Integration of interferon-α/β signalling to p53 responses in tumour suppression and antiviral defence

Abstract

Swift elimination of undesirable cells is an important feature in tumour suppression and immunity. The tumour suppressor p53 and interferon-a and -b (IFN-a/b) are essential for the induction of apoptosis in cancerous cells and in antiviral immune responses, respectively, but little is known about their interrelationship. Here we show that transcription of the p53 gene is induced by IFN-a/b, accompanied by an increase in p53 protein level. IFN-a/b signalling itself does not activate p53; rather, it contributes to boosting p53 responses to stress signals. We show examples in which p53 gene induction by IFN-a/b contributes to tumour suppression. Furthermore, we show that p53 is activated in virally infected cells to evoke an apoptotic response and that p53 is critical for antiviral defence of the host. Our study reveals a hitherto unrecognized link between p53 and IFN-a/b in tumour suppression and antiviral immunity, which may have therapeutic implications.The tumour suppressor p53, activated in response to DNA damage, induces cell cycle arrest or apoptosis through transcriptional activation of its target genes, hence having a central role in tumour suppression [1][2][3][4][5] . So far, it is not known whether p53 contributes to the immune responses that lead to the eradication of pathogens such as viruses. On the other hand, IFN-a/b, both of which are essential cytokines for antiviral immunity, are sometimes referred to as 'negative growth factors' , and manifest anti-oncogenic activities [6][7][8][9][10] . In fact, IFN-a/b are used for the treatment of some forms of human cancer but the molecular basis for the treatment is poorly understood [11][12][13] . Until know, little if anything has been known about the link between the p53 and IFN-a/b system. Induction of p53 protein by IFN-a/bWhen wild-type mouse embryonic fibroblasts (MEFs) were stimulated with IFN-b, a notable increase in the level of p53 was observed (Fig. 1a). A similar observation was made in cells stimulated with IFN-a (data not shown) but not with IFN-g ( Supplementary Fig. 1). The increase in p53 level with IFN-b treatment was dose-dependent, with about fourfold induction achieved at a high concentration of IFN-b (Fig. 1b). The p53 induction by IFN-b was also observed in two human hepatic cancer cell lines, HepG2 and HLE, p53 function being abrogated in the latter cells by a mutation in the DNA-binding domain 14 (Fig. 1c). We performed a pulse-chase experiment to examine whether the observed p53 protein induction is secondary to suppression of the p53 degradation pathway by IFN-b, typically the MDM2-mediated pathway [15][16][17] . However, no difference was observed in the half-life of p53 (40-45 min) between the IFN-treated and untreated MEFs (Fig. 1d), suggesting that p53 protein synthesis is induced by IFN-b stimulation. Induction of the p53 gene by IFN-a/bInformation is limited about the induction of the p53 gene 18 , and the above results prompted us to examine whether IFN-a/b induces p53 gene transcription. Inspection of mouse and human p53...

Treatment of hepatocellular carcinoma with major portal vein thrombosis by combined therapy with subcutaneous interferon-α and intra-arterial 5-fluorouracil; role of type 1 interferon receptor expression

“…A recent report showed that transcription of the p53 gene is induced by IFN-a, accompanied by an increase in p53 protein level (Takaoka et al, 2003). The study suggested that p53 gene might be an important predictor of IFN-a therapy for HCV liver cirrhosis and HCC.…”

Combination therapy with PEG-IFN-α and 5-FU inhibits HepG2 tumour cell growth in nude mice by apoptosis of p53

“…Moreover, the IFN-stimulated gene factor3 (ISGF3) formed by IFN-a has been shown to induce p53 gene expression by binding to at least two IFN-stimulated response element (ISRE) sites in the p53 gene (Takaoka et al, 2003;Vilcek, 2003). We found that while the HepG2 tumours of PEG-IFN-and combination-treated animals showed significantly elevated p53 protein and mRNA levels, only the combination-treated tumours showed increased p53 phosphorylation at serine46 and elevated p53AIP1 mRNA levels.…”

“…Given the central role p53 plays in the induction of cell cycle arrest and apoptosis, it is possible that the IFN-a/5-FU combination therapy activates p53 in some way. Supporting this is that IFN-a has been found to induce p53 gene expression (Takaoka et al, 2003;Vilcek, 2003). To test whether p53 participates in the anti-HCC activity of IFN-a/5-FU combination therapy, we here treated nude mice carrying HepG2 cell tumours with 5-FU and/or IFN-a.…”

“…The IFN-a group of closely related cytokines are typically produced early after infection with viruses and have antiviral and immunoregulatory activities (Samuel, 2001;Takaoka et al, 2003). They also have potent antitumour activities (Samuel, 2001;Takaoka et al, 2003).…”

“…They also have potent antitumour activities (Samuel, 2001;Takaoka et al, 2003). While studies examining the IFN-a-mediated signal transduction pathways have already identified a number of IFN-a-induced genes, it remains unclear whether these genes contribute to the antitumour activities of IFN-a.…”