Viruses' backup plan

Tumour viruses can cause cancer by altering gene expression and protein activity in the host cell. Tumour adenoviruses, however, seem to go to great lengths to ensure that one particular host cell protein, p53, is suppressed.

Analyses of tumour-causing viruses have been instrumental in understanding cancer biology. The first vertebrate oncogene, for example, was discovered on the basis of its sequence similarity to the cancer-causing gene of a chicken retrovirus. Numerous tumour-suppressor genes have also been identified because they are cellular targets of tumour-causing DNA viruses1. On page 1076 of this issue, Soria et al.2 describe a previously unknown mechanism that tumour-inducing adenoviruses use to suppress the activity of the tumour-suppressor protein p53. Their findings call for a revision of the dogma on how these viruses make cells cancerous.

Many tumour-inducing DNA viruses commonly cause abnormal activity of the cellular transcription factor E2F1, through binding to proteins of the retinoblastoma family such as Rb, which would normally be bound to E2F1 (refs 3, 4). In cells that are infected with cancer-causing strains of adenovirus, the viral E1A protein binds to proteins of the host cell's retinoblastoma family, freeing E2F1 to promote not only progression of the cell cycle — a central requirement of the viral life cycle — but also transcription of many viral genes3 (Fig. 1a).

Figure 1: Inactivating p53.

a, The adenoviral protein E1A binds to cellular proteins of the retinoblastoma family (such as Rb). This results in the release of E2F1 from binding to retinoblastoma proteins, which — among other effects — leads to the ARF-mediated inhibition of MDM2. This causes p53 to accumulate because it is not targeted (black cross) for degradation by MDM2-mediated ubiquitylation (Ub is a ubiquitin protein). This increase in p53, in turn, arrests the cell's proliferation and directs its death. b, To counter this effect on the cell's viability, the virus produces another protein, E1B-55k, which (together with the E4-ORF6 protein, not shown) not only binds to p53's transactivation domain, impairing the transcription-factor activity of p53, but also directs p53 to be degraded. c, Soria et al.2 find that, as an additional measure, the virus expresses the gene encoding E4-ORF3 (a process for which E1A is required). E4-ORF3 either selectively or completely silences the expression of p53 target genes by mediating the methylation (Me is a methyl group) of histones at their promoters through its effect on the cellular histone methyltransferase enzymes SUV39H1 and SUV39H2.

Stimulation of cell-cycle progression by E1A would be too simple a route to inducing cancer, and host cells often have safeguard mechanisms to overcome a single precancerous change. In this case, the host cell can counter the possible change because deregulated E2F1 also activates the cellular ARF protein, which inhibits MDM2 — the main inhibitor of p53 (ref. 5). In the absence of MDM2 activity, p53 levels increase, either inhibiting cell-cycle progression or destroying the infected cell.

In the 'cat-and-mouse' games of evolution, tumour-causing adenoviruses have devised ways to deal with this p53 activity that arises as a result of the host cell's response to E1A. Adenoviruses also produce a protein called E1B-55k, which binds to p53 and both inhibits its transcription-promoting activity and directs its degradation by the proteasome6 (Fig. 1b). For many years, this has stood as the central mechanism by which adenoviruses — and by analogy other tumour viruses — are thought to inactivate Rb and p53.

Soria et al.2 were intrigued by their observation that infection with an adenoviral mutant lacking E1B-55k results in high levels of p53 — as expected — but not in the activation of p53's target genes. They proposed that the virus must use a mechanism to inactivate p53 in addition to the effects it exerts through E1B-55k.

The authors' analysis of adenoviruses with several mutations — deletion of the gene encoding E1B-55k, as well as other genes — led to the identification of E4-ORF3 as a second repressor of p53 (Fig. 1c). This protein selectively silences the activation of p53 target genes by mediating the methylation of histone proteins at these genes' promoters. E4-ORF3 does this through its effect on the cellular methylase enzymes SUV39H1 and SUV39H2. Intriguingly, E1A also seems to be required for effective transcription of the gene encoding E4-ORF3.

At first, these results might seem paradoxical — why would an adenovirus, which does not have a genome big enough to afford functional redundancy, have multiple mechanisms to inactivate p53? This question might point to the importance and potency of p53, such that it may be too risky for the virus to rely on just one mechanism for inactivating the protein. Previous work7 also revealed that only a robust decrease in p53 production would inactivate its tumour-suppressive activity. The effects of E1B-55k might therefore be insufficient to inactivate p53 completely, leading to the evolution of other strategies to work in concert.

Alternatively, complete repression of p53 through E1B-55k might not be ideal for the virus. In this case, E4-ORF3 could selectively inhibit p53 target genes that impede viral replication, sparing other targets that might benefit the virus. One target that might fit into the latter category is the gene encoding TIGAR, which redirects intermediates from one metabolic process, glycolysis, to another, the pentose-phosphate pathway8. This alteration in metabolism could be beneficial for the high biosynthetic demands of a virally infected cell.

A pertinent question is whether Soria and colleagues' findings are relevant for human cancers that do not involve a viral component. The authors correctly point out that many of the cellular proteins that bind to E4-ORF3 are mutated in human cancer. Consequently, these mutations might affect the expression of p53 target genes. Nonetheless, in response to stress, many tumour-cell lines carrying wild-type p53 can activate p53 target genes, indicating that it is not a common event in cancer for these genes to be silenced by methylation of the histones at their promoters. Does this therefore mean that the effects that Soria et al. report are specific to tumour viruses or occur only in certain tumour settings? Alternatively, perhaps the methylation of histones at p53-binding sites occurs frequently in human cancer but is lost during the process of establishing tumour-cell lines. Further investigations should yield answers to these intriguing questions.

Undoubtedly, the greatest significance of this study2 will be its contribution to devising strategies to treat cancer. Adenoviruses must inactivate p53 so that they can replicate and subsequently induce the breakdown of the infected cell. Because many tumours lack p53 function5, researchers have engineered viruses that lack E1B-55k with the idea that these viruses would replicate selectively in tumour cells lacking p53 but not in normal cells, eventually leading to the death of the tumour cells9. Although these engineered viruses have proven to be therapeutically beneficial, their replication does not seem to depend on the p53 'status' of the cell10. Soria and co-workers' finding that E4-ORF3 also, at least partly, inactivates p53 function provides an explanation for why this would be the case. Following on from these insights is the exciting prospect that adenoviruses lacking both E1B-55k and E4-ORF3 could be selective and even more potent anticancer agents than viruses lacking just E1B-55k.


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Ryan, K. Viruses' backup plan. Nature 466, 1054–1055 (2010).

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