Judy Lieberman
Department of Pediatrics
Immune Disease Institute
Warren Alpert Building Room 255
200 Longwood Avenue,
Boston, MA 02115
Tel. (617) 278-3106
Fax (617) 278-3134
email:lieberman@idi.harvard.edu
11 Postdoctoral Fellows, 3 Instructors, 4 Graduate Students
Judy Lieberman’s laboratory studies the molecular pathways used by cytotoxic T cells and natural killer cells to induce death of virus infected cells or tumors. They have defined a novel form of programmed cell death induced by the cytotoxic granule serine protease granzyme A. This caspase-independent cell death pathway has all the morphological features of apoptosis but involves single-stranded DNA damage, not double stranded DNA breaks. It does not activate the caspases, and cells that are resistant to the caspase pathway, such as by overexpressing bcl-2, are sensitive to granzyme A. Granzyme A activates a novel form of mitochondrial damage without cytochrome c release. A special target of this cell death pathway is an oxidative stress response complex, called the SET complex, which contains DNA repair enzymes and proteins involved in chromatin modification and transcriptional activation in response to oxidative stress. A key focus is to understand the normal function of the SET complex and its potential role in cellular transformation and the response to stress and DNA damage. Recent work is also aimed at understanding the biochemical and cell biological basis for the function of perforin, the membrane-perturbing protein that delivers the CTL granzyme proteases into cells. The Lieberman laboratory also studies how CTL function is regulated in the setting of chronic infection, with a particular emphasis on HIV infection.
The Lieberman laboratory was the first to demonstrate in an animal model that RNA interference (RNAi) could be used to protect animals from disease. Her laboratory is actively working to harness RNAi for therapeutic use for HIV and other indications and has developed novel strategies for cell-specific targeting of small interfering RNAs that are effective in vivo. The lab is also investigating the role of the endogenous microRNA pathway in cellular differentiation, transformation and viral infection.
References:
- Martinvalet D, Dykxhoorn DM, Ferrini R and Lieberman J. Granzyme A cleaves a mitochondrial complex I protein to initiate caspase independent cell death. Cell 2008; 133:681-692.
- Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C, Huang Y, Hu X, Su F, Lieberman J* and Song E*. let-7 regulates self-renewal and tumorigenicity of breast cancer cells. Cell 2007; 131:1109-1123.
- Palliser D, Chowdhury D, Wang, Q-Y, Lee SJ, Bronson RT, Knipe DM, and Lieberman J. An siRNA-based microbicide protects mice from lethal herpes simplex virus 2 infection. Nature 2006; 439:89-94.
- Chowdhury D, Beresford PJ, Zhu P, Zhang D, Sung J-S, Demple B, Perrino F and Lieberman J. The exonuclease TREX1 is in the SET complex and acts in concert with NM23-H1 to degrade DNA during granzyme A-mediated cell death. Mol Cell 2006; 23:133-142.
- Keefe D, Shi L, Feske S, Massol R, Navarro F, Kirchhausen T and LIEBERMAN J. Perforin triggers a plasma membrane-repair response that facilitates CTL induction of apoptosis. Immunity 2005; 23:249-262.
Immunology webpage updated 12/02/2009