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PMID: 17626074 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Unique signaling properties of CTAR1 in LMP1-mediated transformation.

Journal of virology ·Vol. 81 ·No. 18 ·2007-09-00 ·Pages 9680-92

Mainou BA, Everly DN, Raab-Traub N

Abstract

The Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) gene is considered the EBV oncogene as it is necessary for EBV-mediated transformation of B lymphocytes and itself transforms rodent fibroblasts. LMP1 activates the NF-kappaB, phosphatidylinositol 3-kinase (PI3K)-Akt, mitogen-activated protein kinase, and Jun N-terminal protein kinase signaling pathways through its two signaling domains, carboxyl-terminal activating regions 1 and 2 (CTAR1 and CTAR2). CTAR1 and CTAR2 induce signal transduction pathways through their direct (CTAR1) or indirect (CTAR2) recruitment of tumor necrosis factor receptor-associated factors (TRAFs). CTAR1 is necessary for LMP1-mediated transformation as well as activation of PI3K signaling and induction of cell cycle markers associated with G(1)/S transition. In this study, activation of PI3K-Akt signaling and deregulation of cell cycle markers were mapped to the TRAF-binding domain within CTAR1 and to the residues between CTAR1 and CTAR2. LMP1 CTAR1 also activated the MEK1/2-extracellular signal-regulated kinase 1/2 signaling pathway, and this activation was necessary for LMP1-induced transformation of Rat-1 fibroblasts. Dominant-negative forms of TRAF2 and TRAF3 inhibited but did not fully block LMP1-mediated transformation. These findings identify a new signaling pathway that is uniquely activated by the TRAF-binding domain of LMP1 and is required for transformation.

MeSH Terms
Animals Cell Line Cell Transformation, Viral/physiology Enzyme Activation/physiology Fibroblasts/metabolism,virology G1 Phase/genetics Genes, Dominant/genetics Herpesvirus 4, Human/genetics,metabolism Humans JNK Mitogen-Activated Protein Kinases/genetics,metabolism MAP Kinase Kinase 1/genetics,metabolism MAP Kinase Kinase 2/genetics,metabolism MAP Kinase Signaling System/physiology NF-kappa B/genetics,metabolism Oncogene Proteins, Viral/genetics,metabolism Phosphatidylinositol 3-Kinases/genetics,metabolism Protein Structure, Tertiary/genetics Proto-Oncogene Proteins c-akt/genetics,metabolism Rats S Phase/genetics TNF Receptor-Associated Factor 2/genetics,metabolism TNF Receptor-Associated Factor 3/genetics,metabolism Viral Matrix Proteins/genetics,metabolism
Chemicals
EBV-associated membrane antigen, Epstein-Barr virus NF-kappa B Oncogene Proteins, Viral TNF Receptor-Associated Factor 2 TNF Receptor-Associated Factor 3 Viral Matrix Proteins MAP2K2 protein, human Phosphatidylinositol 3-Kinases Proto-Oncogene Proteins c-akt JNK Mitogen-Activated Protein Kinases MAP Kinase Kinase 1 MAP Kinase Kinase 2
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Mainou Bernardo A
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Everly David N
Raab-Traub Nancy
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Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
0022-538X
DOI
10.1128/JVI.01001-07
Published
2007-09-00
Epub
2007-00-11
Pages
9680-92
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC2045399
Subset
IM
Grants
NCI NIH HHS · P01 CA019014 · United States
NCI NIH HHS · R01 CA032979 · United States
NCI NIH HHS · CA 19014 · United States
NCI NIH HHS · CA 32979 · United States
External Links
PubMed source DOI: 10.1128/JVI.01001-07 PMC Full Text View journal details
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