Nuclear factor-kappaB activation is involved in LMP1-mediated transformation and tumorigenesis of rat-1 fibroblasts.
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)-kappaB 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-kappaB 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 I kappaB alpha was introduced into the transformed Rat-1-LMP1 cells. The presence of I kappaB alpha significantly suppressed both focus formation and tumorigenicity of Rat-1-LMP1 cells. Our results suggest that the activation of NF-kappaB may play an important role in LMP1-mediated cell transformation and tumorigenesis.
He
Z
Z
Department of Microbiology, The University of Hong Kong, SAR, China.
Xin
B
B
Yang
X
X
Chan
C
C
Cao
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L
D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D005347:Fibroblasts / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology*; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D014158:Transcription, Genetic; D014763:Viral Matrix Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016328:NF-kappa B; D009856:Oncogene Proteins, Viral; D011994:Recombinant Proteins; D014763:Viral Matrix Proteins