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LMP1 TRAFficking Activates Growth and Survival pathways

  • Vishal Soni
  • Ellen Cahir-McFarland
  • Elliott Kieff
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 597)

Abstract

Epstein-Barr Virus (EBV) Latent Infection Membrane Protein 1 (LMP1) is expressed in all the EBV related malignancies. LMP1 expression is critical for transformation of human B-cells by EBV. LMP1 expression in human B cells induces activation and adhesion molecule expression and cell clumping, which are characteristic of CD40 activated B lymphocytes. In immortalized fibroblasts, LMP1 mimics aspects of activated ras in enbling serum, contact, and anchorage independent growth. Reverse genetic analyses implicate six transmembrane domains (TM), TM1-6, and two C-terminal cytosolic domains, transformation effector sites 1 and 2 (TES1 and 2) or C-terminal activation regions 1 and 2 (CTAR1 and 2) as the essential domains for LMP1 effects. The 6 transmembrane domains cause intermolecular interaction, whereas the C-terminal domains signal through tumor necrosis factor receptor (TNFR) associated factors (TRAFs) or TNFR associated death domain proteins (TRADD) and activate NF-κB, JNK, and p38. LMP1 TES1/CTAR1 directly recruits TRAFs 1, 2, 3 and 5 whereas LMP1 TES2/CTAR2 indirectly recruits TRAF6 via BS69. LMP1 TES1/CTAR1 activates TRAF2, NIK, IKKα and p52 mediated noncanonical NF-κB pathway and LMP1 TES2/CTAR2 activates TRAF6, TAB1, TAK1, IKKα/IKKβ/IKKγ mediated canonical NF-κB pathway. Interestingly, TRAF3 is a negative regulator of noncanonical NF-κB activation, although a positive role in LMP1 signaling has also been described. LMP1 mediated JNK activation is predominantly TES2/CTAR2 dependent and requires TRAF6. LMP1 specifically increases TRAF3 partitioning into lipid rafts and interestingly does not induce degradation of any of the TRAFs upon NF-κB activation. Studies of the chemistry and biology of LMP1-TRAF interaction mediated activation of signaling pathways are important for controlling EBV infected cell survival and growth.

Keywords

Lipid Raft Tumor Necrosis Factor Receptor Latent Membrane Protein NFkappaB Activation Oncogenic Latent Membrane Protein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Landes Bioscience and Springer Science+Business Media 2007

Authors and Affiliations

  • Vishal Soni
  • Ellen Cahir-McFarland
  • Elliott Kieff
    • 1
    • 2
  1. 1.Channing Laboratory and Infectious Disease Division, Department of MedicineBrigham and Women’s HospitalBostonUSA
  2. 2.Department of Microbiology and Molecular GeneticsHarvard Medical School and UniversityBostonUSA

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