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...

Nox3, a member of the superoxide-producing NADPH oxidase (Nox) family, participates in otoconia formation in mouse inner ears, which is required for perception of balance and gravity. phox , and the Nox3-dependent superoxide production is totally dependent on p22 phox . The organizers p47 phox and Noxo1 are capable of enhancing the superoxide production by Nox3 in the absence of the activators, and the enhancement requires the interaction of the organizers with p22 phox , further indicating a link between Nox3 and p22 phox . The p47 phoxenhanced Nox3 activity is further facilitated by p67 phox or Noxa1, whereas the activators cancel the Noxo1-induced enhancement. On the other hand, the small GTPase Rac, essential for the gp91 phox activity, is likely dispensable to the Nox3 system. Thus Nox3 functions together with p22 phox as an enzyme constitutively producing superoxide, which can be distinctly regulated by combinatorial use of the organizers and activators.

No abstract

Cytochrome P450IIE1 (P450IIE1) is involved in metabolic activation of carcinogenic nitrosamines, aniline and benzene. We detected a restriction fragment length polymorphism of the human P450IIE1 gene with the restriction endonuclease Oral. The population was thus divided into three genotypes, namely, heterozygotes (CD) and two forms of homozygotes (CC and DD). The distribution of these genotypes among lung cancer patients differed front that among controls with statistical significance of P< 0.05 (x2=7.01 with 2 degrees of freedom). This result strongly suggests that host susceptibility to lung cancer is associated with the Dral polymorphism of the P450IIE1 gene.

No abstract