Abstract

In this project we are taking a multifaceted approach to studying molecular basis of programmed cell death in lymphocytes. Our attack is based on the hypothesis that there are principally two mechanisms of programmed death of T cells: i) lymphokine deprivation death (LDD) and ii) propriocidal death (PD) due to antigen stimulation of activated T cells. With regard to LDD, we are trying to understand how withdrawal of a trophic stimulus, IL-2 in the case of T cells, can initiate the death program. We have found that lymphokine withdrawal leads to the activation of the c-jun N-terminal kinase (JNK) pathway and we conjecture that this leads to a gene activation event that initiates the death program. In studying PD, we have focused on the activation of a protease termed Flice/Mach1 (caspase 8) which can directly carry out the death program.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000718-03
Application #
6160720
Study Section
Special Emphasis Panel (LI)
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
National Institute of Allergy and Infectious Diseases
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

Freundt, Eric C; Yu, Li; Park, Elizabeth et al. (2009) Molecular determinants for subcellular localization of the severe acute respiratory syndrome coronavirus open reading frame 3b protein. J Virol 83:6631-40
Yu, Li; Strandberg, Lindsey; Lenardo, Michael J (2008) The selectivity of autophagy and its role in cell death and survival. Autophagy 4:567-73
(2008) Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 4:151-75
Liu, Zhihua; Lenardo, Michael J (2007) Reactive oxygen species regulate autophagy through redox-sensitive proteases. Dev Cell 12:484-5
Bolton, Diane L; Lenardo, Michael J (2007) Vpr cytopathicity independent of G2/M cell cycle arrest in human immunodeficiency virus type 1-infected CD4+ T cells. J Virol 81:8878-90
Yu, Li; Wan, Fengyi; Dutta, Sudeshna et al. (2006) Autophagic programmed cell death by selective catalase degradation. Proc Natl Acad Sci U S A 103:4952-7
Sakai, Keiko; Dimas, Joseph; Lenardo, Michael J (2006) The Vif and Vpr accessory proteins independently cause HIV-1-induced T cell cytopathicity and cell cycle arrest. Proc Natl Acad Sci U S A 103:3369-74
Yang, Jin Kuk; Wang, Liwei; Zheng, Lixin et al. (2005) Crystal structure of MC159 reveals molecular mechanism of DISC assembly and FLIP inhibition. Mol Cell 20:939-49
Speirs, Christina; van Nimwegen, Erik; Bolton, Diane et al. (2005) Analysis of human immunodeficiency virus cytopathicity by using a new method for quantitating viral dynamics in cell culture. J Virol 79:4025-32
Clancy, Lauren; Mruk, Karen; Archer, Kristina et al. (2005) Preligand assembly domain-mediated ligand-independent association between TRAIL receptor 4 (TR4) and TR2 regulates TRAIL-induced apoptosis. Proc Natl Acad Sci U S A 102:18099-104

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