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LMP1 of Epstein–Barr virus suppresses cellular senescence associated with the inhibition of p16INK4a expression

Oncogene volume 19, pages 2002–2013 (2000)Cite this article

Abstract

Epstein–Barr virus is associated with a number of human proliferative and malignant diseases. It is capable of immortalizing human primary B-lymphocytes in vitro. Studies indicate that latent membrane protein LMP1 is one of the viral proteins essential for this process. In this report, LMP1 was shown to prevent primary mouse embryonic fibroblasts from entering into replicative senescence in vitro. It further suppresses the senescence-associated induction of p16INK4a, commonly believed to be a key regulator of replicative senescence. In addition, LMP1 was shown to prevent premature senescence provoked by oncogenic ras in mouse embryonic fibroblasts, and to inhibit the oncogene ras-mediated induction of p16INK4a and p21WAF1. In parallel, LMP1 also prevents ras-induced premature senescence in rat embryonic fibroblasts REF52 and human diploid fibroblasts IMR90. Moreover, LMP1 is capable of suppressing the p16INK4a promoter in REF52 and Saos-2 cells in a promoter reporter assay. Our findings suggest that with the expression of p16INK4a and replicative senescence being suppressed, LMP1 may play a key role in Epstein–Barr virus-associated proliferative diseases, and it may further contribute to cancer development by preventing premature senescence induced by mitogenic oncogenes.

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Acknowledgements

We are very grateful for Drs FA Grasser for the LMP1 plasmid, D Thorley-Lawson for S12 antibody against LMP1, SW Lowe for the pLNSX-H-rasV12 plasmid, JR Nevins for the adenovirus with H-ras61L and REF52 cell line, G Peters for the p16 promoter reporter plasmid, B Vogelstein for the WAF1 promoter reporter plasmid, and D Goeddel for the ELAM-luciferase reporter plasmid. We also thank Ms CP Chan for assistance in data preparation, Drs J Zhong and DY Jin for comments on the manuscript. This work was supported by grants from RGC of Hong Kong and Croucher Foundation to L Cao.

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

    Xinhai Yang, Zhimin He, Baozhong Xin & Liang Cao

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Yang, X., He, Z., Xin, B. et al. LMP1 of Epstein–Barr virus suppresses cellular senescence associated with the inhibition of p16INK4a expression. Oncogene 19, 2002–2013 (2000). https://doi.org/10.1038/sj.onc.1203515

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