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

Oncogene. 2000 Apr 13;19(16):2002-13. doi: 10.1038/sj.onc.1203515.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Division
  • Cell Line
  • Cell Line, Transformed
  • Cellular Senescence / genetics
  • Cellular Senescence / physiology*
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / metabolism
  • Diploidy
  • Embryo, Mammalian / cytology
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Gene Expression Regulation
  • Genes, ras
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Promoter Regions, Genetic
  • Rats
  • Transfection
  • Viral Matrix Proteins / genetics
  • Viral Matrix Proteins / metabolism*


  • CDKN1A protein, human
  • Cdkn1a protein, mouse
  • Cdkn1a protein, rat
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • EBV-associated membrane antigen, Epstein-Barr virus
  • Viral Matrix Proteins