Integration of interferon-a/b signaling to p53 response in tumor suppression and antiviral defence

Nature, 424: 516-523, 2003

Speaker : 吳鳳翎                                      Place: Room 601

Commentator : 翁舷誌 老師                 Time: 2003/11/26  15:00-16:00

Abstract:

The tumour suppressor p53 plays a pivotal role in induction of apoptosis in cancerous cells. Interferons (IFNs) are a large family invoving in antiviral activity, cell growth regulation and immune activation. It is not clear whether p53 contributes to inhibit the viral replication.  In this paper, authors demonstrate transcription of the p53 gene is induced by IFN-a/b following an increase of p53 protein level.  The special sequence ISRE (interferon stimulating response element) within the promoter region of p53 gene is activated by the ISGF3 (IFN-activated transcription factor) (1). IFN activated p53 through the transcriptional activation of the gene by ISGF3 performing chromatin immunopreciptation assay by treating wild-type MEFs (mouse embryonic fibroblasts) with IFN-b, followed by immunoprecipitation with anti-Stat2 antibody. Futhermore, the p53 protein level is decreased by HPV E6 gene expression, but countered by IFN-b which exerts a strong anti-oncogenic activity in E6 dependent cell transformation mediated by sustaining p53 expression via transcriptional induction of the gene. Previous study reported that the effect of IFN-b on the DNA damage-induced apoptosis of MEFs expressing E1A is p53-dependent (2), and p53 function and IFN signaling are inhibited by products of oncogenic virus (3); however, it is not clear whether p53 has any role in the antiviral and anti-tumor activity linking with IFN. In this study, IFN treatment enhances p53-dependent apoptosis in response to DNA damage agent including X-ray and 5-FU. Moreover, MEFs infected with virus markedly phosphorylation Ser 18 of p53 and this effect was ATM kinase-dependent. Finally, the p53 induction by virus-induced IFN-a/b may enhance the apoptotic response in virally infected MEFs and mice. These findings suggest that the early phase of virus infection, virus-infected cells produce IFN-a/b and eventually undergo p53 -dependent apoptosis and contribute to inhibiting the spread of virus.

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