The tumor necrosis factor (TNF-alpha) regulates many biological activities, including immune responses, inflammation and programmed cell death (apoptosis). TNF-alpha exerts its function by activating multiple intracellular signaling effectors, such as caspases, NF-kappaB and c-Jun N-terminal protein kinase (JNK). While caspase activation is required for TNF-alpha induced apoptosis, activation of NF-kappaB suppresses the apoptotic process. The role of JNK in TNF-alpha induced apoptosis is unclear. Using genetic and biochemical approaches, we found that activation of NF-kappaB prevents prolonged JNK activation induced by TNF-alpha through induction of a group of inhibitors. Inhibition of prolonged JNK activation suppresses TNF-alpha induced apoptosis, suggesting that part of the anti-apoptotic effect of NF-kappaB is mediated by inhibition of prolonged JNK activation. This work is novel as it provides evidence that will lead to delineation of the molecular basis of how TNF-alpha signaling is integrated in the apoptotic process and should provide information critical to the development of novel strategies in regulation of TNF-alpha induced apoptosis. Two hypothesis-driven specific aims will be pursued to determine the mechanisms by which activation of NF-kappaB prevents prolonged JNK activation in response to TNF-alpha and the mechanism by which prolonged JNK activation contributes to TNF-alpha induced apoptosis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA100460-03
Application #
6911773
Study Section
Special Emphasis Panel (ZRG1-CAMP (01))
Program Officer
Yassin, Rihab R,
Project Start
2003-06-01
Project End
2008-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
3
Fiscal Year
2005
Total Cost
$317,200
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Yan, Jie; Xiang, Jialing; Lin, Yutin et al. (2013) Inactivation of BAD by IKK inhibits TNF?-induced apoptosis independently of NF-?B activation. Cell 152:304-15
Liu, Jing; Yan, Jie; Jiang, Shan et al. (2012) Site-specific ubiquitination is required for relieving the transcription factor Miz1-mediated suppression on TNF-?-induced JNK activation and inflammation. Proc Natl Acad Sci U S A 109:191-6
Deng, Hongbin; Zhang, Jingpu; Yoon, Taewon et al. (2011) Phosphorylation of Bcl-associated death protein (Bad) by erythropoietin-activated c-Jun N-terminal protein kinase 1 contributes to survival of erythropoietin-dependent cells. Int J Biochem Cell Biol 43:409-15
Liu, Jing; Zhao, Yingming; Eilers, Martin et al. (2009) Miz1 is a signal- and pathway-specific modulator or regulator (SMOR) that suppresses TNF-alpha-induced JNK1 activation. Proc Natl Acad Sci U S A 106:18279-84
Deng, Hongbin; Yu, Fei; Chen, Jianqun et al. (2008) Phosphorylation of Bad at Thr-201 by JNK1 promotes glycolysis through activation of phosphofructokinase-1. J Biol Chem 283:20754-60
Shen, Chengyong; Chen, Yongfeng; Liu, Huaqing et al. (2008) Hydrogen peroxide promotes Abeta production through JNK-dependent activation of gamma-secretase. J Biol Chem 283:17721-30
Zhang, Jiyan; Bui, Truc N; Xiang, Jialing et al. (2006) Cyclic AMP inhibits p38 activation via CREB-induced dynein light chain. Mol Cell Biol 26:1223-34
Hickson, Jonathan A; Huo, Dezheng; Vander Griend, Donald J et al. (2006) The p38 kinases MKK4 and MKK6 suppress metastatic colonization in human ovarian carcinoma. Cancer Res 66:2264-70
Liu, Jing; Yang, Dan; Minemoto, Yuzuru et al. (2006) NF-kappaB is required for UV-induced JNK activation via induction of PKCdelta. Mol Cell 21:467-80
Zhang, Jiyan; Liu, Jing; Yu, Chenfei et al. (2005) BAD Ser128 is not phosphorylated by c-Jun NH2-terminal kinase for promoting apoptosis. Cancer Res 65:8372-8

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