p53 is a pro-apoptotic protein that is required for the programmed death of tumour cells in response to DNA damage, and type-I interferons (IFN-α and IFN-β) are known to be involved in anti-viral immune responses. Despite the successful use of IFN-α/β for the treatment of some types of human cancer, the relationship between p53 and IFN-α/β is unknown.

When mouse embryonic fibroblasts (MEFs) and the hepatic cancer cell line HepG2 were treated with IFN-α/β, the level of p53 protein was increased in a dose-dependent manner. IFN treatment did not affect the half-life of p53, and so does not increase protein degradation. IFN-β induced the expression of Trp53 mRNA by MEFs, indicating that gene transcription is increased. The mouse and human TP53 genes were both shown to contain IFN-stimulated response elements (ISREs) in their promoter or first intron, which are known to be activated by a transcription-factor complex, known as ISGF3, that contains IFN regulatory-factor 9 (IRF9); p53 induction in response to IFN-β was not observed in Irf9−/− MEFs.

IFN-β stimulation did not induce the serine phosphorylation and hence activation of p53 protein and had no effect on the induction of p53 target genes. Therefore, the authors propose that although type I IFNs do not activate p53, they increase the sensitivity of cells to stress stimuli that activate p53 by increasing the level of p53 protein. They went on to show that the interaction between IFN and p53 pathways has implications for defence against both tumours and viruses.

The human papilloma virus (HPV) protein E6 induces the degradation of p53 and, together with another oncoprotein such as HRAS, can induce the transformation of primary MEFs. However, when IFN-β was added, the level of p53 protein was restored and there was a marked decrease in the number of transformed colonies. Similarly, IFN-β enhanced the p53-dependent apoptosis of MEFs expressing adenovirus E1A oncoprotein in response to X-ray radiation.

In terms of anti-viral responses, MEFs and HepG2 cells infected with various viruses were shown to have marked phosphorylation of p53. The apoptosis of virus-infected cells mediated by p53 was significantly suppressed in MEFs deficient for IFN-α/β receptor 1 (IFNAR1), whereas p53 phosphorylation still occurred, which supports the theory that IFN signalling is required for enhancement of the p53 response by p53 induction rather than activation. p53-deficient MEFs infected with vesicular stomatitis virus gave a higher virus yield than wild-type MEFs, which indicates that p53-dependent apoptosis (enhanced by IFN-α/β signalling) is important for controlling virus replication.

This information could have important implications for cancer therapy as it indicates that IFN-treated cells should be more susceptible to DNA-damaging chemotherapeutic agents such as 5-fluorouracil (5-FU), allowing lower doses to be used. In agreement with this, the authors showed that the death of HepG2 cells was increased by IFN-β at a dose of 5-FU that had minimal effects on its own.