Functionally Significant Mutations in the Epstein-Barr Virus LMP1 Gene and Their Role in Activation of Cell Signaling Pathways

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S. V. Diduk, K. V. Smirnova, O. A. Pavlish^#, and V. E. Gurtsevitch^*

Blokhin Cancer Research Center, Russian Academy of Medical Sciences, Kashirskoe Shosse 24, 115478 Moscow, Russia; fax: (495) 324-1205; E-mail: gurtsevitch@crc.umos.ru

^# Deceased.

^* To whom correspondence should be addressed.

Received April 15, 2008; Revision received April 25, 2008

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Latent membrane protein 1 (LMP1) of the Epstein-Barr virus is a constitutively activated analog of the tumor necrosis factor receptor TNF-R1. LMP1 serves as a viral oncogene able to transform human B-lymphocytes and rodent fibroblasts via activation of numerous cellular signal cascades. Two specific motifs within LMP1 are responsible for interaction of this viral protein with the receptor protein beta-TrCP/HOS SCF of the ubiquitin ligase E3 complex, playing an important role in degradation of numerous cellular proteins including NF-kappaB inhibitor IkappaBalpha. In this study, we demonstrate for the first time the importance of point mutations affecting HOS-recognizing motifs of LMP1 for activation of NF-kappaB, AP1, and PI3K/Akt signaling pathways. It has also been shown that rat fibroblast cell lines (Rat-1) expressing different HOS mutants of LMP1 produce different amounts of reactive nitrogen species. Our data confirm the hypothesis that point mutations in the C-terminal region of the LMP1 cytoplasmic domain can influence the transforming potential of the Epstein-Barr virus.

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KEY WORDS: Epstein-Barr virus, LMP1 protein, HOS mutations, NF-kappaB, NO

DOI: 10.1134/S0006297908100106

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