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Nuclear Factor-B Activation Is Involved in LMP1-mediated Transformation and Tumorigenesis of Rat-1 Fibroblasts¹

Department of Microbiology, The University of Hong Kong, Hong Kong, SAR, China

The mechanism of latent membrane protein LMP1 of EBV in inducing cell transformation and tumorigenesis was investigated in Rat-1 fibroblasts. A plasmid encoding a site-specific mutant of LMP1 defective in binding to tumor necrosis factor receptor-associated death domain protein was constructed. This LMP1^TRADD gene is 75% defective in nuclear factor (NF)-B activation and 100% defective in activator protein-1 activation. When introduced into Rat-1 cells through retrovirus, the Rat-1-LMP1^TRADD cells showed a significant reduction of focus formation and decreased tumor growth in nude mice as compared with Rat-1-LMP1 cells, suggesting that NF-B or activator protein-1 activation may be important for LMP1-induced cell transformation. To further delineate the determinants of LMP1-mediated cellular transformation, a retrovirus with a dominant-negative IB was introduced into the transformed Rat-1-LMP1 cells. The presence of IB significantly suppressed both focus formation and tumorigenicity of Rat-1-LMP1 cells. Our results suggest that the activation of NF-B may play an important role in LMP1-mediated cell transformation and tumorigenesis.

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