Oncogenes of DNA Tumor Viruses1

[CANCER RESEARCH 48. 493-496. February I. 1988] Perspectives in Cancer Research Oncogenes of DNA Tumor Viruses1

Arnold J. Levine Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544

Experiments carried out over the past 10-12 years have the cellular oncogenes. It will attempt to identify where more created a field or approach which may properly be termed the information is required or contradictions appear in the devel molecular basis of cancer. One of its major accomplishments oping concepts. Finally, this communication will examine ex has been the identification and understanding of some of the amples of cooperation between oncogenes and other gene prod functions of a group of cancer-causing genes, the oncogenes. ucts which modify the mode of action of the former. If we are The major path to the oncogenes came from the study of cancer- on the right track, then general principles may well emerge. causing viruses. The oncogenes have been recognized and stud Tumor formation in animals or transformation in cell culture ied by two separate but related groups of virologists focusing has been demonstrated with many different DNA-containing upon either the DNA (1) or RNA (2) tumor viruses (they even viruses (1). In most cases it has been possible to identify one or have separate meetings now that these fields have grown so a few viral genes and their products that are responsible for large). From their studies it has become clear that the oncogenes transformation or, in some cases, tumorigenesis. A list of these of each virus type have very different origins. Indeed it is a viral gene products is presented in Table 1. With two notable curious fact that virtually every group of the DNA viruses exceptions, infection of cells and selection for the transformed studied (papova-papilloma, adenoviruses, herpesviruses, hepad- phenotype always result in a clone of cells containing and naviruses, poxviruses) has a representative virus which has been expressing viral gene products (1) and in some cases, these viral shown to produce, or be closely associated with, tumors in proteins have been shown to be required for the maintenance animals. Many DNA viruses have been shown to be tumor of the transformed state (14). The first exception is HSV2-1 or viruses under the appropriate and often specialized circum -2 and CMV, where it has been difficult to find reproducible stances of an experiment (1). In contrast, among the thousands viral genetic information or gene products in transformed cells of RNA viruses, only the retroviruses contain examples of viral (15, 16). Several explanations have been put forth to account agents that cause tumors. While the viral oncogenes that reside for these observations: (a) a "hit-and-run" hypothesis where the in the genome of the DNA tumor viruses bear little or no viral gene products act (via inducing mutation, for example) homology to cellular genes, the oncogenes of retroviruses are and are then no longer required (17); (b) insertion of a small clearly derived from and are closely related to their cellular viral DNA element (a promoter, for example) in the chromo counterparts, the protooncogenes (3). The evidence demonstra some activating a cellular oncogene (16). The insertion-pro ting that viral (DNA tumor viruses) and cellular (RNA tumor moter model, demonstrated with other viruses (18), has yet to viruses) derived oncogenes participate in the development of a be proven with HSV or CMV; (c) the frequency of HSV or cancer cell is quite convincing and accepted by most critical CMV transformation in cell culture is so low (at background scientists in the field, but not without some reservations (4, 5). level) (15, 16) that no real proof exists for the transforming Research, pursuing the isolation and functions of the cellular abilities of these viruses. In this case no explanation or mech oncogenes, has proceeded rapidly and been very productive with anism of transformation would be required. Epidemiological frequent reviews of this field (6-8). Less visible but equally evidence for the role of HSV-1 or -2 or CMV in human cancer valuable is the information accumulating about the viral onco is not convincing and what was accepted previously (HSV-2 genes of DNA tumor viruses. The justifications for focusing on and cervical carcinoma) is, in light of new data, no longer held this topic are, in the end, the same reasons why the cellular to be correct (19). The other example of a DNA virus with no oncogenes are important in the understanding of cancer: (a) known oncogene or protooncogene is hepatitis B virus. The some of the DNA tumor viruses (human papilloma viruses 16, epidemiological association between chronic hepatitis B virus 18, 33; hepatitis B virus; Epstein-Barr virus) are closely and infection and hepatocellular carcinoma is quite excellent (10); continuously associated with specific human cancers and prob however, the mechanism of carcinogenic action is unclear. ably contribute to one of several events that cause these cancers Some ideas such as (a) an increased risk of mutagenic or (9-11); (b) a study of the mechanisms of action of these viral carcinogenic events following destruction caused by chronic oncogenes will provide fundamental information about the infection, (b) the polymerase of the virus (reverse transcriptase) control of cell growth. There is already good evidence that some has a high error frequency and acts as a "mutator gene", and viral transforming gene products act upon normal cellular pro (c) a yet-to-be-found HBV protein that can act as an oncogene tooncogene products and alter their activities or levels (12,13). or cooperate with an oncogene (i.e., we still need an assay to Other viral oncogenes act to bypass the normal cellular control detect it), have all been put forth to explain these data. The mechanisms regulated by the protooncogenes and their prod development of model systems such as transgenic animals car ucts. A little consideration and several key experiments lead to rying this virus or some isolated viral genes could go a long the conclusion that a study of the DNA viral oncogenes will way to testing some of these ideas (20). inevitably bring us back to the cellular protooncogenes. The majority of the DNA tumor viruses (Table 1) have genes The goal of this "Perspective" will be to focus upon the DNA that encode protein products that actively participate in the virus oncogenes and their interactions and relationships with creation of a cancer cell and the transformed phenotype (1).

Received 10/1/87; accepted 10/28/87. 2The abbreviations used are: HSV, herpes simplex virus; CMV, cytomegalovi- 1This work was supported by Grants CA09528 and CA38757 from N1H and rus; BPV, bovine papilloma virus; EBV, Epstein-Barr virus; EGF, epidermal MV-47 from the American Cancer Society. growth factor; p53, a protein with a molecular weight of 53,000. 493

Table l DNA tumor virus oncogena Functions, location, mode Viruses Oncogenes of action Papovaviruses SV40 Large T-antigen Nucleus-membrane, +/â€”*transcription, mitogenic, tumor- specific transplantation antigen, complex-p53 Small t-antigen Cytoplasm Polyoma Large T-antigen Nucleus, +/â€”transcription, DNA synthesis Middle t-antigen Inner plasma membrane, perinuclear membranes, complex-sir Small t-antigen Cytoplasmic Papillomaviruses (BPV, human) ES protein Plasma membrane E6 protein Nucleus, membrane

Adenoviruses E\\-M, 26,000 â€”transcription E \\-M, 36,000 + transcription E1B-AÃ•,21,000 Nuclear membrane E\B-M, 55,000 mRNA transport, complex-p53

Herpesviruses Epstein-Barr virus Lymphoproliferative Latent membrane protein malignancy Epstein-Barr nuclear Nuclear antigen antigen-II Herpes simplex types 1 and 2 Cytomegalovirus

Hepadnaviruses Hepatitis B virus

Poxviruses (vaccinia) Vaccinia growth factor Related to EGF and transforming growth factor-a; binds to Rabbit fibroma EGF receptor-mitogen Yaba tumor virus Fowlpox

These may be proteins localized in the nucleus (SV40-polyoma residues deleted, and so increased enzyme activity is achieved large T-antigen, BPV-E6, adenovirus EIA, El B proteins, EBV- via a similar loss of regulation (2). The second interaction of a Epstein-Barr nuclear antigen-2), in the cytoplasm (small t- viral transforming gene product with a cellular protooncogene antigens SV40, polyoma), or in or on the plasma membrane is observed with the SV40 large T-antigen-p53 association (12, (BPV-E5, Py middle t, EBV-LMP) (1). Some of these viral 31). In normal cells, p53 protein levels are kept low due to the oncogenes are tumor-specific transplantation antigens (SV40 short half-life (6-20 min) of this protein. In many transformed large T-antigen, probably adenovirus EIA) (21, 22) or are cells, p53 levels are 10 to 100-fold higher and the half-life of recognized by T-lymphocytes (the EBV-latent membrane pro p53 is much increased (32). In SV40 transformed cells, p53 is tein is likely to be the lymphocyte determined membrane anti found in an oligomeric protein complex with SV40 T-antigen, gen or LYDMA) (23). There has been a wide variety of func and temperature-sensitive mutants of T-antigen regulate p53 tions associated with these proteins. The SV40 large T-antigen levels in a temperature-sensitive fashion (33). p53 has been and adenovirus EIA gene products can negatively or positively shown to be an oncogene because complementary DNA clones regulate transcription of viral and probably cellular genes (24, of p53 can immortalize cells in culture (34) and cooperate with 25). The adenovirus ElB-A/r 55,000 protein appears to be the ras oncogene to transform primary rat cells (35). Indeed, involved in mRNA transport from the nuclear to the cyto p53 is the only oncogene to date which was first described by plasm ic compartments (26). Some of these viral oncogenes have the impact of a DNA tumor virus oncogene product (large T- been shown to directly stimulate cell growth or division. Mi- antigen) upon a cellular protein (p53) (12, 31). Several of the croinjection of the large T-antigen of SV40 into the nucleus of properties ascribed to SV40 T-antigen (i.e., stimulation of quiescent cells stimulates these cells to synthesize DNA (27). cellular DNA synthesis) can also be ascribed to p53. The Some poxviruses, which produce benign tumors, probably do microinjection of anti-p53 antibodies into the nuclei of cells so because they encode a gene for a growth factor (vaccinia stimulated to divide by mitogens blocks the entry of these cells growth factor) (28). The gene product is closely related in into S phase (36). It is not surprising, then, that p53 levels are sequence to EGF and a transforming growth factor. Vaccinia regulated during the entry of cells into the growth phase (37). growth factor is known to bind to the EGF receptor and increase Interestingly, a second virus, adenovirus type 5, has an onco the level of tyrosine specific protein kinase activity leading, gene product, ElB-A/r 55,000 protein, that also binds to p53 most likely, to cell proliferation (29). This is a case where the (38) and in adenovirus transformed cells p53 levels are high pathway utilized by a viral protein interacts with a cellular and the half-life of the p53 protein is much longer than in receptor that is itself a protooncogene (erb-B oncogene is related normal cells. It is clear that some DNA tumor virus oncogenes to the EGF-receptor) (30). There are three clear-cut cases of act through or interact with the cellular protooncogenes to the DNA virus oncogene products interacting with cellular affect a transformation event. protooncogene products. The middle t-antigen of polyoma as Several different lines of evidence have demonstrated that sociates with the cellular src (c-.vir) protein at the inner plasma viral or viral and cellular oncogenes must interact in complex membrane and increases its specific tyrosine kinase activity up ways (in several steps or events) to produce a cancer cell or to 50-fold (13). The middle t-pro tein appears to do this by transformed cell. First, there are a number of examples of viral blocking the phosphorylation of specific tyrosine residues in c- oncogenes that can transform one cell line in culture, but not a xrc that, when phosphorylated, modulate down c-.vrcactivity. In related cell population or line. The BPV-E6 gene transforms the Rous sarcoma virus, the v-.vrcproduct has these amino acid (produces foci) murine C127 cells but fails to transform 494

NIH3T3 mouse cells (39). Interestingly, the BPV-E5 gene can termed tumor evolution, most likely results from the selection transform both of these cell lines (39). Similarly, the NH2- of cells (for growth potential) from a population of cells whose terminal fragment of SV40 large T-antigen that contains the pattern of gene expression, genomic stability, or mutation rate first 120 amino acids (out of 709 residues) will transform is heterogeneous. One can imagine that a number of events 10T1/2 cells but not NIH3T3 cells (40). Clearly the host cell such as oncogene activation, developmental signals or inducers, used in an assay for the transformed phenotype of a virus or the immunological recognition of a cell, and its response to oncogene can affect the result. A related example is the obser hormones or virus infections could all contribute to the evolu vation that an oncogene can transform one cell type but when tionary consequences of tumor development. A fundamental placed in a different cell type the oncogene may induce terminal question that remains unanswered at this time is whether the differentiation or cell death (41). Yet a slightly different point first event, or an early event, in the development of a cancer is made by the example of erb A (related to the receptor for cell (for example, low levels of T-antigen, oncogene mutations, thyroid hormone) in that it is not an oncogene by itself, but expression of adenovirus EIA, or myc) could result in the permits erb B transformed cells to grow and divide under a increased probability of a second event (such as mutation rates, wider variety of conditions (pH variations, etc.) (42). In this genomic instability, etc.). Does tumor evolution proceed by the case, a cellular gene product, involved in modulating the differ accumulation of two or three truly independent events or does entiated state of a cell, broadens the potential of erb B (related one event predispose a second or third action? It seems likely to the EGF receptor) to act as an oncogene and promote cancer. that some genes or gene products will effect subsequent events The search for these types of gene products that interact with (e.g., mulater genes) while others will indeed act independently. or enhance oncogene function should form an important part The field of tumor evolution now needs experimental design of the future research initiatives in the molecular biology of and imaginative approaches to provide these answers. Although cancer. not discussed in detail here, it is worth emphasizing that many The second way in which oncogenes have been shown to exogenous influences (such as the immune system, hormonal interact is the requirement for two or more oncogenes to environment, exposure to tumor promoters or viruses) will play produce transformed cell foci using primary rat embryo fibro- fundamental roles in tumor evolution. One needs only to be blasts (43,44). Two classes of viral and cellular oncogenes have reminded that a simple agent, such as adenovirus, carries three been recognized with adcnovirus EIA, polyoma large T, p53, sets of different genes that are designed to overcome the host's and myc in one group and ras, polyoma middle t, and the immune defenses. The EIA gene products can act to modulate adenovirus El B genes in a second group (43,44). One example down the major histocompatibility class I gene products, prob from each category is required in this assay to produce immor ably at the level of transcription of these cellular genes (25,47). talized foci of rat cells. Exactly what each oncogene contributes The viral E3-A/r 19,000 glycoprotein also reduces the level of remains unclear. One interpretation is that the first class of class I proteins at the cell surface by blocking protein glycosyl- oncogenes immortalizes these cells and the second produces ation in the Golgi apparatus of infected cells (48). Finally, the morphological and cell growth changes (foci). Alternatively, in VA (virus-associated) gene products overcome the effects of the case of the ras oncogene, it could well be lethal to these interferon by inactivating the EIF-2 a-kinase which regulates cells when expressed alone, and the first oncogene may alleviate the initiation of translation in interferon treated cells (49). Viral the expression of this lethal phenotype. For example, ras might agents that contribute oncogenes responsible for tumor initia promote terminal differentiation of rat cells while the oncogene tion can also contribute additional activities (not oncogenic myc might prevent the commitment to a differentiated state themselves) that have striking effects upon tumor evolution. permitting raj-induced foci to form. The impression one gets This is very much like the erb A-erb B interactions in erythro- from this kind of interpretation is that oncogenic processes are leukemia (30, 42). related to developmental processes in interesting ways. To put Several general points (I hesitate to call them principles) it another way, oncogene products can function, depending emerge from this line of reasoning. Foremost is the clear upon their cellular environment, in several different ways. An demonstration that viral and cellular oncogenes need to be oncogene in one cell type is a developmental gene in another defined in the context of the cell type or host cell in which they cell type. act. These proteins do different things in different backgrounds The third reason to believe that multiple steps are involved (differentiated states and maybe genetic backgrounds). We need in the evolution of a cancer cell can be seen in the development to identify the proteins and structures that oncogenes interact of tumors themselves. In transgenic mice carrying the gene for with in each of these cells in order to understand the ways in the SV40 large T-antigen, several discrete steps in tumor pro which they function. This investigation has begun and in some duction have been recognized (45). To begin with, low levels of cases oncogene-oncogene interactions emerge (T-p53, ElB-A/r SV40 large T-antigen have been detected in normal tissues 55,000-p53, middle t-.vrc). In other cases cellular proteins that prior to the first signs of tissue pathology. SV40 T-antigen has regulate the differentiated state (erb A) enlarge the environment been observed 2-4 weeks prior to the development of multiple for the action of an oncogene (erb B) (42). Clearly we need to small foci of anaplastic cells. These cells have an increased understand more about these genes and gene products that act mitalic index but foci can be present for as long as 1-2 months in concert with oncogenes to produce cancer. All of these before high levels of T-antigen are observed in the tissue and a phenomena are encompassed in the emerging field of tumor rapid growth of tumor cells ensues. It is a common observation evolution, i.e., the collection of a small number of "indepen in transgenic mice carrying the SV40 oncogenes that the tumors dent" events that accumulate, are selected for, and emerge as a are well differentiated morphologically (45) and even express malignant tumor. We must understand these events and deter differentiated gene products at a normal level (46). As these mine if they are indeed independent or predisposed by previous tumors grow larger, begin to invade the surrounding tissue, and actions. The genetic endowment, state of differentiation, and cause visible symptoms, the differentiated appearance of the immunological state of the cell and organism will come to play tumor cells in the tumor is lost and papillomas develop into a most important role in the future analysis of oncogene action. carcinomas (45). This description of events, appropriately The number of variables that are recognized to impact upon 495

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Cancer Res 1988;48:493-496.

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