, H., Bergeron, L., Cryns, V., Pasternack, M. S., Zhu, H., Shi, L., Greenberg, A., Yuan, J. (1997) Activation of caspase-2 in apoptosis. J. Biol. Chem. 272, 21010-21017.