Tumor necrosis factor (TNF or TNFcz) is a key mediator in the establishment and maintenance of multiple inflammatory and autoimmue diseases, such as rheumatoid arthritis and inflammatory bowl disease. TNF- receptor signaling can simultaneously activate caspase 8, the transcription factor, NF-KB and the kinase, JNK. While activation of caspase 8 is required for TNF-induced apoptosis, and induction of NF-rd3 inhibits cell death, the precise function of JNK activation in TNF signaling is not clearly understood. We have shown that TNF-mediated caspase 8 cleavage and apoptosis require a sequential pathway involving JNK, Bid, and Smac/DIABLO. Activation of JNK induces caspase 8-independent cleavage of Bid at a distinct site to generate the Bid cleavage product jBid. Translocation ofjBid to mitochondria leads to preferential release of Smac/DIABLO, but not cytochrome c. The released Smac/DIABLO then disrupts the TRAF2-cIAP 1 complex. We propose that the JNK pathway is required to relieve the inhibition imposed by TRAF2-cIAP1 on caspase 8 activation and induction of apoptosis. In this proposal, we will explore the signaling mechanisms underlying the choice between cell survival and cell death in TNF response. Since TNF- mediated apoptosis plays a crucial role in both physiological and pathophysiological functions of TNF, understanding the regulation of TNF response will provide new avenues of therapeutic intervention for TNF- mediated inflammatory and autoimmue diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI063063-06
Application #
7535219
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Peyman, John A
Project Start
2004-12-15
Project End
2010-11-30
Budget Start
2008-12-01
Budget End
2010-11-30
Support Year
6
Fiscal Year
2009
Total Cost
$279,050
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Surgery
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Huang, Shaoyi; Ren, Xiaoyang; Wang, Lai et al. (2011) Lung-cancer chemoprevention by induction of synthetic lethality in mutant KRAS premalignant cells in vitro and in vivo. Cancer Prev Res (Phila) 4:666-73
Zhang, Ling; Ren, Xiaoyang; Alt, Eckhard et al. (2010) Chemoprevention of colorectal cancer by targeting APC-deficient cells for apoptosis. Nature 464:1058-61
Ren, Xiaoyang; Xu, Zhengming; Myers, Jeffery N et al. (2007) Bypass NFkappaB-mediated survival pathways by TRAIL and Smac. Cancer Biol Ther 6:1031-5