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Reading assignment s144

  1. 1. Oncogene (2003) 22, 6517–6523 & 2003 Nature Publishing Group All rights reserved 0950-9232/03 $25.00 and cancer: lessons from the human polyomavirus, JCVKrzysztof Reiss1 and Kamel Khalili*,11Center for Neurovirology and Cancer Biology, Temple University, Philadelphia, PA 19122, USAThe possible role of eucaryotic viruses in the development vated and causes PML when the immune system isof cancer has been the subject of intense investigation impaired.during the past 50 years. Thus far, a strong link between Prior to the AIDS epidemic, PML was considered ansome RNA and DNA viruses and various cancers in extremely rare disorder associated with immunocom-humans has been established and the transforming activity promising diseases such as lymphomas, or was seen inof several of the viruses in cell culture and their renal transplant and chemotherapy patients as aoncogenecity in experimental animals has been well complication of immunosuppressive therapies. How-documented. Perhaps, one of the most common themes ever, recent reports indicate that 70% of all HIV-1-among the oncogenic viruses rests in the ability of one or infected patients will exhibit neurological disorders andmore of the viral proteins to deregulate pathways involved between 5 and 8% of all HIV-1-infected patients willin the control of cell proliferation. For example, inactiva- develop PML (Berger and Concha, 1995). PML istion of tumor suppressors through their association with characterized by demyelination due to the cytolyticviral transforming proteins, and/or impairment of signal destruction of oligodendrocytes, the subset of glial cellstransduction pathways upon viral infection and expression in brain that are responsible for myelin production.of viral proteins are among the key biological events that Other hallmarks of PML include giant bizarrecan either trigger and/or contribute to the process of astrocytes, hyperchromatic oligodendrocyte nuclei, andcancer. In recent years, more attention has been paid to multiple foci of demyelination (Major et al., 1992).human polyomaviruses, particularly JC virus (JCV), The viral genome is comprised of a closed, circular,which infects greater than 80% of the human population, double-stranded DNA that can be divided into earlydue to the ability of this virus to induce a fatal and late coding sequences, and the viral regulatorydemyelinating disease in the brain, its presence in various region. The regulatory region of JCV encompasses thetumors of central nervous system (CNS) and non-CNS viral origin of DNA replication and a bidirectionalorigin, and the oncogenic potential of this virus in several promoter composed of two 98 base pair repeats. Thelaboratory animal models. Here, we will focus our viral early sequence that is transcribed before DNAattention on JCV and describe several pathways employed replication is responsible for the production of T-by the virus to contribute to and/or accelerate cancer antigen, whereas the viral late genes that are transcribeddevelopment. after DNA replication, produce capsid proteinsOncogene (2003) 22, 6517–6523. doi:10.1038/sj.onc.1206959 VP1, VP2, and VP3 and the accessory Agnoprotein (Frisque and White, 1992). The lytic cycle of JCVKeywords: tumorigenesis; T-antigen; oncogene; JC explains some of the pathological features of PML,virus; PML hallmarks of which are the destruction of myelin sheaths and oligodendrocytes, the myelin-producing cells; and the appearance of astrocytes that exhibit trans-Introduction formed cell morphology. Evidently, lytic infection with JCV results in cytolytic destruction of oligoden-The human neurotropic JC virus (JCV) is the etiologic drocytes, while its abortive replication in astrocytesagent of progressive multifocal leukoencephalopathy causes morphological changes leaving astrocytes(PML), a fatal demyelinating disease of the central that resemble transformed cells. In cell culture systems,nervous system (CNS) (Berger et al., 1998). JCV is a JCV exhibits a narrow tissue specificity in that themember of the polyomaviruses whose other members virus can replicate most efficiently in primary humaninclude BK virus and the well-known simian virus 40 fetal glial cells. Studies have also reported weak(SV40). JCV coexists within the human population, as replication of the virus in B cells (Monaco et al.,greater than 80% of adults worldwide exhibit JCV- 1996). Owing to the species specificity of the DNAspecific antibodies (Major et al., 1992). Subclinical polymerase, JCV can only replicate in primates, andinfection with the virus occurs in early childhood and humans are thought to represent the natural viral hostthe virus remains in a latent stage throughout life, (Frisque and White, 1992).although on rare occasions the virus becomes reacti- In addition to its primary role in the development of PML, JCV has been shown to be associated with several*Correspondence: K Khalili; E-mail: human tumors (Del Valle et al., 2001a). While the
  2. 2. Viruses and cancer K Reiss and K Khalili6518 etiologic role for JCV in the development of cancer in cells by JCV. Expression of the JCV early protein from humans remains to be established, there have been the Mad-4 strain of JCV in transgenic animals contain- several experimental animal models that verify the ing only the early DNA sequences of JCV results in oncogenic potential of JCV in vivo. Furthermore, the the development of two distinct phenotypes. One line ability of the JCV early protein to transform human exhibited dysmyelination of the central nervous system fetal cells has led to the development of several cell lines due to reduced production of myelin proteins, while the that possess tumorigenic activity in vivo. In this review, other set developed adrenal neuroblastoma (Small et al., we have summarized the most recent observations on 1986a, b; Franks et al., 1996). Expression of the JCV JCV-transformed tumor cells in which the viral protein, early protein from the archetype strain of JCV in FVB/ T-antigen deregulates several cellular pathways that N mice leads to the development of primitive neuroec- control proliferation. These observations can provide an todermal tumors resembling medulloblastoma (Krynska alternative working platform for studying oncogenic et al., 1999b). Of note, no evidence for abnormal pathways utilized by various viruses to induce cancer in myelination of the brain was observed in transgenic humans. mice harboring tumors. In a different series of studies, transgenic animals were created using the C57BL/6 JCV and cancer: in vitro and in vivo observations mouse strain expressing the JCV Mad-4 early genome. After 6–8 months, the mice exhibited pituitary adeno- Similar to the well-studied SV40, JCV possesses the mas (Gordon et al., 2000). Curiously, some of the ability to infect and transform primary cultures, animals that had not developed pituitary adenomas including primary human fetal glial cells and human instead developed malignant peripheral nerve sheath vascular endothelial cells, albeit to a lesser degree than tumors (MPNST) (Shollar and Gordon, unpublished SV40 (Fareed et al., 1978; Walker and Padgett, 1978). observations). Histological examination of the various Almost all JCV-infected transformed cells express the JCV-induced tumors in transgenic mice revealed that viral early protein and they exhibit altered morphology, while all cells contain the transgene, as expected, only a enhanced growth rate in low serum medium, the ability subset of cells express T-antigen. Interestingly, results to form foci in culture, and in some but not all cases, from studies on cell cultures derived from PNETs induce tumors in Nude mice (Gallia et al., 1998a; Del showed that after several passages, T-antigen-positive Valle et al., 2001a). Also, transformation of primary cells lose their expression of T-antigen, yet retain their hamster brain cells by various strains of JCV, including transforming phenotype. While the mechanism involved Mad-1 and Mad-4, have generated rapidly growing cells in the extinction of T-antigen remains unknown, its has with several characteristics of a transformed phenotype, been suggested that a ‘hit-and-run’ mechanism may be including growth in low serum, enhanced production of involved in JCV-induced cancer cells. Results from plasminogen activator, and anchorage-independent in vitro studies have indicated that T-antigen-positive growth (Frisque et al., 1980; Kang and Folk, 1992). In and T-antigen-negative medulloblastoma cells derived addition to the cells of neural origin that seem to be from transgenic mice exhibit similar growth patterns in readily transformed by the virus, a low incidence of monolayer cultures (Wang et al., 2001). Under ancho- JCV-mediated transformation in baby hamster kidney rage-independent growth conditions, however, the cells and in rat fibroblasts has been reported (Bollag T-antigen-positive cells manage to survive in the absence et al., 1989; Haggerty et al., 1989). In laboratory animals of serum and proliferate upon treatment of cells with JCV infection often results in the development of insulin-like growth factor 1 (IGF-1). Under similar tumors. Newborn Syrian hamsters develop a broad conditions, T-antigen-negative cells demonstrate an range of tumors, including medulloblastomas, primitive attenuated response when stimulated with IGF-1 (Wang neuroectodermal tumors, astrocytomas, glioblastoma et al., 2001). Similarly, T-antigen-positive cells form multiforme, and peripheral neuroblastomas after brain tumors when injected subcutaneously in Nude mice, inoculation with JCV (Walker et al., 1973; Varakis, while the T-antigen-negative cells show limited, if any, 1978; Zu Rhein and Varakis, 1979). While no evidence growth (Krynska et al., 2000). for productive infection of the tumor cells by JCV has been observed, expression of the viral early, but not late, Molecular basis of JCV T-antigen-mediated promoter in the tumor cells leads to the accumulation of transformation large amounts of T-antigen (Raj et al., 1995). Similarly, injection of JCV into the brains of newborn rats induces While the precise mechanism responsible for cellular undifferentiated neuroectodermal tumors in the cere- transformation by JCV is not fully understood, it is brum of 75% of the animals (Ohsumi et al., 1986). In believed that the early proteins of the virus, particularly owl and squirrel monkeys, intracerebral, subcutaneous, T-antigen, by associating with several cellular proteins, or intravenous inoculation of JCV causes the develop- plays a critical role in this event (Sullivan et al., 2000). ment of astrocytomas, glioblastomas, and neuroblasto- Like SV40 T-antigen, JCV T-antigen has a modular mas by 16–24 months of age (London et al., 1983). In structure with multifunctional activities including accord with the observations in the JCV hamster model, ATPase, helicase, DNA binding, and a-polymerase; all expression of the JCV early genome was observed in the of which are essential for the process of DNA absence of the viral late proteins and viral DNA replication (Pipas, 1992; Sullivan et al., 2000). Further- replication ruling out productive infection of the tumor more, results from protein–protein interaction studiesOncogene
  3. 3. Viruses and cancer K Reiss and K Khalili 6519 tumor cells (Darbinian et al., 2001). Thus, one may p53, pRb Tumor Suppressor Pathway envision a role for T-antigen in the inactivation of Pura by association in cells in which Pura contributes to the control of cell proliferation. The cellular chaperone hsp70 and the insulin receptor substrate 1 (IRS-1), a key component of the type 1 insulin-like growth factor p53 JCV-T receptor (IGF-1R), have also been shown to associate with T-antigen (Baserga, 1999; Sullivan et al., 2000; p53 JCV-T Lassak et al., 2002). The association of T-antigen and IRS-1 is of p21WAF1 X particular interest as recent studies have suggested thatcyclin-cdk *cyclin-cdk the IGF-1 signaling pathway contributes to prolifera- tion and survival of medulloblastoma cell lines (Patti P et al., 2000; Wang et al., 2001; Del Valle et al., 2002a, b). cdk Rb:E2F Rb + E2F An abundance of IGF-1R, overexpression of IRS-1, andcyclin phosphorylation of IGF-1R and IRS-1 have all been E2F detected in JCV T-antigen murine cell lines, suggesting that IGF-1R and T-antigen may cooperate in cellular transformation (Wang et al., 2001). The use of an JCV-T Rb JCV-T G1 S antisense strategy against IGF-1R mRNA and domi- nant-negative mutants for IGF-1R in in vivo and in vitro assays established the importance of IGF-1R in growth Tumor of JCV T-antigen tumor cells (Wang et al., 2001; Reiss 2002). A Of interest, IRS-1 has been found in the Figure 1 The p53, pRb tumor suppressor pathways. The nucleus of T-antigen-positive cell lines and human association of T-antigen with p53 leads to inactivation of p53 and downregulation of p21WAF-1 that eventually affects the status tumor samples, suggesting that T-antigen expression of pRb phosphorylation by cyclin cdk and the release of E2F. may lead to nuclear localization of IRS-1 (Del Valle Further, E2F is liberated from pRb:E2F by the interaction of et al., 2002a; Lassak et al., 2002, Tu et al., 2002). T-antigen with pRb Mapping studies have determined that the N-terminal portion of IRS-1 interacts with JCV T-antigen and that this binding is independent from IRS-1 tyrosinerevealed that JCV T-antigen has the capacity to interact phosphorylation and can be strongly inhibited by IRS-with several critical tumor suppressor proteins including 1 serine phosphorylation. Importantly, competition forp53 and members of the pRb family (Bollag et al., 1989; IRS-1–T-antigen binding by a dominant-negative mu-Haggerty et al., 1989; Del Valle et al., 2001a). It is tant of IRS-1 inhibited anchorage-independent prolif-believed that the association of T-antigen with p53 and eration of JCV T-antigen-transformed medulloblastomathe pRb family can lead to the inactivation of these cells (Lassak et al., 2002). All of these observations havetumor suppressors in cells expressing T-antigen and led us to propose a model in which the interaction ofthus, promote uncontrolled proliferation. According to T-antigen and IRS-1 may lead to the uncoupling ofone model, the association of JCV T-antigen with p53 IRS-1 from the IGF-1R and the translocation of IRS-1abrogates the ability of p53 to augment transcription of to the nucleus (Figure 2). Further studies are needed top21/WAF-1, an inhibitor of cyclin kinases, including determine the nuclear function of IRS-1 in the presencecyclins A and E, and their associated kinases. Under and absence of JCV T-antigen.normal conditions, a decrease in kinase activity of G1/S In light of recent studies demonstrating the involve-cyclins:cdks maintains pRb in a hypophosphorylated ment of Wnt signaling in various cancers, includingand active state that in turn sequesters the S phase- medulloblastomas (Morin, 1999; Eberhart et al., 2000)specific transcription factor, E2F. Not mutually exclu- and the association of JCV with these tumors, it wassive, T-antigen’s association with pRb can liberate E2F hypothesized that JCV exerts its oncogenic activity, atfrom the pRb:E2F complex and permit E2F to exert its least in part, through deregulation of the Wnt signalingaffect on cell proliferation by promoting unscheduled pathway. In normal cells, b-catenin, a key modulator oftranscription of S phase genes (Figure 1). Support for the Wnt pathway, is modified on its N-terminal serinepRb regulation of T-antigen-induced tumors comes and threonine by phosphorylation and then ubiquiti-from studies illustrating that overexpression of pRb2/ nated and rapidly degraded by the proteosome pathwayp130 can overcome JCV–T-antigen-mediated tumori- (for review see Polakis 2000; Gao et al., 2002).genecity in experimental animals (Howard et al., 1998). Degradation of b-catenin occurs by a multiproteinJCV T-antigen has also been associated with other cytoplasmic complex containing GSK3b, Axin 1, andcellular proteins such as YB-1 and Pura (Gallia et al., APC. When cells are stimulated by Wnt proteins, the1998b; Safak et al., 1999). The association of T-antigen function of the GSK3b/Axin1/APC complex is inhibitedwith Pura is relevant to the transforming ability of by a lesser known pathway leading to the accumulationT-antigen, as earlier results have demonstrated that of unphosphorylated and stable b-catenin in thePura overexpression suppresses the growth of several cytoplasm. Oncogene
  4. 4. Viruses and cancer K Reiss and K Khalili6520 Wnt Signaling Pathway IGF-1 Signaling Pathway JCV-T β-catenin (GSK3β. Axin1, APC) wt β-catenin β-catenin P JCV-T wt JCV-T mut β-catenin wt LEF IRS-1 β-catenin β-catenin IRS-1 JCV-T mut LEF degradation MAPK PI3K Nucleus PDKs Activation of c-myc, cycln D1 Others Akt/PKB cell cycle Nucleus Apoptosis Tumor Cell Others? Figure 3 The Wnt signaling pathway. The Wnt signaling pathway Cycle? DNA and its well-studied cytoplasmic protein, b-catenin, is regulated by Repair? Tumor a series of proteins with kinase activity such as GSK3b, Axin, and APC. A mutation in b-catenin immunizes this protein against phosphorylation in which the stable proteins associate with LEF-1 Figure 2 The IGF-1 signaling pathway. The IGF-1 signaling and translocate to the nucleus where they stimulate c-myc, cyclin pathway via its key component, IRS-1, alters phosphorylation and D1, and several other cell proliferation genes. JCV T-antigen, by activity of MAPK and PI3 K that eventually led to tumor associating with wild-type b-catenin, increases the stability of b- development. The interaction of T-antigen with IRS-1 translocates catenin and accelerates its nuclear import IRS-1 to the nucleus where it can affect cell cycle parameters as well as other critical events such as DNA repair small t-antigens, one may ascribe similar functions as Cytoplasmic b-catenin translocates into the nucleus those established for SV40 small t-antigen for the JCV where it forms a heterocomplex with DNA binding protein. For example, the cysteines and the central transcription factors such as TCF/LEF, which have the proline of SV40 small t-antigen appear to be important potential to stimulate transcription of genes related to for its interaction with and the inhibition of cellular cell cycle regulation such as c-myc and cyclin D1 (He phosphatase PP2A. As a consequence of PP2A inhibi- et al., 1998; Shtutman et al., 1999). In several cancer tion by small t-antigen, several cellular kinases are cells, including PNETs, it was shown that mutations at hyperphosphorylated and their activity is elevated. This the site of phosphorylation of b-catenin results in was first described for MAPK and its kinase, ERK, then stabilization of b-catenin, its nuclear import, and extended to JNK and a key ion transporter, the Na/H enhanced expression of cell cycle regulators (Figure 3). antiporter (Sontag et al., 1993). Activation of the Examination of the Wnt signaling pathway in JCV T- MAPK family kinases by small t-antigen also leads to antigen-positive cells compared to T-antigen-negative increased transcription from AP-1-driven promoters, cells revealed enhanced levels of b-catenin, LEF-1, and consistent with activation of the Elk-1 family of their downstream target, c-myc, suggesting a role for T- transcription factors (Wheat et al., 1994). Also, JCV antigen in deregulating the Wnt pathway (Gan et al., small t-antigen may influence protein phosphorylation 2001). Further studies have revealed the ability of T- cascades involved in CREB-related transcriptional antigen to associate physically with b-catenin and activities (Wheat et al., 1994). In general, the effects of stabilize wild-type b-catenin. This event was concurrent small t-antigen on intracellular kinases promote cell with increased levels of b-catenin in the nucleus and growth presumably by accelerating cell entry into the enhancement of c-myc gene expression (Figure 3). S phase by a complex mechanism that involves proteo- Through alternative splicing, the early region of JCV some degradation of p27 (Sheaff et al., 1997). Of note, can also encode several smaller isoforms of large efficient degradation of p27 is required for the accumu- T-antigen including small t-antigen and T0 135, T0 136, lation of cyclin A and S phase progression (Zerfass- and T0 165 (Bollag et al., 2000; Prins and Frisque, 2001). Thome et al., 1997). Thus, by favoring the elimination of Initial studies with the T0 proteins have suggested that p27, small t-antigen may allow cyclin A/cdk2 to these proteins may contribute to replication of viral orchestrate cell cycle progression. DNA and suspected to possess some oncogenic poten- In addition to multiple viral early proteins, the JCV tial (Prins and Frisque, 2001). Little is known about the late region encodes a small protein, named Agnoprotein, function of JCV small t-antigen, and its potential role in whose open reading frame resides in the leader of the cellular transformation. However, based on sequence late transcripts. In SV40, Agnoprotein plays a role in the homology between specific regions of SV40 and JCV lytic cycle of the virus by facilitating nuclear import ofOncogene
  5. 5. Viruses and cancer K Reiss and K Khalili 6521the capsid protein (Carswell and Alwine, 1986; Resnick in 28 (32.9%) of 85 tested samples. In a separate seriesand Shenk, 1986; Khalili et al., 1988). Similarly, of studies, the presence of JCV in medulloblastomas hasAgnoprotein plays a critical role in productive replica- been established. Parallel reports demonstrate immuno-tion of JCV, as mutations in the Agnoprotein hamper histochemical detection of JCV T-antigen in 17.3 andreplication of JCV in primary astrocytes (Safak et al., 45% of samples obtained from two separate groups of2001, unpublished observations). With respect to its medulloblastoma patients (Krynska et al., 1999a; Deleffect on host cells, results from in vitro studies have Valle et al., 2002c). In addition to T-antigen, analysis ofdemonstrated that the expression of Agnoprotein in cells medulloblastoma samples has revealed the presence ofleads to upregulation of cyclin A and p21/WAF-1. Agno DNA sequences in 11 (69%) out of 16 samples,Interestingly, results from protein binding studies have and immunohistochemical analysis showed the presencerevealed the ability of Agnoprotein to interact, although of Agnoprotein in cytoplasm of 11 (55%) out of 20weakly, with p53, and that the region between residues samples. Importantly, the JCV early gene product, large1–36 of Agnoprotein that contain a helix–loop–helix T-antigen, was detected in nine (45%) out of 20motif is essential for this interaction. Thus, it is evident medulloblastoma cases examined.that in addition to well-studied large T-antigen, other In addition to tumors of the nervous system, moreJCV proteins including small t-antigen, Agnoprotein, recent studies have detected JCV DNA sequences andand perhaps T0 may play a role in the oncogenic expression of the viral proteins in colorectal carcinoma,potential of this human polyomavirus. rather than tumors arising from within the nervous system (Ricciardiello et al., 2001; Enam et al., 2002).Association of JCV with human cancer Greater than 50% of the tumor samples were found to express the viral proteins T-antigen and Agnoprotein,As mentioned earlier, prior to the discovery of JCV, while a number of T-antigen-positive samples alsoseveral reports indicated an association between PML contained b-catenin protein localized to the nucleusand brain tumors. The first observations were made by (Enam et al., 2002). While VP-1 DNA sequences can beRichardson in which the post-mortem examination of a amplified from significant numbers of these tumors, VP158-year-old man with chronic lymphocytic leukemia and expression by immunohistochemistry has not beenPML revealed the presence of an oligodendroglioma observed in any tumor type, suggesting that the tumors(Richardson, 1961). In other studies of PML cases cells are not productively infected with JCV, but ratherassociated JCV with multiple astrocytomas (Sima et al., transformed by the virus.1983) and numerous foci of anaplastic astrocytes Interestingly, recent evidence has shown the presence(Castaigne et al., 1974) were reported. In these cases, of JCV in untreated urban sewage, suggesting transmis-viral particles were observed in both oligodendrocytes sion of the virus via the fecal–oral route (Bofil-Mas et al.,and astrocytes, but not in the neoplastic astrocytes. 2001). In addition, JCV DNA has also been found in theRecently, Shintaku et al. (2000) reported a case of normal human gastrointestinal tract, which furtherdysplastic ganglion-like cells in association with PML. supports the possibility that JCV, and other polyoma-Detailed immunohistochemical studies revealed that viruses, may colonize the gut (Ricciardiello et al., 2000).the neurons were infected with JCV and expressed These data, taken together with several reports of SV40JCV T-antigen in the absence of capsid protein, VP1. detection in human mesothelioma, osteosarcoma, and In addition to cases of simultaneous PML and B-cell lymphoma, suggest that JCV may be observedcerebral neoplasm, JCV has been found in human brain within other tumor types throughout the body. Thetumors in the absence of any PML lesions. In our recent observations from such clinical samples along with thework (Del Valle et al., 2001b), 85 clinical specimens data from cell culture and experimental animals addfrom the United Kingdom, Greece, and the United further evidence of the involvement of JCV in theStates have been examined for their possible association process of cellular transformation, and strongly suggestwith JCV. These multiple samples represented various a possibility that this human neurotropic polyomavirushuman brain tumors, including oligodendroglioma, may play a role in the development of human brainastrocytoma, pilocytic astrocytoma, oligoastrocytoma, tumors.anaplastic astrocytoma, anaplastic oligodendroglioma,glioblastoma multiforme, gliomatosis cerebri, gliosarco-ma, ependymoma, and subependymoma. Gene amplifi-cation using primers that recognize the JCV DNA Acknowledgements We express our appreciation to past and present members ofsequences followed by Southern blot hybridization have the Center for Neurovirology and Cancer Biology for theirdemonstrated the presence of the viral early sequences in contribution, and to Cynthia Schriver for editorial assistance.49 (69%) of 71 samples. More importantly, results of This work was made possible by grants awarded by NIH toimmunohistochemical analysis have demonstrated the KR and KK.expression of JCV T-antigen in the nuclei of tumor cellsReferencesBaserga R. (1999). Exp. Cell Res., 253, 1–6. Berger JR, Levy RM, Flomenhoft D and Dobbs M. (1998).Berger JR and Concha M. (1995). J. Neurovirol., 1, 5–18. Ann. Neural., 44, 341–349. Oncogene
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