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Carcinogenesis Advance Access originally published online on March 7, 2007
Carcinogenesis 2007 28(6):1140-1144; doi:10.1093/carcin/bgm048
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Control of virus infection by tumour suppressors

César Muñoz-Fontela1,4, María A. García2, Manuel Collado3, Laura Marcos-Villar1, Pedro Gallego1, Mariano Esteban2 and Carmen Rivas1,*

1 Departamento de Microbiología II, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ramón y Cajal s/n, Madrid 28040, Spain
2 Departamento de Biologia Molecular y Celular, Centro Nacional de Biotecnología, CSIC, Campus Universidad Autónoma de Madrid, Madrid 28049, Spain
3 Molecular Oncology Program, Spanish National Cancer Centre (CNIO), 3 Melchor Fernández Almagro, Madrid 28029, Spain
4 Department of Oncological Sciences, Mount Sinai School of Medicine, One Gustave L, Levy Place, Box 1130, NY 10029, USA

* To whom correspondence should be addressed. Tel: +34 913941746; Fax: +34 913941745;Email: mdcrivas{at}farm.ucm.es


   Abstract
Top
 Abstract
Introduction
 References
 
An increasing number of tumour suppressor genes are induced by interferons (IFNs) and may play an important role in the control of cell proliferation induced by this cytokine. In addition, pathways triggered by both tumour suppressors and IFN converge as common targets for non-related tumour viruses. The inhibition of the IFN response by animal viruses is explained by the fundamental role that IFN plays to control virus infection. However, the reasons why many viruses, including those that do not require the replication of the host, target tumour suppressor pathways are varied and are still under investigation. Here we review those findings that support that tumour suppressors may have a role in the control of virus infection.

Abbreviations: ARF, alternative reading frame; IFN, interferon; PKR, dsRNA-dependent protein kinase; PLSCR1, phospholipid scramblase 1; PML, promyelocytic leukaemia; VSV, vesicular stomatitis virus


   Introduction
Top
 Abstract
 Introduction
References
 
Interferon (IFN) is a family of pleiotropic cytokines that regulate cell proliferation and apoptosis and are responsible for providing vertebrates with innate immunity against a wide range of viruses and other microbial pathogens (1). IFN{alpha}/ß are produced upon viral infection by many different cell types, and they exert their antiviral function through the induction of different IFN-regulated genes. The list of IFN-regulated genes is in constant revision. In this sense, an increasing number of tumour suppressors, previously identified as target of small DNA tumour viruses, are suggested as mediators of the inhibition of cell proliferation induced by IFN. Targeting of tumour suppressor genes by small DNA tumour viruses has been associated with the viral requirement to induce cell division in order to reach DNA replication. However, some of the viruses that target these tumour suppressors can replicate in non-dividing cells. Significantly, it has been recently described that these tumour suppressors can inhibit infection by viruses that replicate in non-dividing cells (see references below). These new reports have thus pointed to several tumour suppressors as mediators of the antiviral activities of IFN, suggesting that they serve a broader biological role. An old hypothesis: tumour suppressors as sensors of viral stress (2–6) is now re-emerging. In this review, we provide an insight of the limited, yet expanding, list of tumour suppressors that exhibit antiviral function (Figure 1).


Figure 1
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  		Fig. 1. Diagram of the IFN-signalling pathway showing the induction of proteins with antiviral action and tumour suppressor function. IFN has a wide range of biological functions including antiviral, antiproliferative and immunomodulatory properties through the induction of >200 genes. The binding of IFN{alpha}/ß to the specific receptor IFNAR1-2 results in the cross-activation of the Jak–Tyk–STAT pathway by phosphorylation that promotes the migration of the IFN-stimulated gene factor 3 (ISGF3) to the nucleus, where it can activate the transcription of the IFN-stimulated genes (ISGs). Some of the IFN-stimulated genes with demonstrated tumour suppressor function and antiviral activity are included. Some of the mechanisms that mediate the antiviral activity of the different tumour suppressors are indicated. Note that a same tumour suppressor can control the replication of nuclear or cytoplasmic viral agents. SFV, semliki forest virus; EMCV, encephalomyocarditis virus; VV, vaccinia virus, LCMV, lymphocytic choriomeningitis virus and HFV, human foamy virus.

 
Promyelocytic leukaemia
The promyelocytic leukaemia (PML) protein acts as a cell growth regulator and tumour suppressor (7,8), is regulated during the cell cycle (9) and induces apoptosis (10,11). In normal cells, the PML protein is found in 5–30 subnuclear domains of ~0.3–1 µm in diameter, which are known as PML nuclear bodies (12). PML expression is frequently lost in prevalent human malignancies, is associated with tumour grade and progression (13) and is transcriptionally up-regulated by IFN (14,15), an indication of its role as a defence mechanism against viral infection. The antiviral activity of PML is also suggested by the frequent observation of disruption or delocalization of the PML bodies caused by many viral agents such as lymphocytic choriomeningitis virus (16), human T-cell leukaemia virus type 1 (17), rabies virus (18), adenovirus (19,20), Epstein-Barr virus (21), human cytomegalovirus (22) and herpes simplex virus (23). The existence of viral proteins capable of directly inhibiting PML further supports a role for PML in innate antiviral defence. Thus, for example, the Hepatitis C virus core protein interacts with endogenously expressed PML isoform IV, inhibits PML isoform IV-induced apoptosis and interferes with the coactivator function of PML isoform IV for pro-apoptotic p53 target genes (24). Finally, over-expression of PML induces resistance to infection by vesicular stomatitis virus (VSV), influenza virus or lymphocytic choriomeningitis virus (25,26) and leads to a drastic decrease of the human foamy virus gene expression (27).

p53
Since its discovery as a cellular protein able to interact with SV40 large T antigen (28), p53 has been linked to the study of viral oncoproteins from DNA tumour viruses. During their evolution, many of these viruses have evolved mechanisms designed to abrogate p53 function. Viral oncoproteins such as the already mentioned large T antigen, and many others such as HPV E6, adenovirus E1B-55K, hepatitis B virus HBX, human T-cell leukaemia virus type 1 Tax, Epstein-Barr virus Zta or Kaposi's sarcoma-associated herpesvirus (KSHV) proteins LANA1, k-bZIP and LANA2, block p53-dependent response in infected cells and, in some cases, target this protein for its degradation through the proteasome (29–38). The mechanisms evolved by small DNA tumour viruses such as adenovirus or papillomavirus to drive non-dividing cells into S phase could be based on the requirement of cellular S phase-associated functions for their own DNA replication. However, this unscheduled DNA synthesis also activates p53, resulting in the transcriptional activation of p53-responsive genes and the ensuing p53-dependent apoptosis of the cell. Cellular suicide limits viral spread through the organism and it is considered an efficient antiviral mechanism. This situation provides an alternative view on why those viruses have also to target the tumour suppressor p53 pathway in their own benefit. In addition, viruses that can replicate in non-dividing cells, such as HIV-1 or herpes simplex virus types 1 and 2, also contain proteins that target p53, revealing a different benefit in the viral action other than the mere pushing of the cells into proliferation. In parallel to this p53 targeting, several reports demonstrated an increase of p53 protein levels as a consequence of viral infection with Friend murine leukaemia virus (39) or influenza A virus (39,40). This up-regulation of p53 was again in agreement with a role for p53 in responding to the DNA damage caused by viral replication. However, an increase of the cellular level of p53 after type I IFN described by Johnson et al. (41) and the demonstration of the presence of an active IFN-stimulated response element in the p53 promoter (42) placed this tumour suppressor as one of the genes directly activated by type I IFN. These findings established a new link between tumour suppression and antiviral defence, and suggested that in many ways, the cell response to both types of stresses (DNA damage and virus infection) can follow the same steps. In this sense, IFN-dependent activation of p53 has been demonstrated to be successful in the treatment of several disorders such as the decrease of the inflammatory activity and fibrosis in chronic hepatitis C, injury of endothelium induced by reactive oxygen species, treatment of renal cell carcinoma or the reversion of the hairy appearance of B cells in hairy cell leukaemia (43–46). A direct demonstration of the antiviral activity of the tumour suppressor p53 in vivo and in vitro was provided by Takaoka et al. (42) using VSV. In addition, Muñoz-Fontela et al. (47) demonstrated a dose–response correlation between p53 gene dosage and apoptosis induction after VSV infection and an inverse correlation with viral yield production. Later on, the requirement of p53 for influenza virus-induced cell death and limited viral replication was also documented (48).

ARF
The alternative reading frame (ARF) is one of the two unrelated products encoded by the INK4a–ARF locus, one of the most frequently mutated genes in cancer (49,50). Initially, ARF activity was linked to p53 stabilization after oncogenic stress (51), but more recently p53-independent functions have been also described (52), placing this tumour suppressor as sensor of different types of stress. Several reports described the activation of ARF after the expression of viral proteins (53,54), type I IFN treatment (55), or after virus infection (56,57), suggestive of a physiological role for ARF during virus infection. However, due to the well-known connection between ARF and p53, a direct antiviral activity for ARF independent of p53 activation had not been considered before. A role for ARF in antiviral defence has only recently been demonstrated including the demonstration of functional Interferon regulatory factor 3 (IRF3) elements in its promoter region (56). ARF is protective against IFN-sensitive viruses such as VSV, Sindbis virus or a recombinant vaccinia virus rendered IFN sensitive by deletion of the dsRNA-dependent protein kinase (PKR) inhibitory gene, E3L. The antiviral action executed by ARF is mediated, at least in part, by PKR, a classical IFN-induced gene with an undisputed antiviral activity and with a putative tumour suppressor function [reviewed by Garcia et al. (58)]. Induction of PKR is achieved by ARF indirectly through a mechanism that involves ARF-dependent retention of the multifunctional protein nucleophosmin in the nucleolus, which in turn is an inhibitor of PKR. These data provide a rationale for the existence of viral proteins such as adenovirus protein V that induces redistribution of nucleophosmin from nucleolus to cytoplasm or hepatitis D virus delta antigen that up-regulates nucleophosmin expression (59,60).

Phospholipid scramblase
Phospholipid scramblase 1 (PLSCR1) is an IFN-inducible, multiply palmitoylated protein which is localized in either the cell membrane or nucleus, with a role in cell signalling, maturation and apoptosis. PLSCR1 suppressed ovarian carcinoma in an animal model (61), showed antileukaemic roles in an inducible PLSCR1-expressing leukaemic cells (62) and elevated expression of PLSCR1 has been shown to be required for normal myeloid differentiation (63). The marked transcriptional up-regulation of PLSCR1 expression in tumour cells after IFN treatment was suggested to contribute to the tumour-suppressive action of this cytokine (61) and suggested a potential antiviral activity. Accordingly, VSV replicated to higher titres in human cells in which PLSCR1 expression was decreased with short interfering RNA or in mouse PLSCR1–/– embryonic fibroblasts than in identical cells expressing PLSCR1. This antiviral effect correlated with increased expression of a subset of IFN-stimulated genes, including ISG15, ISG54, p56 and guanylate-binding proteins, suggesting that PLSCR1 provides a mechanism for amplifying and enhancing the IFN response through increased expression of a selected subset of potent antiviral genes (64).

RNase L
RNase L is an IFN-induced endoribonuclease that inhibits virus replication by degrading viral RNA molecules required for the production of viral proteins and formation of infectious virus. RNase L acts in concert with other IFN-induced enzymes, such as 2'-5'-oligoadenylate synthetases that upon binding to dsRNA generate small 2'-5'-oligonucleotides from ATP (pp)p5'A2'(p5'A2')n, referred to as 2-5A, that, in turn, activate the latent RNase L [reviewed by Castelli et al. (65)]. In the absence of virus infection, RNase L has been suggested to function as a tumour suppressor as evidenced by the finding that patients in which RNase L is mutated exhibit an increased risk for hereditary prostate cancer (66,67), for the more aggressive tumours of pancreatic cancer (68) and the recent results which demonstrate that RNAse L plays a critical role in the inhibition of fibrosarcoma growth in nude mice (69). An antiviral effect mediated by RNase L activation has been demonstrated for encephalomyocarditis virus (70,71), vaccinia virus (72) and reovirus infections (73). In addition, introduction of 2-5A into cells has been shown to reduce the cytopathic effects of several viruses such as encephalomyocarditis virus, poliovirus and semliki forest virus (74).

PKR
As mentioned above, several lines of evidence suggest that the PKR, an IFN-induced enzyme with potent antiviral action, can function as a tumour suppressor. The expression of PKR mutants leads to malignant transformation and causes tumorigenesis in nude mice (75–77). PKR is also involved in different types of cancer, like leukaemias and lymphomas (78,79), and an increased expression of PKR correlates with better patient prognosis for certain tumours (80–82). The consideration of PKR as a tumour suppressor will permit to include this enzyme in the list of proteins with a dual antiviral and antitumour function.

Other putative candidates
Since the list of tumour suppressor genes regulated by IFN is in constant revision, we just want to mention some of the putative candidates that in our view deserve future in-depth analysis. The tumour suppressor retinoblastoma protein, pRB, is a classical target of small DNA tumour viruses (83–85), but it is also blocked by large DNA tumour viruses (86–88), non-tumour DNA viruses (89,90) and RNA viruses (91,92). The targeting of the pRB pathway by viral proteins together with the activation of pRB after IFN-alpha treatment (93) point to this protein as a potential candidate acting as a sensor of viral stress. Interestingly, other tumour suppressors such as the cyclin-dependent kinase inhibitors p15Ink4b or p27Kip1 have been also described as up-regulated after IFN treatment (94–96). In addition, the list of tumour viruses that regulate p15Ink4b or p27Kip1 activity (97–104) is in constant revision, suggesting again a dual role for these cellular proteins. The demonstration of an antiviral role for these candidates will be required to confirm if this re-emerging hypothesis can be supported.

In summary, the reports described above highlight an important role of different tumour suppressors in the complex innate antiviral host defence. While the field of tumour suppressors with antiviral function is in its infancy, future work will unravel a wider significance of tumour suppressors in host cell defence against pathogens. Understanding how tumour suppressors exert their antiviral function will be relevant in the potential use of viruses as oncolytic agents and for gene therapy.


   Acknowledgments
 
M.E. is funded by the Spanish Ministry of Education and Science (BIO2005-06264) and Fundación Marcelino Botín. C.R. is funded by the Spanish Ministry of Education and Science (BIO2005-00599) and Fundación de Investigación Médica Mutua Madrileña. M.C. is an investigator of the Ramon y Cajal Programme.

Conflict of Interest Statement: None declared.


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Received November 30, 2006; revised February 12, 2007; accepted February 26, 2007.


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