J. Marie Hardwick
Molecular Microbiology & Immunology|
|Phone Numbers||(410) 955-2716|
Fax: (410) 955-0105
|School of Medicine Address||Public Health E5132|
615 N. Wolfe St.
Baltimore MD 21205
|Link to Lab Homepage|
Research Topic: Molecular mechanisms of programmed cell death and its role in viral pathogenesis
Our laboratory studies the basic molecular mechanisms of programmed cell death, an evolutionarily conserved process to eliminate cells. Because these pathways normally contribute to the millions of cell deaths that occur per day per individual, defects in cell death underlie the range of human disorders from cancer (insufficient cell death) to neurological diseases (excessive death). We study these processes in the nervous system, in cancer models and during virus infection using mouse models, yeast genetics and biochemical approaches.
We have shown that viruses can trigger cells to activate programmed cell death (Levine et al., Nature, 1993), and that both viral and cellular regulators of apoptosis, such as Bcl-2 family proteins and many other factors, can alter the outcome of a virus infection (Lewis et al., Nature Med, 1999). We seek the mechanisms that explain why Sindbis virus induces neuronal cell death in young animals, but fails to activate the death pathway in neurons of adult brains and in mosquitoes that transmit the virus in nature. Interestingly, cell death factors can also be cell survival factors (Cheng et al., Science, 1997), leading us to pursue their important alternative functions, or ‘day-jobs’, such as regulating mitochondrial fission and bioenergetics, synaptic activity in neurons, or nutrient-sensing in yeast. Although it remains controversial as to whether or not unicellular organisms are capable of undergoing programmed cell death, we have new compelling evidence that these pathways are evolutionarily conserved. Therefore, we have launched an effort to apply the genetic and proteomic tools available for yeast to model the death and survival mechanisms that are conserved between yeast and mammals.
Berman SB, Chen YB, Qi B, McCaffery JM, Rucker EB 3rd, Goebbels S, Nave KA, Arnold BA, Jonas EA, Pineda FJ, Hardwick JM
. Bcl-x L increases mitochondrial fission, fusion, and biomass in neurons. J Cell Biol. 2009 Mar 9;184(5):707-19.PubMed Reference
Cheng WC, Teng X, Park HK, Tucker CM, Dunham MJ, Hardwick JM
. Fis1 deficiency selects for compensatory mutations responsible for cell death and growth control defects. Cell Death Differ. 2008 Dec;15(12):1838-46.
Qi B, Hardwick JM
. Bcl-2 turns deadly. Nat Chem Biol. 2008 Dec;4(12):722-3.
Galonek HL, Hardwick JM
. Upgrading the BCL-2 network. Nat Cell Biol. 8:1317-1319, 2006.
Ivanovska, I and Hardwick, JM
. Viruses activate a genetically conserved cell death pathway in a unicellular organism. J Cell Biol. 170:391-399, 2005.
Fannjiang, Y, Cheng, WC, Lee, SJ, Qi, B, Pevsner, J, McCaffery, JM, Hill, RB, Basañez G, and Hardwick, JM. Mitochondrial fission proteins regulate programmed cell death in yeast. Genes & Dev 18:2785-2797, 2004.
Fannjiang, Y, Kim, CH, Huganir, RL, Zou, S, Lindsten, T, Thompson, CB, Mito, T, Traystman, RJ, Larsen, T, Griffin, DE, Mandir, AS, Dawson, TM, Dike, S, Sappington, AL, Kerr, DA, Jonas, EA, Kaczmarek, LK, & Hardwick, JM. BAK alters neuronal excitability and can switch from anti- to pro-death function during postnatal development. Develop. Cell 4:575-585, 2003.
Clem, RJ, Sheu, TT, Richter, BWM, He, WW, Thornberry, NA, Duckett, CS and Hardwick, JM. c-IAP1 is Cleaved by Caspases to Produce a Pro-apoptotic C-terminal Fragment. J. Biol. Chem. 276:7602-7608, 2001.
Chau, BN, Cheng, EHY, Kerr, D, Hardwick, JM
. Aven, a novel inhibitor of caspase activation binds Bcl-xL and Apaf-1. Molecular Cell 6:31-40, 2000.PubMed Reference