Levels of p53 in Epstein-Barr virus-infected cells determine cell fate: apoptosis, cell cycle arrest at the G1/S boundary without apoptosis, cell cycle arrest at the G2/M boundary without apoptosis, or unrestricted proliferation.
The marked increases in p53 and p21/WAF1 levels that occur during Epstein-Barr virus (EBV) infection and the generation of immortal B lymphoblastoid cell lines (LCL) do not lead to growth arrest or apoptosis, although increasing wild-type (wt) p53 levels in EBV-infected cells by transfection or DNA damage induce these effects. We hypothesized that the concentration of p53 relative to that of LMP1 determines whether EBV-infected B cells undergo growth arrest and apoptosis. Cell cycle arrest and apoptosis were evaluated in LCL expressing varying p53 levels achieved by treating the cells with increasing concentrations of cisplatin, and we supplemented this approach with experiments in EBV-infected Burkitt's lymphoma (BL) cells transfected with a temperature-sensitive (ts) mutant human p53 and studies in LCL infected with recombinant adenoviruses expressing wt and ts mutant p53. Small increases in p53 and p21/WAF1 led to cell cycle arrest at the G2/M boundary, but not to apoptosis; moderate increases resulted in growth arrest at the G1/S boundary, also without apoptosis; and large increases also induced apoptosis. These results confirm the hypothesis and reveal unanticipated complexities in cell cycle regulation by p53.
Chen
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Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California, 92037, USA.
Huang
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Cooper
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D017209:Apoptosis; D002453:Cell Cycle; D002455:Cell Division; D002460:Cell Line; D002945:Cisplatin / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D016193:G1 Phase; D016195:G2 Phase; D006566:Herpesviridae Infections / Q000378:metabolism* / Q000473:pathology; D004854:Herpesvirus 4, Human; D006801:Humans; D011956:Receptors, Cell Surface / Q000378:metabolism; D016196:S Phase; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014412:Tumor Virus Infections / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation; D014763:Viral Matrix Proteins / Q000378:metabolism
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D011956:Receptors, Cell Surface; D016159:Tumor Suppressor Protein p53; D014763:Viral Matrix Proteins; D002945:Cisplatin