Tumor necrosis factor (TNF) has been considered as an anti-cancer agent since its discovery two decades ago. Members of the TNF receptor (TNFR) superfamily can send both survival and death signals to cells, and play important roles in a wide range of biological effects that include acute phase responses and lymphocyte activation. CD40, as a member of this receptor family, activates multiple signaling pathways, induces expression of dozens of genes, and is essential for many important events in T-cell-dependent humoral responses. Our goal is to find connections that can link the CD40 receptor to multiple signal transduction pathways, and that link each signaling pathway to its downstream effector genes and to the CD40-mediated biological functions. The recent discovery of several early signaling mediators, including the TNF receptor-associated factor (TRAF) family proteins, the TRAF- associated NF-kappaB activator (TANK) and the NF-kappaB-inducing kinase (NIK), has provided an opportunity to dissect multiple CD40-mediated signal transduction pathways. This proposal will focus on the early events of CD40 receptor-initiated signaling. First, we will determine the specificities of multiple TRAF proteins for receiving signals from CD40 and for sending out downstream signals to activate both the NF-kappaB and stress-activating protein kinase (SAPK) signal transduction pathways. Second, we will determine the molecular mechanisms of TRAF and TANK cooperation. We will also test the possible role of TANK as a switching molecule in controlling the threshold of CD40-induced NF-KB and SAPK activation. Our work will: 1) provide new insights into the molecular mechanisms by which a single receptor interacting with its ligand can generate multiple signal transduction pathways and control multiple biological events; and 2) identify new therapeutic targets in the multiple CD40 and TNF signaling pathways for treatment of cancers and immune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM057559-02S1
Application #
6326731
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Marino, Pamela
Project Start
1999-02-01
Project End
2004-01-31
Budget Start
2000-07-01
Budget End
2001-01-31
Support Year
2
Fiscal Year
2000
Total Cost
$92,268
Indirect Cost
Name
University of California Los Angeles
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Oganesyan, Gagik; Saha, Supriya K; Pietras, Eric M et al. (2008) IRF3-dependent type I interferon response in B cells regulates CpG-mediated antibody production. J Biol Chem 283:802-8
Zarnegar, Brian J; Wang, Yaya; Mahoney, Douglas J et al. (2008) Noncanonical NF-kappaB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK. Nat Immunol 9:1371-8
Zarnegar, Brian; Yamazaki, Soh; He, Jeannie Q et al. (2008) Control of canonical NF-kappaB activation through the NIK-IKK complex pathway. Proc Natl Acad Sci U S A 105:3503-8
He, Jeannie Q; Saha, Supriya K; Kang, Jason R et al. (2007) Specificity of TRAF3 in its negative regulation of the noncanonical NF-kappa B pathway. J Biol Chem 282:3688-94
Pietras, Eric M; Saha, Supriya K; Cheng, Genhong (2006) The interferon response to bacterial and viral infections. J Endotoxin Res 12:246-50
He, Jeannie Q; Zarnegar, Brian; Oganesyan, Gagik et al. (2006) Rescue of TRAF3-null mice by p100 NF-kappa B deficiency. J Exp Med 203:2413-8
Ni, Chao-Zhou; Oganesyan, Gagik; Welsh, Kate et al. (2004) Key molecular contacts promote recognition of the BAFF receptor by TNF receptor-associated factor 3: implications for intracellular signaling regulation. J Immunol 173:7394-400
Zarnegar, Brian; He, Jeannie Q; Oganesyan, Gagik et al. (2004) Unique CD40-mediated biological program in B cell activation requires both type 1 and type 2 NF-kappaB activation pathways. Proc Natl Acad Sci U S A 101:8108-13
Ronni, Tapani; Agarwal, Vishal; Haykinson, Michael et al. (2003) Common interaction surfaces of the toll-like receptor 4 cytoplasmic domain stimulate multiple nuclear targets. Mol Cell Biol 23:2543-55
Dadgostar, Hajir; Doyle, Sean E; Shahangian, Arash et al. (2003) T3JAM, a novel protein that specifically interacts with TRAF3 and promotes the activation of JNK(1). FEBS Lett 553:403-7

Showing the most recent 10 out of 14 publications