Environmental and Molecular Mutagenesis 45:304^325 (2005)

Review Article

Impact of Transforming on Cellular Mutagenesis, Stability, and Cellular Transformation

Michael L.Gatza,1,2 Chandtip Chandhasin,2 Razvan I. Ducu,2 and Susan J. Marriott1,2* 1Interdepartmental Program in and Molecular , Baylor College of Medicine, Houston, Texas 2Department of Molecular and Microbiology, Baylor College of Medicine, Houston, Texas

It is estimated that 15% of all are etiologi- been explicitly linked to the expression of onco- cally linked to viral infection. Specific cancers encoded by these viruses. This review including adult T-cell , hepatocellular car- discusses mechanisms utilized by these viral onco- cinoma, and uterine cervical are associated proteins, Tax, HBx, and E6/E7, to mediate geno- with infection by human T-cell leukemia type I, mic instability and cellular transformation. Environ. virus, and high-risk human papilloma Mol. Mutagen. 45:304–325, 2005. c virus, respectively. In these cancers, genomic 2005 Wiley-Liss, Inc. instability, a hallmark of multistep cancers, has

Key words: viral transformation; genomic instability; viral-associated cancer; human T-cell leukemia virus type I; hepatitis B virus; human papilloma virus

INTRODUCTION hepatitis B virus (HBV), and human papilloma virus (HPV). These viruses, respectively, are the etiologic The World Health Organization estimates that each agents of adult T-cell leukemia (ATL), hepatocellular car- year approximately 10 million new cancer cases will be cinoma (HCC), and uterine cervical cancer (UCC). reported worldwide and an estimated 6 million people (12% of worldwide deaths) will succumb to some form of this disease (www.who.int/cancer/en). In the United States OVERVIEW OF VIRUSES alone, 2.3 million new cancer cases will be diagnosed and Adult T-Cell Leukemia and HTLV-1 an estimated 556,000 Americans (> 1,500 per day) will die each year from cancer [American Cancer Society, HTLV-1 was the first human oncogenic dis- 2003]. Worldwide, it has been estimated that 15% of can- covered [Poiesz et al., 1980] and is now recognized as the cer cases are etiologically linked to viral infection, etiological agent of both ATL and a neurodegenerative accounting for nearly 1.5 million new cases and 900,000 disease, tropical spastic paraparesis/HTLV-1-associated deaths annually [Butel, 2000]. myelopathy (TSP/HAM). HTLV-1 is endemic in parts of Viruses have been etiologically linked to specific forms Japan, South America, Africa, and the Caribbean and is of cancer (Table I), and many other viruses not formally currently estimated to infect nearly 20 million people implicated in human tumorigenesis encode proteins cap- worldwide [Franchini, 1995]. Transmission of this virus able of immortalizing cells in culture and causing tumors in transgenic animals. As in most cancers, cancers asso- *Correspondence to: Susan J. Marriott, Department of Molecular Virol- ciated with these viruses demonstrate gross chromosomal ogy and Microbiology, Baylor College of Medicine, One Baylor Plaza, abnormalities, which have been argued to cause, or at Houston, TX 77030. E-mail: [email protected] least contribute to, cellular transformation and tumor pro- Invited article: 25th anniversary of Environmental and Molecular gression. This review focuses on mechanisms of genomic Mutagenesis instability and cellular transformation mediated by the DOI 10.1002/em.20088 oncoproteins encoded by three well-studied oncogenic Published online 11 January 2005 in Wiley InterScience (www.interscience. viruses: human T-cell leukemia virus type 1 (HTLV-1), wiley.com). c 2005 Wiley-Liss, Inc. Impact of Transforming Viruses 305

ic occurs horizontally through the transfer of body fluids ma rs ease g

ithial (i.e., intravenous drug use, blood transfusion, and sexual spast dis n othe ep l thelio T-A bone, ’s

known contact) and vertically through the ingestion of milk- SV40 cells, meso borne lymphocytes during breastfeeding [Hino et al., tropica None 5.2 6 Kidney dsDNA Lg/Sm Unknow Brain,

); 1985; Sugiyama et al., 1986; Wiktor et al., 1993; Ferreira Hodgkin et al., 1997]. Due in part to the long latency period (SV40

(BL); (2–4 decades), only 4–5% of the infected population are

40 expected to develop ATL, mostly those who were oma

horosis infected as children [Johnson et al., 2001]. Despite the virus cirr

an relatively low incidence of ATL, it is a rapidly progres- lymph HCV cytes sing fatal disease that does not respond to any known simi NA C mmon ); rkitt’s treatments and has a mean survival time of 6 months epatitis, epato S3? C u H 9.4 ssR Co 9 H N H B [Jaffe et al., 1984; Shimoyama et al., 1988]. ; (HCV The HTLV-1 genome encodes several proteins that CC) (H

virus appear to contribute to infection and oncogenesis. How-

C ever, numerous studies have established the viral tran- itis oplakia scriptional transactivator, Tax, as the major viral onco- ithial omas ep leuk carcinoma [Grassmann et al., 1992]. Tanaka et al. [1990] hepat V lls ar

EB demonstrated that Tax can transform NIH 3T3 and Rat1 lymph hairy B-ce yngeal , l cells and confirmed these observations using mutational D (EBV); ocellul H ora 0 analysis. Later Tax alone, and in combination with Ras, 90 cells, virus IM, 172. dsDNA Common LMP-1 * Orophar BL, hepat was shown to be capable of transforming primary rodent r embryo fibroblasts [Pozzati et al., 1990; Smith and Greene, 1991]. Tax transgenic mice developed neurofibro- (ATL); ein-Bar

ital mas and mesenchymal tumors when Tax was ubiquitously Epst emia cells

; expressed in all tissues, but developed primary peripheral eous) l skin, warts leuk

anogen comprised of CD8þ T- and NK cells when cutan (HPV)

nx, the Tax was targeted to lymphocytes using epithia HPV genital T-cell sal, cervical, the lymphocyte-specific human granzyme B- t ous virus and a ophary E7 [Hinrichs et al., 1987; Nerenberg et al., 1987; Grossman adul (muco or et al., 1995]. Although these studies provide strong Skin 8–10 8.0 Uterine dsDNA E6, Squam Common pillom

(IM); evidence for the involvement of Tax in tumorigenesis, the pa

sis exact mechanisms of Tax function have yet to be fully elucidated. Generally, it is believed that Tax promotes human ucleo and a a ); tumorigenesis by increasing genomic instability through incidence Asia Afric

cells the disruption of normal host-cell processes, including monon (HBV V od B

ran cellular , DNA repair mechanisms, and cell Viruses high cirrhosis H , theast blo

s, cycle progression. virus cytes, Sou B infectious in sub-Saha white ); itis Hepatiti 4 3.2 dsDNA HCC Common HBx Hepato and HBV hepat /HAM

Transforming HBV is a double-stranded DNA virus with a ubiquitous (TSP (ds). n, worldwide distribution. It is estimated that over 75% of LV-1); Asia thy the world’s population lives in regions of high infection ded merica, (HT Human A 1 M [Hollinger and Liang, 2001]. Similar to HTLV-1, HBV is elopa Caribbea e th theast

HTLV-1 transmitted both horizontally through transfer of body le-stran my NA typ L P/HA Sou Sou cells pan, , T fluids and vertically from mother to child, and 70–90% of ted TS 6 ssR 9.0 Ja A Tax T- doub

Common mothers chronically infected with HBV will pass the virus virus of (ss); on to their child, many of whom will become lifelong car-

emia riers. Although the exact mechanism of vertical transmis- nt anded leuk age

sion is not clear, virus-associated has been found ll in cers of acid eases in amniotic fluid, cord blood, breast milk, and vaginal ing Properties gle-str T-ce dis can . (kB) nce tion esis/HTLV-1-associa I secretions, suggesting perinatal rather than transplacental sin E an tropism ze ucleic umber L transmission [Chen et al., 2004]. It has been estimated B infec N Si N A hum Prevale T Characteristic Genome Cell a Human Human Transform parapar (HD); that over 350 million people are chronic carriers of HBV 306 Gatza et al. and it is believed that over time the infection, potentially Uterine Cervical Cancer and HPV in combination with other environmental factors including aflatoxin B ingestion, cigarette smoking, and alcohol con- HPV is one of the most common sexually transmitted sumption, may result in the development of cirrhosis and diseases (STDs) worldwide and is believed to be the most HCC. In fact, it is currently believed that over 80% of all prevalent STD in the United States. Despite the fact that HCC cases are the result of infection by either HBV or genital HPV infection is not a reported disease, it is esti- virus (HCV) [Chen et al., 1997]. mated that between 1 and 5.5 million new cases occur each HCC is the fifth most frequently diagnosed cancer and year, and the overall prevalence of infection is greater than the fourth leading cause of cancer-related deaths 20 million people in the United States alone [Cates, 1999]. (> 500,000 annually) worldwide. Although the incidence HPV is most often transmitted by direct contact between rate in industrialized nations is rather low, due in part to two epithelial surfaces and is facilitated in part by the pre- immunization programs, HCC is the leading cause of can- sence of abrasions or lesions [Oriel, 1971; Moy et al., cer-related deaths among adults in Southeast Asia and 1989; Euvrard et al., 1993]. The incidence of HPV infec- sub-Saharan Africa. Worldwide, the mortality-to-incidence tion correlates directly with the number of sexual partners rate is close to or greater than 1, indicating that most an individual has encountered and infections are rare in patients will not survive longer than 1 year [Hollinger sexually inexperienced and/or young women [Rosenfeld and Liang, 2001]. et al., 1989; Moscicki et al., 1990; Fairley et al., 1992; The HBV genome encodes several proteins required for Bauer et al., 1993; Andersson-Ellstrom et al., 1994; viral infection and replication. The X-protein (HBx) has Gutman et al., 1994; Rylander et al., 1994]. been shown to have a cofactor role in HBV-mediated cel- Over 100 different papilloma virus family members lular transformation and similar to HTLV-1 Tax, its exact exist and, in humans, are responsible for a variety of function in oncogenesis remains controversial. Several benign proliferations, including warts, epithelial cysts, reports have demonstrated that human HCC tumors, simi- intraepithelial neoplasia, anogenital, orolaryngeal, and lar to ATL and HTLV-1 Tax, often contain the HBx oropharyngeal papillomas, keratoacanthomas, and other sequence. HCC cells appear to maintain HBx expression types of hyperkeratoses. Infection with specific high-risk throughout all stages of tumorigenesis, unlike ATL cells, HPVs, including HPV-16 and -18, is associated which lose Tax protein expression following transforma- with approximately 90–99% of uterine cervical cancers tion [Wollersheim et al., 1988; Paterlini et al., 1995; Wei (HPV-16, specifically, accounts for 50–60% of positive et al., 1995; Su et al., 1998; Sirma et al., 1999]. Although biopsies; HPV-18, 10–20%) and more than 50% of other the mere presence of HBx DNA and/or protein in HCC anogenital tumors, including cancers of the vagina, vulva, does not prove etiological involvement, studies of HBx penis, and anus, as well as a small percentage of head expression in cultured cells and transgenic animals sup- and neck tumors [zur Hausen, 1996]. In fact, numerous port a role for HBx in cellular transformation. studies have demonstrated that the association between Early studies demonstrated that HBx is able to trans- infection with high-risk HPV and uterine cervical cancer form SV40-immortalized rodent cells both in culture and is greater than the association between cigarette smoking in nude mice [Hohne et al., 1990; Gottlob et al., 1998; and lung cancer [Burd, 2003]. Uterine cervical cancer in Yu et al., 1999]. Several HBx transgenic mouse lines adult women is the fourth most diagnosed form of cancer have been generated and demonstrate accelerated liver in the United States and the most commonly diagnosed tumor formation [Kim et al., 1991; Yu et al., 1999]. form in developing countries, where it accounts for Studies of other HBx transgenic lines, however, have approximately 25% of all female cancers [Harro et al., reported that HBx alone does not stimulate tumorigenesis 2001; Jemal et al., 2004]. Furthermore, cervical cancer but rather sensitizes liver cells to environmental car- ranks second to breast cancer as the leading cause of cinogens, including diethylnitrosamine and aflatoxin B female cancer-related deaths worldwide [Jin et al., 1999]. [Dragani et al., 1990; Slagle et al., 1996]. Furthermore, Despite these facts, the development of UCC from persis- bitransgenic mice overexpressing HBx and c-Myc tent high-risk HPV infection occurs only in a minority of develop liver tumors at an accelerated rate, suggesting infected women and, like cancers related to HTLV-1 and that HBx, like Tax, cooperates with cellular proto- HBV, requires a long latency period, suggesting that the to transform cells [Terradillos et al., 1997; accumulation of within the host genome and Lakhtakia et al., 2003]. Although these data do not other predisposing or environmental factors are required delineate the mechanisms of HBx-mediated cellular trans- for transformation [Duensing and Munger, 2004]. formation, they do demonstrate that HBx enhances HBV- HPVs are small double-stranded DNA viruses that induced tumorigenesis. Similar to Tax, it is believed that encode several proteins, two of which, E6 and E7, are HBx mediates transformation by increasing genomic essential for HPV-mediated cellular transformation. Like instability and frequency through dysregulation HTLV-1 and HBV, the exact mechanisms of HPV- of cellular processes. mediated transformation have not been fully elucidated. Impact of Transforming Viruses 307

Several reports have determined that, similar to HTLV-1 conclusive, the exact mechanisms leading to transforma- and HBV and their associated cancers, the HPV-16 and tion by these oncoproteins have not been fully elucidated. -18 can be isolated from cervical cancer biopsies However, similar to Tax and HBx, it is known that E6 [Durst et al., 1983; Boshart et al., 1984]. Furthermore, and E7 affect a variety of cellular processes including cell several groups have reported the presence of the E6 and cycle progression, cellular transcription, and the DNA- E7 proteins in all stages of HPV-positive cancers cells, damage response. suggesting that these proteins are required for both the initiation and progression of tumorigenesis [zur Hausen, VIRALLY MEDIATED GENOMIC INSTABILITY 1996]. Although it is not entirely clear what role the E6 and Chromosomal aberrations and genomic instability play E7 proteins play in these processes, these proteins, despite a major role in the development and progression of multi- their independent oncogenic properties, cooperate in med- step cancers, including ATL, HCC, and UCC. In fact, it iating cellular transformation [Munger et al., 1989]. has been argued that a series of five to six independent Expression of E6 alone is sufficient to induce anchorage- genetic events is required for healthy cells to become independent growth of NIH 3T3 cells and immortalize transformed [Fearon and Vogelstein, 1990; Hanahan and human mammary epithelial cells, while expression of E7 Weinberg, 2000]. The four types of genetic alterations by itself leads to transformation of NIH 3T3 cells and, at that typically occur in tumors include single or small a very low efficiency, to immortalization of the natural nucleotide sequence changes, altered chromosomal num- host cell, human keratinocytes [Munger et al., 1989; Band bers, chromosomal translocations, and gene amplifications et al., 1990; Sedman et al., 1991; Storey and Banks, [Lengauer et al., 1998]. It is not surprising that each of 1993; Kiyono et al., 1998; Liu et al., 1999; Riley et al., these modifications has been identified in HTLV-1-related 2003]. Coexpression of E6 and E7 efficiently transforms ATL, HBV-mediated HCC, and HPV-dependent UCC, as human keratinocytes [Hawley-Nelson et al., 1989; Munger well as a number of other virally mediated cancers. Geno- et al., 1989]. Interestingly, in contrast to Tax- or HBx- mic changes associated with these virus-associated can- transformed cells, E6-, E7-, or E6/E7-transformed cells cers have been explicitly linked to the expression of each rarely produce tumors when transplanted into nude mice of the viral-specific oncoproteins. [Kaur and McDougall, 1988; Pirisi et al., 1988; Wood- Single or small nucleotide changes involving base sub- worth et al., 1988]. However, numerous versions of E6, stitutions, deletions, or insertion of one to a few nucleo- E7, and E6/E7 transgenic mice develop either benign tides can alter the amino acid composition, and tumors or cancers [Kondoh et al., 1991; Arbeit et al., presumably function, of a protein. Unlike other types of 1993, 1994; Griep et al., 1993; Lambert et al., 1993; mutations, nucleotide changes cannot be detected through Searle et al., 1994; Comerford et al., 1995; Herber et al., cytogenetic analysis. Instead, investigators rely on func- 1996; Song et al., 1999]. The frequency and type of tional and sequence analysis of genomically integrated seems to depend largely on the promoter used reporter genes to estimate the overall cellular mutation to drive expression of the viral (s). Furthermore, frequency and spectrum. Although a number of cellular a recent report utilizing chronic estrogen administration genes isolated from ATL, HCC, and UCC tumors are with E6, E7, or E6/E7 transgenic mice demonstrated that mutated, little evidence links these specific mutations to E7 was sufficient to produce high-grade cervical dysplasia the expression of Tax, HBx, or E6/E7. However, several and invasive cervical , while mice expressing studies have reported that Tax, E6, and HBx are each E6 alone only developed low-grade cervical dysplasia and associated with increased mutation frequencies within the did not show additional neoplastic progression. In double- cellular genome. transgenic mice, the E6 protein enhanced the malignant Miyake et al. [1999] demonstrated that Tax expression produced by E7, resulting in larger and more in Big Blue Rat-2 cells (BBR-2; Stratagene, La Jolla, CA), extensive cervical cancers. Since these observations which contain a genomically integrated lacI gene, resulted depended on chronic estrogen administration, the coopera- in a 2.8-fold increase in mutation frequency compared to tive transforming effects of E6 and E7 appear to require non-Tax-expressing cells. Additional studies by these and additional stimuli [Riley et al., 2003]. In fact, HPV- other investigators showed that exposure of BBR-2 cells infected women who smoke cigarettes, take oral contra- to other mutagens (i.e., ultraviolet light, ethylnitroso- ceptives, are overweight, or have been exposed to other urea, dimethylbenz[a]anthracene) at levels capable of STDs are more likely to develop UCC than those infected transforming cells resulted in mutation frequencies similar women who have not been exposed to these additional to those in Tax-expressing cells [Manjanatha et al., 1996; risk factors [Daling et al., 1996; Kjellberg et al., 2000]. Zimmer et al., 1996]. These results suggest that the Taken together, these studies demonstrate that E6 and increased mutation frequency observed in the presence of E7 are necessary, but not sufficient, for HPV-mediated Tax may be physiologically important in the process of cellular transformation. Although these data are fairly transformation. 308 Gatza et al.

Increased mutations frequencies have also been asso- Several reports have investigated the chromosomal in- ciated with the expression of high-risk HPV E6 but not tegrity of HCC cells and have identified deletions in low-risk HPV E6 or E7 [Havre et al., 1995]. Cells expres- portions of 1p, 6q, 7q, 8p, 13q, 16p, and sing high-risk E6 protein demonstrated a fivefold increase 17p and LOH at regions containing (17p13), RB in spontaneous mutations when compared to control cells (13q14), AXIN1 (16p13), and a number of other cellular and a twofold increase when compared to low-risk HPV genes that are commonly affected in HBV-positive HCC E6-expressing cells. Additionally, sequence analysis of tumors [Murakami et al., 1991; Boige et al., 1997; Nagai the Hprt gene showed a dramatic increase in deletions, et al., 1997; Satoh et al., 2000]. Portions of amplified rearrangements, and point mutations in the presence of chromosomes that are also frequently identified in HCC high-risk E6. Since these changes were prevalent in cells include regions encoding the c-MYC oncogene at 1q and expressing high-risk but not low-risk E6, these data sug- other cellular oncogenes present at 3q, 6p, 7p, 8q, and gest that increases in mutation frequency contribute to 17q [Levy et al., 2002]. Thus, the amplification of proto- cellular transformation. oncogenes coupled with partial or complete loss of tumor Although studies to determine mutation frequency in suppressor genes most likely contributes to HBV- HBx-expressing cells have not been reported, double- mediated cellular transformation and tumor progression. transgenic mice expressing HBx and possessing an inte- Of the three cancer types reviewed here, HPV-positive grated l transgene reporter have been used to determine UCCs demonstrate the longest list of gross chromosomal whether HBx enhances the accumulation of spontaneous rearrangements. Several investigators have reported partial mutations in the livers of these animals. These studies or complete loss of chromosomes 1p, 2q, 3p, 4p and q, demonstrated that HBx alone does not increase the rate of 5q, 6q, 7q, 8p, 9p and q, 11q, 12q, 13q (including the RB spontaneous mutations; however, when these mice were gene), 14q, 17p and q, 18q, and 19p and q, in a variety of treated with aflatoxin B, a 24% increase in overall muta- combinations. LOH has also been reported at a number of tion frequency was observed [Madden et al., 2000, 2002]. other sites, including 3p, 4p and q, 5p, 6p and q, and 11q. Sequence analysis of the transgene demonstrated an Similar to ATL and HCC cells, UCC cells demonstrate a altered mutation spectrum with a twofold increase in gain of chromosomes 1q, 3p, 5p, and 8q, which include G:C?A:T transversions in response to aflatoxin B treat- regions encoding cellular proto-oncogenes, such as the ment. Together, these reports suggest that HBx is not suf- c-MYC gene (1q) [Mitra, 1999; Buendia, 2002; Rao et al., ficient for tumor development, but rather enhances the 2004]. Thus, the spectrum of chromosomal rearrange- effects of, or sensitizes cells to, other mutagens. ments found in UCC, ATL, and HCC likely cause or con- Alterations in number are found in all types tribute to cellular transformation and tumor progression. of tumors and are designated as either , the gain Micronuclei (MN), which are produced as by-products or loss of whole chromosomes, or loss of heterozygosity of DNA damage, are small nuclei-like bodies found out- (LOH), the gain or loss of chromosome sections or single side of the nucleus. As a result of treatment with aneuploi- genes [Lengauer et al., 1998]. Cytogenetic and microsatel- dogenic agents, cells produce MN with whole chromo- lite analysis of ATL, HCC, and UCC tumors, as well as somes or centric chromosomal fragments, whereas cells some virally infected or transformed cells, has demon- treated with clastogenic compounds produce MN contain- strated both aneuploidy and LOH. These changes are ing acentric fragments [Majone et al., 1992]. MN provide thought to alter the expression or function of cellular onco- a measure of a cell’s ability to repair damaged DNA and genes, tumor suppressors, and/or other essential proteins. segregate chromosomes after exposure to specific muta- ATL cells express a number of random chromosomal gens. Consistent with observations of chromosomal anomalies. Although no uniform karyotypic abnormalities abnormalities in ATL, HCC, and UCC tumors, several have been consistently identified in all tumors [Kao et al., researchers have demonstrated an increased prevalence of 2000], specific abnormalities including trisomy 3 and 7, MN in Tax, HBx, and EBV LMP-1 immortalized or trans- amplification of 14q [also commonly identified in fected cells. Epstein-Barr virus (EBV)-associated Burkitt’s ], Majone et al. [1993] investigated MN in HTLV-1-trans- deletions of 1q and 6q, monosomy of the X chromosome, fected cells using wild-type Tax, transcriptionally active and loss of the Y chromosome are more prevalent than Tax mutants, and transcriptionally inactive Tax mutants. others in ATL cells [Zech et al., 1976; McCaw et al., Their results demonstrated a 1.5–1.7% frequency of MN 1977; Fukuhara and Rowley, 1978; Ueshima et al., 1981; in cells that express wild-type Tax or transcriptionally Miyamoto et al., 1983; Rowley et al., 1984; Whang-Peng active Tax mutants compared to MN frequencies of only et al., 1985, 1993; Sanada et al., 1987; Fujita et al., 1989; 0.4–0.7% when the transcriptionally inactive Tax mutants Kamada et al., 1992]. Loss of certain regions such as were analyzed. Additionally, these authors report an chromosome 17p is especially interesting because it is increase in kinetochore-positive and -negative MN, demon- also commonly deleted in HCC tumors and contains the strating both clastogenic and aneuploidogenic effects of p53 gene [Hatta et al., 1998]. Tax [Majone et al., 1993; Majone and Jeang, 2000]. Impact of Transforming Viruses 309

Together, these data suggest that Tax-mediated over- amplifications occur in response to chromosomal breaks expression of certain cellular genes coupled with transcrip- that result from incorrectly resolved DNA recombination tional repression of other genes represses DNA repair [Kuo et al., 1994; Wettergren et al., 1994; Coquelle et al., while enabling DNA replication and progres- 1997]. These abnormalities are most prevalent when p53 sion in the presence of mutagen-induced DNA lesions. is inactivated in mammalian cells [Yin et al., 1992]. The Replication of these unrepaired lesions may potentially ability of viral oncoproteins including Tax, HBx, and lead to the accumulation of mutations and contribute to E6/E7 to repress or functionally inactivate p53 and certain Tax-mediated genomic instability. DNA repair mechanisms suggests that these viral onco- In addition to Tax-mediated MN formation, several proteins may contribute to gene amplification. other viral oncoproteins have been investigated for their Although few published studies have directly investi- ability to induce MN in transformed cells. EBV LMP- gated the potential effects of viral oncoproteins on gene 1-expressing epithelial cells were recently shown to con- amplification, increased gene amplification in Tax-expres- tain increased numbers of both spontaneous and bleomy- sing cells and a possible mechanistic explanation for these cin-induced MN [Liu et al., 2004]. Furthermore, Livezey observations have been recently reported by our group et al. [2002] reported nearly a threefold increase in MN [Lemoine and Marriott, 2002]. Using the PALA [N-(phos- in HBx-expressing cells compared to HBx-negative con- phonoacetyl)-L-aspartate] , which measures amplifi- trol cells. Although there have been no reports of MN cation of the trifunctional enzyme, CAD (carbamyl associated with HPV infection or expression of its onco- phosphate synthetase/aspartate transcarbamylase/dihydro- proteins, MN formation may be a shared mechanism orotase), we demonstrated a four- to fivefold increase in among viral oncoproteins and should be investigated more gene amplification in the presence of Tax. In addition, thoroughly. cells failed to undergo a typical p53-dependent, PALA- In addition to increased MN in HBx-expressing cells, mediated G1 arrest in the presence of Tax, suggesting that these cells also demonstrated an increase in chromosomal the ability of Tax to alter PALA-dependent cell cycle translocations when compared to HBx-null cells [Livezey arrest depends on its ability to repress p53 activity et al., 2002]. Chromosomal translocations are fusions of [Lemoine and Marriott, 2002]. Although the effect of different chromosomes or of noncontiguous segments of a viral oncoproteins on gene amplification remains poorly single chromosome. As a result, two deleterious outcomes defined, this evidence combined with an overall under- are possible. First, the fusion can place a specifically regu- standing of factors that contribute to gene amplification lated gene under the control of an improperly regulated (loss of p53 function and DNA repair mechanisms) pre- promoter, leading to altered expression of the protein. dicts that other viral oncoproteins may also contribute to Second, a fusion between two genes can occur, resulting this form of genomic instability. in the formation of a novel protein with an unknown and Thus far, we have reviewed data that support a role of potentially oncogenic function [Lengauer et al., 1998]. the viral oncoproteins Tax, HBx, and HPV E6/E7 in med- These chromosomal abnormalities often result from the iating cellular transformation and, in some cases, tumor improper repair of DNA damage. Since many viral onco- progression in ATL, HCC, and UCC, respectively. proteins repress DNA repair mechanisms, it is not surpris- Increasing evidence suggests that expression of these viral ing that viral-associated cancers demonstrate these oncoproteins is associated with chromosomal abnormal- abnormalities [Savage, 2002]. Similar to HBx, HPV ities found in their respective cancers, including point E6- and E7-transformed epithelial cells, as well as SV40 mutations, altered chromosome numbers, chromosomal T-antigen-transformed cells, also demonstrate extensive translocations, and gene amplifications. Although exact duplications and translocations, the former involving chro- mechanisms of virus-mediated transformation are not mosomal aberrations at regions 11q13q22;q23 [Hoffschir fully understood, viral oncoproteins are known to affect a et al., 1988; Sutherland et al., 1988; Ray et al., 1990; number of common cellular mechanisms that are likely to Macoska et al., 2000]. Furthermore, sister chromosome be involved in cellular transformation and in some cases translocation at the 11q loci has been observed in an tumor progression. These mechanisms include altered cel- EBV-transformed lymphoblastoma cell line [Seki et al., lular transcription and cell cycle progression, as well as 1992]. Despite the fact that this genetic abnormality is repression of tumor suppressor genes and DNA repair common in viral-associated tumors and in cells trans- pathways (Table II). formed by viral oncoproteins, the exact mechanisms by which chromosomal translocations contribute to tumori- TRANSCRIPTION MODULATION BY genesis remain to be fully defined. VIRAL ONCOPROTEINS It is well recognized that gene amplification occurs at a greater rate in cancer cells than in normal cells; how- Although mutations are probably the most important ever, very little is known about the mechanism of gene cellular event leading to neoplastic transformation, onco- amplification [Lengauer et al., 1998]. It is believed that genic viruses have evolved ways to alter host gene 310 Gatza et al.

TABLE II. Summary of the Effects of Viral Oncoproteins on Cellular Processes

Tumor suppressor Oncoprotein Transcription Cell cycle proteins DNA repair

Tax Activates/represses through CREB/ATF, Stimulates bypass of G1/S and Inactivates p53 Inhibits NER, BER, and SRF, and NF-kB pathways; can also G2/M checkpoints; disrupts and pRB may affect double-stranded interact with and affect the function of the mitotic spindle checkpoint break repair basal transcription factors HBx Activates transcription through cis Stimulates bypass of G1/S Inactivates p53 Inhibits NER elements (XRE), which include binding and G2/M checkpoints and pRB sites for AP-1, AP-2, NF-kB, SRF, c/EBP, ETS, ATF-1, and CREB; HBx may also interact with basal transcription factors E6/E7 Interferes with signaling pathways and Overrides cell cycle controls; Inactivates p53 Inhibits NER may have a global affect on transcription disrupts mitosis and pRB by altering the function of basal transcription factors (TBP and TAF-110) expression without changing gene structure. Generally, interaction between HBx and some of these cellular tran- complex viruses encode one or several nonstructural tran- scription factors has been well documented, the majority, scription regulators that ensure optimal viral gene expres- including AP-1, NF-kB, and SRF, do not appear to bind sion and dictate profound changes in host gene expression HBx. In these latter cases, the transactivation mechanism to create a favorable cellular environment for virus repli- is believed to rely on more general processes such as cation. Viral oncoproteins can affect transcription by modulation of signaling cascades and interaction of HBx binding directly to the transcription machinery, interacting with the basal transcriptional machinery. Although HPV with specific transcription factors, or influencing upstream E6 and E7 are not primarily considered to be transcription signaling pathways. All of these mechanisms are modulators, they can interfere with several cellular signal- employed by Tax, HBx, and HPV E6/E7 to modulate ing pathways leading to altered function of transcription cellular transcription pathways and are believed to contri- factors such as NF-kB and AP-1. HPV E7 can also inter- bute to the transforming properties of these oncoproteins act with transcription coactivators and several basal tran- by interfering with cellular mechanisms that prevent the scription factors, including the TATA binding protein accumulation of mutations or limit cell proliferation in (TBP) and TBP-associated factor-110 (TAF-110), suggest- the presence of DNA damage. ing that it may have a global effect on cellular transcrip- Tax was originally described as a potent transactivator tion [Mazzarelli et al., 1995; Massimi et al., 1996; of the HTLV-1 whose effect was Phillips and Vousden, 1997]. mediated by three copies of a cyclic AMP response ele- Cyclic AMP (cAMP)-responsive element-binding factor ment (CRE) located within the viral promoter [Sodroski (CREB) and its closely related orthologs, activating tran- et al., 1984]. The transcriptional activity of Tax affects scription factor-1 (ATF-1) and the cyclic AMP response four discrete pathways: CREB/ATF element modulator (CREM), belong to the basic leucine [Franklin et al., 1993; Adya et al., 1994; Low et al., 1994; zipper (bZip) family of transcription factors and may addi- Adya and Giam, 1995], NF-kB [Ballard et al., 1988; tionally alter their DNA binding specificity. They respond Leung and Nabel, 1988; Ruben et al., 1988; Kanno et al., to increased levels of the secondary messenger cAMP 1994; Sun et al., 1994], SRF [Fujii et al., 1991, 1992], and through phosphorylation induced by protein kinase A (PKA) AP-1 [Armstrong et al., 1993; Fujii et al., 2000; Mori [Gonzalez and Montminy, 1989]. PKA phosphorylation of et al., 2000]. By exploiting these pathways, Tax modulates CREB at serine 133 recruits the coactivators p300/CBP to the expression of more than 50 cellular genes, including the CRE, thereby activating transcription [Chrivia et al., growth factors and their receptors, cytokines, transcription 1993; Arias et al., 1994]. Both Tax and HBx are able to factors, cell cycle control proteins, DNA repair proteins, bypass the normal cAMP signaling pathway by interacting and cell adhesion molecules, which collectively contribute with CREB and CBP, resulting in transcriptional activa- to cellular transformation [Lemoine et al., 2001]. tion in a phosphorylation-independent manner [Harrod Like Tax, HBx is a promiscuous transcriptional modu- et al., 1998; Van Orden and Nyborg, 2000; Pflum et al., lator that can activate transcription of HBV as well as a 2001]. Furthermore, Tax and HBx can increase DNA bind- wide variety of cellular promoters through cis elements, ing and dimerization and may alter the specificity of sev- generically designated XREs. These elements include eral bZip transcription factors. For example, it is well binding sites for AP-1, AP-2, NF-kB, SRF, c/EBP, established that Tax enhances CREB-dependant transacti- ETS, ATF1, and CREB [Murakami, 1999]. Although an vation of the imperfect viral CRE, but not the consensus Impact of Transforming Viruses 311 cellular sequence [Fujisawa et al., 1989; Adya and Giam, 1993; Wang et al., 1994]. In addition, HBx exerts direct 1995]. Based on this finding, it has been postulated inhibitory effects on the transcription of the p21 gene, that degenerate cellular CRE sequences resembling the independently of p53, suggesting that it is able to prevent viral element might be targets for Tax activation [Paca- cell cycle arrest by targeting a critical factor downstream uccaralertkun et al., 1994; Laurance et al., 1997]. of p53 [Ahn et al., 2001]. Lastly, the HPV E6 oncoprotein The transcriptional effects of viral oncoproteins are has the ability to bind CBP/p300 and disrupt CBP- broad, ranging from transactivation to transcriptional mediated acetylation of p53, thereby reducing the DNA repression, and lead to profound perturbations in cell binding affinity of p53 and its transactivation potential cycle progression and apoptosis. Through the CREB/ATF [Gu and Roeder, 1997; Patel et al., 1999]. Taken together, pathway, Tax upregulates the expression of BCL-xl, an these data suggest that viral oncoproteins have evolved antiapoptotic factor, and cyclin D2, which has a role in different ways to inhibit the expression of certain critical cell cycle progression [Santiago et al., 1999; Tsukahara genes involved in cell cycle control and DNA repair, ulti- et al., 1999]. In contrast, Tax represses the cyclin A and mately leading to unchecked cell proliferation and gen- cyclin D3 genes through a CRE by an unknown mechan- ome instability. ism that is believed to involve the formation of different NF-kB signaling is a common target of viral infection. complexes on the respective promoters [Kibler and Jeang, In resting cells, NF-kB proteins are bound and maintained 2001]. This may affect cell cycle progression through in the cytoplasm by inhibitory partners, such as IkBa, S-phase, as well as mitotic exit. Other genes, including IkBb, p100, and p105 [Chen and Greene, 2004]. Cellular ICAM-1, fucosyltransferase, and galectin-3, are upregu- stimulation and activation of cellular signaling pathways lated by Tax through CRE elements and have been shown induce phosphorylation of the inhibitory proteins and tar- to play an important role in leukemic cell infiltration and get them for ubiquitination and subsequent degradation. metastasis [Hsu et al., 1996; Tanaka et al., 1996; Hiraiwa As a result, the nuclear localization sequence of NF-kB is et al., 2003]. Interestingly, HBx also upregulates galectin- unmasked, and the active form translocates to the nucleus, 3 expression resulting in increased metastatic properties where it activates target genes. HTLV-1-infected cells, as of liver tumors [Hsu et al., 1999]. NF-IL6, another bZip well as cells expressing Tax, induce and maintain an acti- family member, mediates HBx transactivation of the IL-8 vated NF-kB pathway. Tax directly interacts with the gene in human hepatoma cells, probably providing the inhibitory proteins IkBa and IkBb, as well as the IKKg transformed cells with a continuous autocrine growth subunit of the kinase regulatory complex, collectively stimulus [Mahe et al., 1991]. leading to disruption of inactive cytoplasmic NF-kB com- In addition to activating gene expression, the interac- plexes and nuclear translocation of active NF-kB [Hirai tion of Tax with CBP is proposed to have inhibitory et al., 1992; Beraud et al., 1994; Kanno et al., 1994; effects on the transcription of certain cellular promoters. Suzuki et al., 1995]. Exploiting the NF-kB pathway, Tax Jeang et al. [1990] first described repression of the DNA activates a large number of cellular genes that promote polymerase b gene by Tax and identified an E-box DNA lymphocyte growth, activation, and survival. These genes element responsible for this effect. It was subsequently fall into several categories, including cytokines and reported that p53, p18INK4C, and, more recently, the growth factors such as IL-1, IL-2, IL-6, IL-8, IL-15, and human telomerase (hTERT) promoters, all of which con- TGFb, growth factor receptors such as IL-2Ra and OX40, tain the E-box recognition sequence, are repressed by Tax and antiapoptotic factors such as BCL-xl [Lemoine et al., [Akagi et al., 1995; Suzuki et al., 1999b; Gabet et al., 2001]. Special importance is attributed to Tax activation 2003]. It is hypothesized that this repression results from of the cellular proto-oncogene, c-MYC, which can inde- direct competition between Tax and E-box binding tran- pendently mediate cellular transformation via NF-kB reg- scription factors of the b helix-loop-helix family for ulation [Keath et al., 1984; Adams et al., 1985]. recruitment of CBP/p300 [Suzuki et al., 1999b]. Tax Additionally, NF-kB-dependent stimulation of both IL-2 expression was found to diminish the binding of p53 to and IL-2 receptor expression is thought to create an CBP, an interaction that was previously shown to be autocrine feedback loop that can stimulate growth factor- required for enhanced p53-mediated transcription. This independent proliferation of infected cells in vivo [Ballard effect is probably also due to competitive binding of Tax et al., 1988; Wano et al., 1988]. to CBP and contributes to the inhibition of p53 transacti- HBx also usurps pathways to activate vating function by Tax [Ariumi et al., 2000]. HBx can NF-kB- and AP-1-dependent transcription [Murakami, also repress p53 transcription through an E-box; however, 1999]. Direct interactions between HBx and components the exact mechanism remains to be identified [Lee and of the MAPK, SAPK, and PKC signaling pathways have Rho, 2000]. The interaction of HBx with p53 also appears been demonstrated, and it has been speculated that HBx to play an important role in the functional inactivation of may act as an adaptor or kinase activator to enhance the this tumor suppressor by inhibiting p53 sequence-specific phosphorylation of associated proteins [Cross et al., 1993; DNA binding and transactivating ability [Feitelson et al., Kekule et al., 1993; Diao et al., 2001]. Additional 312 Gatza et al. mechanisms of NF-kB activation by HBx include direct Cell cycle progression is controlled by interplay bet- interaction with inhibitory proteins, such as the p105 pre- ween positive and negative regulators. One mechanism cursor and IKKa, and induction of oxidative stress by that viral oncoproteins use to override cell cycle control mitochondrial-associated HBx protein [Su and Schneider, is association with cyclin and cyclin-dependent kinase 1996; Waris et al., 2001]. Regardless of the mechanism, (cyclin-CDK) complexes and/or molecules that regulate HBx induction of NF-kB and AP-1 activity ultimately their activities, termed cyclin-dependent kinase inhibitors leads to the acceleration of cell cycle progression, (CKIs). During G1, D-type cyclins (D1, D2, D3) form enhanced proliferation, and may contribute to repression active complexes with CDK4 or CDK6. These activated of apoptosis. cyclin D-CDK4/6 complexes phosphorylate the retinoblas- As an additional mechanism to induce cell prolifera- toma protein (pRB), causing it to dissociate from E2F. tion, Tax binds to (SRF) and The active E2F protein then transcribes genes necessary induces aberrant expression of several immediate early for S-phase entry [Adams, 2001]. These genes include nuclear oncogenes, including c-FOS, Fos-related-antigen- those that encode cyclins E and A, two essential media- 1 (FRA-1), early growth response gene-1 (EGR-1) and tors of the G1-S transition in mammalian cells [Weinberg, EGR-2 [Alexandre and Verrier, 1991; Fujii et al., 1992, 1995]. Tax has been shown to interact with CDK4 and 1995; Suzuki et al., 1993]. Recruitment of CBP to these CDK6 and enhance their binding to cyclin D2. This cellular promoters is required for Tax activation [Shuh results in earlier onset of cyclin D-CDK4/6 kinase activity and Derse, 2000]. It was recently reported that HBx followed by an accumulation of hyperphosphorylated pRB directly interacts with EGR-2 and EGR-3 and enhances in Tax-expressing cells compared to cells not expressing their interaction with CBP to activate FAS ligand gene Tax [Haller et al., 2002]. As a result, E2F is released in expression in hepatoma cells [Yoo et al., 2004]. This Tax-expressing cells early in G1, shortening the length of effect was proposed to confer an immune-privileged status G1 and accelerating S-phase entry [Lemoine and Marriott, to the tumor, promoting cell proliferation in vivo. 2001]. The data reviewed here described various mechanisms HBx has also been shown to stimulate cell cycle pro- used by viral oncoproteins to manipulate cellular tran- gression by accelerating transit through the G1/S and scription pathways in order to alter cellular gene expres- G2/M checkpoints [Benn and Schneider, 1995]. Compared sion. While changes in transcription do not directly lead with serum stimulation, HBx strongly increases the rate to cellular transformation, they can induce a highly prolif- and level of CDK2 and CDC2 kinase activation and their erative state, which is generally thought to be a sine qua respective formation of active complexes with cyclins A non for oncogenesis. In addition, these changes can affect and E or cyclin B [Koike et al., 1994]. HBx also causes the capacity of the host cell to respond properly to geno- cyclin D1 overexpression, which is maintained throughout toxic agents by altering the efficient cellular concentration the cell cycle [Klein et al., 2003]. In addition, analysis of of proteins involved in repair of DNA damage, cell cycle temperature-sensitive mutants demonstrated that HBx acti- control, and apoptosis, ultimately inducing genomic vates the cyclin A promoter via its ATF/CREB transcrip- instability and promoting oncogenic transformation. tion factor binding site and that this activation depends on the Src (RAS-RAF-MAPK) pathway [Bouchard et al., 2001]. Studies have also reported the interaction of HBx DYSREGULATION OF CELL CYCLE PROGRESSION with the RPB5 subunit of RNA polymerase [Cheong et al., 1995] as well as the interactions of HBx or Tax Mammalian cells have evolved mechanisms to maintain with TBP [Caron et al., 1993; Qadri et al., 1995]. These genomic integrity by inducing cell cycle arrest in response observations raise the possibility that direct modulation of to DNA damage. Such checkpoint mechanisms allow time transcription factors by Tax and HBx can contribute to to repair DNA damage before the cell commits to DNA cell cycle deregulation. replication and cell division. Through the function of their The HPV E6 and E7 oncoproteins also override cell oncoproteins, viruses have developed several strategies to cycle controls to induce cellular hyperproliferation. subvert key regulatory factors in order to promote DNA Similar to HBx, HPV E7 is able to activate transcription replication and cellular proliferation (Fig. 1). Reprogram- from the cyclin A and E promoters. Transient ming of the cell cycle may benefit the virus by promoting assays showed that activation of cyclin A and E transcrip- efficient replication of the viral genome in the host cell. tion by E7 is indirect and requires the synthesis of addi- Viral oncoproteins mediate this reprogramming by abro- tional cellular gene products [Benn and Schneider, 1995; gating negative growth signals and checkpoint controls. Bouchard et al., 2001]. E7 also interacts indirectly with As a result, viral oncoproteins contribute to the pro- cyclin E-CDK2, mediated through p107, a pRB-related liferation and accumulation of cells that are geneti- protein [McIntyre et al., 1996]. Interestingly, E7 was cally unstable, some of which may contain transforming shown to downregulate cyclin D1 expression and, in the mutations. presence of E6, was shown to disrupt cyclin D1-CDK4 Impact of Transforming Viruses 313

Fig. 1. Effects of viral oncoproteins Tax, HBx, and E6/E7 on cell cycle cation and cellular proliferation in the presence of DNA damage. The progression following DNA damage. Following DNA damage, cell cycle mechanisms utilized by these oncoproteins include inhibition of the tumor progression is halted by the activation of negative regulators of cyclin/ suppressor proteins p53 and pRB as well as the cyclin-dependent kinase CDK complexes (black lines and arrows). The viral oncoproteins Tax, inhibitors p21Waf1/Cip1, p27Kip1, p16INK4a, p15INK4b, p18INK4c, p19INK4d, HBx, and E6/E7 have evolved mechanisms to subvert these negative reg- and the mitotic-phase regulators MAD-1 and -2. In addition to preventing ulators (red lines) or activate positive regulators (green arrows) in order the functions of cell cycle checkpoint proteins, the viral oncoproteins also to promote cell cycle progression and subsequently promote DNA repli- activate cyclin/CDK complexes to stimulate cell cycle progression. complexes [Xiong et al., 1996]. This is unlike the func- by regulating cyclin-CDK kinase activities, CKIs are tions of Tax and HBx, which stimulate cyclin D-CDK recognized as tumor suppressor proteins and are fre- kinase activities during G1. It is possible that E7 downre- quently deleted in human cancer cells [Sherr and Roberts, gulates cyclin D-CDK activity in order to shorten the 1995; Sherr, 2004]. Thus, the functional inhibition of length of G1 so that cells progress more rapidly into S- CKIs by viral oncoproteins may allow these viruses to phase. In support of this theory, the E7/cyclin E/CDK2 mimic the effects of deleting these genes in cancer cells complex exhibited kinase activity throughout the cell in order to promote constitutive activation of cyclin-CDK cycle with a significant peak in S-phase [McIntyre et al., complexes and cell cycle progression. 1996]. Thus, inhibition of G1-specific CDK activity and Tax has been shown to bind p15INK4b and p16INK4a and induction of S-specific CDK activity may be a mechanism block the inhibitory effects of these CKIs on cyclin by which HPV promotes DNA replication in the presence D-CDK4 activity [Suzuki et al., 1996, 1999a; Low et al., of antiproliferative signals. 1997; Iwanaga et al., 2001; Hatta and Koeffler, 2002]. The enzymatic activities of cyclin-CDK complexes are This would reverse p15INK4b- and/or p16INK4a-induced G1 controlled by CKIs, including p21Waf1/Cip1, p27Kip1, growth arrest and remove barriers that normally restrict p15INK4b, p16INK4a, p18INK4c, and p19INK4d [Peter and replication of damaged DNA. As previously discussed, Herskowitz, 1994; Morgan, 1995; Sherr and Roberts, Tax represses transcription through E-box elements, 1995]. Since these inhibitors can cause cell cycle arrest including those in the p18INK4c and p19INK4d promoters. 314 Gatza et al.

This correlates with a marked reduction of p18INK4c and EFFECTS OF VIRAL ONCOPROTEINS ON TUMOR p19INK4d mRNA levels in HTLV-1-infected T-cells SUPPRESSOR PROTEINS [Suzuki et al., 1999a]. Thus, these observations indicate that Tax can suppress the activity of INK4 family mem- Transforming viruses can deregulate cell cycle progres- bers through two independent mechanisms: by functional sion by overriding growth suppressive functions of the inhibition via direct protein-protein binding and by repres- p53 tumor suppressor and retinoblastoma (pRB) proteins. sing transcription. These effects may play roles in HTLV- pRB and its related proteins p107 and p130 play impor- 1-induced deregulation of the cell cycle, thereby promot- tant roles in regulating E2F-mediated transcription. In its ing cellular transformation by Tax. In contrast, numerous hypophosphorylated form, pRb forms a protein-protein studies have reported the activation of p21Waf1/Cip1 complex with E2F and inhibits its transcriptional activity expression by Tax [Akagi et al., 1996; Cereseto et al., [Weinberg, 1995; Sherr, 2004]. Activation of cyclin 1996; De La Fuente et al., 2000; Hatta and Koeffler, D-CDK kinase complexes during G1/S-phase of the cell 2002]. This observation was unexpected since it is well cycle leads to hyperphosphorylation of pRB and subse- known that p21Waf1/Cip1 inhibits DNA replication and quent release of active E2F [Matsushime et al., 1994]. allows cells to repair DNA damage [Fotedar et al., 2004]. This results in transcriptional activation of E2F-responsive Thus, stimulation of p21Waf1/Cip1 by Tax suggests that this genes, which promote cell cycle progression into S-phase. traditional inhibitor may have an alternate function that The E7 protein of high-risk HPV has been shown to bind may be required for cellular transformation by Tax. the hypophosphorylated form of pRB, disrupting the abil- p21Waf1/Cip1 stimulates the NF-kB pathway [Joyce et al., ity of pRB to bind and inactivate E2F [Pagano et al., 2001], which functions in cellular transformation by Tax. 1992]. Once bound, E7 destabilizes pRB by inducing its Recent studies report that p21Waf1/Cip1 is involved in sta- degradation via a ubiquitin-proteosome pathway [Boyer bilization and transport of active cyclin D-CDK4 kinase et al., 1996]. However, recent studies have shown that E7 complexes [Haller et al., 2002]. It is possible that stimula- may confer acute biological effects that are independent tion of p21Waf1/Cip1 expression by Tax could increase the of its ability to inactivate pRB. Using a Cre-lox system to steady-state levels of active cyclin D-CDK4 and enhance abrogate pRB expression in the epidermis of transgenic its phosphorylation of pRB. This would describe another mice, Balsitis et al. [2003] showed that epidermis lacking role for p21Waf1/Cip1 in Tax-mediated transformation and pRB displayed epithelial hyperplasia, aberrant DNA explain the upregulation of p21Waf1/Cip1 in Tax-expressing synthesis, and improper differentiation. Remarkably, cells. mouse epidermis deleted in pRB and expressing E7 Studies of HPV E6 and E7 proteins show that these showed increased hyperplasia and dysplasia, indicating viral oncoproteins can also inactivate the function of CKIs that other activities besides E7’s inactivation of pRB must and increase the proliferative potential of cells. The E7 contribute to the biological properties of E7 in vivo. protein binds and inactivates p21Waf1/Cip1 and p27Kip1 Indeed, E7 has been reported to bind many different [Funk et al., 1997; Jones et al., 1997], reversing the inhi- cellular proteins in addition to pRB. These include the bitory effects of these CKIs on cyclin A-CDK2 and cyclin pRB-related proteins p107 and p130 [Dyson et al., 2003]. E-CDK2, respectively [Martin et al., 1998; Schulze et al., In transient tranfection assays, E7 was shown to decrease 1998]. In other studies, transient transfection assays show steady-state levels and half-lives of p107 and p130 that E6 expression dramatically decreases the level of p21 [Gonzalez et al., 2001]. Like pRB, p107 and p130 bind to mRNA [Li et al., 1994b; Xiong et al., 1996], suggesting and modulate the function of E2F family members [Mulli- that this CKI may also be transcriptionally inhibited by gan and Jacks, 1998]; thus, in a pRB-deficient environ- HPV. ment, it is possible that E7 may retain the ability to Similar to the mechanism used by E6, HBx regulates dysregulate the cell cycle and DNA synthesis through p21Waf1/Cip1 on a transcriptional level; however, the pre- inactivation of p107 and p130. As mentioned above, E7 cise mechanism of this regulation remains controversial can also bind and inactivate CDK inhibitors p21 and p27 [Kwun and Jang, 2004]. Additionally, the results of recent [Funk et al., 1997; Jones et al., 1997], thus providing studies suggest that epigenetic alterations through methy- another mechanism through which E7 can disrupt these lation may be a mechanism by which HBV transcription- cellular processes. Because of the multifunctional nature ally regulates tumor suppressor proteins. Interestingly, of E7, its role in transformation remains unclear. methylation of the p16INK4a promoter was detected in HTLV-1 Tax has also been shown to overcome pRB- 50% of HBV-positive HCC cases, but was absent in all mediated cell cycle arrest; however, unlike E7, Tax does noncancerous tissues examined [Narimatsu et al., 2004]. so indirectly by affecting events upstream of pRB. Tax is Analogous results were obtained when similar studies believed to regulate pRB phosphorylation by stimulating were performed on the p15INK4b promoter [Yang et al., cyclin D-associated kinase activities. In experiments uti- 2003]. Whether or not aberrant promoter methylation can lizing a Tax-inducible cell line, Tax expression caused a be attributed to HBx activity remains to be seen. 50% increase in pRB phosphorylation when compared to Impact of Transforming Viruses 315 cells not expressing Tax [Neuveut et al., 1998; Haller Thus, the abnormal chromosomal segregation observed et al., 2002]. This increase in pRB phosphorylation corre- in E6- and E7-expressing cells could in part be due to the lated with a sevenfold increase in cyclin D-associated deregulation of this kinase, the events of which seem to kinase activity as well as with activation of E2F-respon- require the cooperative functions of both E6 and E7 sive genes. Tax induction also caused faster progression proteins. of cells into S-phase when compared to cells not expres- Although several groups have documented a direct sing Tax. Moreover, Tax has been shown to associate interaction between p53 and HBx, the functional signifi- directly with cyclin D3, and this interaction resulted in cance of this interaction is not fully understood. As pre- increased cyclin D3-associated kinase activity in vitro viously discussed, HBx binding to p53 inhibits the [Neuveut et al., 1998]. Finally, Tax can bind and inacti- sequence-specific DNA binding and transcriptional acti- vate p16INK4a, removing a negative regulator of cyclin D vating properties of p53 [Feitelson et al., 1993; Elmore activity [Suzuki et al., 1996; Low et al., 1997]. Taken et al., 1997; Lin et al., 1997]. This interaction also alters together, these data suggest that Tax subverts cyclin D, formation of the p53 preinitiation transcription complex an upstream regulator of pRB, through multiple mechan- [Wang et al., 1994]. Additional studies showed that HBx isms. Like Tax, HBx does not bind pRB [Farshid et al., inhibits the interaction between p53 and several DNA 1997], and recent evidence suggests that HBx may also repair proteins [Lee et al., 1995; Wang et al., 1995b, function upstream of pRB by causing cyclin D1 overex- 1996]. Several reports also demonstrated an inhibitory pression and increasing intranuclear cyclin D1 accumula- effect of HBx on p53-mediated apoptosis, although this tion when expressed in mammary epithelial cells [Klein remains controversial [Wang et al., 1995a; Elmore et al., et al., 2003]. 1997; Huo et al., 2001]. The inhibition of apoptosis by In mammalian cells, p53 protein is crucial for maintain- HBx correlated with sequestration of p53 in the cyto- ing genome integrity by controlling the cell’s response to plasm, which was not detected in HBx-null hepatocytes a variety of stresses such as DNA damage and oncogene [Ueda et al., 1995]. This result suggests that decreased activation. p53 participates in several cell cycle check- nuclear p53 levels in HBx-expressing cells may inhibit points and is upregulated during the DNA damage apoptosis and contribute to hepatocellular . response. As a consequence of its pivotal role in guarding Unlike E6/E7 and HBx, HTLV-1 Tax does not bind against cellular transformation, p53 is a major target for p53 [Yamato et al., 1993; Pise-Masison et al., 1998]. inactivation by viral oncoproteins. The E6 protein of However, Tax does have the ability to abrogate the trans- high-risk HPV interacts directly with p53 to cause its activating function of p53 and override p53-mediated cell inactivation. E6 induces rapid proteasomal degradation of cycle arrest or apoptosis in HTLV-1-infected cells [Uit- p53 by interacting with the host-cell protein E6-AP, an tenbogaard et al., 1995; Pise-Masison et al., 1998; Ariumi E3 ubiquitin ligase [Scheffner et al., 1990, 1993]. The et al., 2000]. One mechanism by which Tax inhibits p53 E6/E6-AP enzymatic complex then binds to p53 and med- function involves differential phosphorylation of p53 via iates the conjugation of ubiquitin moieties to p53, target- the p65/RELA subunit of NF-kB, which could alter the ing it for proteolytic degradation [Scheffner et al., 1993]. interactions of p53 with a variety of transcription factors As a consequence, cells expressing E6 do not accumulate [Jeong et al., 2004]. Tax, as discussed above, also sup- high levels of p53 in response to DNA damage and, as a presses p53-mediated transactivation by competing result, fail to induce the G1/S cell cycle checkpoint prop- with p53 for binding to the transcriptional coactivator erly. Recent evidence showed that p53 degradation CBP/p300, thereby disrupting p53-dependent G1 arrest mediated by E6 and disruption of RB family member or apoptosis [Grossman, 2001]. The inhibition of p53- functions mediated by E7 are both required to induce dependent cellular genes blocks induction of the G1/S polyploidy in human keratinocytes [Patel et al., 2004]. In checkpoint [Van Orden et al., 1999; Ariumi et al., 2000]. this study, polyploidy was not caused by failure in cyto- As a consequence, DNA replication proceeds even in the kinesis, but rather from a disruption in mitosis. The presence of negative growth-suppressive signals. authors hypothesized that the mitotic failure may have Unchecked cell cycle progression resulting from contin- been the result of deregulation of G2-M phase genes by ued proliferative signals might then lead to immortaliza- E6 and E7 proteins. In microarray analyses, a number of tion and cellular transformation. genes involved in the G2-M transition of the cell cycle upregulated in E6/E7-expressing cells, including PLK1, a serine/threonine kinase known to regulate several events IMPAIRMENT OF CELLULAR DNA REPAIR PATHWAYS BY involved in mitotic exit and in events leading to cytokin- VIRAL ONCOPROTEINS esis [Patel et al., 2004]. Similar to the induction of poly- ploidy, upregulation of PLK1 protein in E6/E7 cells was Although no common type of chromosomal damage dependent on the ability of E6 mutants to degrade p53 has been associated with the development of ATL, and on the ability of E7 mutants to bind and repress pRB. HTLV-1-transformed lymphocytes isolated from patients 316 Gatza et al. or immortalized in demonstrate a large variety replication without affecting the PCNA-dependent repair. of chromosomal aberrations, including deletions, duplica- However, excessive PCNA can overcome the p21waf1/Cip1- tions, translocations, rearrangements, and aneuploidy induced replication block, allowing the polymerase to [Miyamoto et al., 1983; Rowley et al., 1984; Itoyama synthesize DNA through template lesions, resulting in et al., 1990]. Tax expression interferes with various pro- nucleotide misincorporation [Li et al., 1994a]. Interest- cesses involved in DNA metabolism, normal progression ingly, the ability of Tax to suppress NER has been through the cell cycle, and apoptotic elimination of cells directly related to its ability to activate the PCNA promo- containing dangerous amounts of DNA damage. However, ter transcriptionally, resulting in elevated levels of PCNA Tax itself does not directly induce DNA lesions [Saggioro protein [Lemoine et al., 2000]. et al., 1994]. DNA alterations resulting from exogenous Several studies demonstrating that HBx expression inhi- genotoxic factors or normal replication processes are cor- bits cellular DNA repair pathways showed that unsched- rected by several repair pathways, including nucleotide uled DNA synthesis and host-cell reactivation of UV- excision repair (NER), (BER), mis- damaged reporter genes are compromised by HBx match repair (MMR), homologous recombination (HR), [Becker et al., 1998; Groisman et al., 1999; Jia et al., and nonhomologous end joining (NHEJ) [Sancar et al., 1999]. The increased rate of liver tumor development in 2004]. Suppression of some of these pathways by Tax HBx transgenic mice exposed to chemical carcinogens is may increase the occurrence of mutations, potentially consistent with HBx inhibition of hepatocyte DNA repair contributing to cellular transformation. [Slagle et al., 1996]. Inhibitory effects of HBx on NER The first indication that Tax expression may affect are thought to be mediated by direct interaction of HBx DNA repair came with the finding that Tax can repress with UV-damaged DNA as well as with several proteins transcription of DNA polymerase b, an essential enzyme involved in cellular DNA repair. A yeast-two-hybrid involved in BER [Jeang et al., 1990]. BER removes a approach was used to identify a cellular protein, XAP-1 wide variety of genomic lesions, including hydrolytic (HBx-associated protein 1), as the human homologue of DNA depurination, deamination of cytosine and 5-methyl- the simian UV-damaged DNA-binding protein (UV-DDB) cytosine, reaction products of hydroxyl-free radicals, and [Lee et al., 1995]. Later, this interaction was shown to covalent DNA adducts [Wood and Shivji, 1997]. Two dis- inhibit the host-cell NER pathway [Becker et al., 1998]. tinct BER mechanisms correct these specific types of These authors proposed that the binding of HBx to XAP- lesions. Short-patch repair involves single nucleotide fill- 1 and UV-damaged DNA inhibits the first step of NER, ing after removal of individual altered nucleotides, which involves recognition of DNA lesions. Since the whereas long-patch repair resolves DNA segments up to HBV genome must be converted from partially double- 10 nucleotides in length. DNA polymerase b is only stranded DNA to covalently closed circular DNA required for short-patch repair, the major BER pathway (cccDNA) by an unknown host mechanism, they also [Matsumoto and Kim, 1995]. As a consequence, HTLV-1- speculated that these effects of HBx on the host DNA transformed cells, as well as cells transiently expressing repair machinery might ensure correct processing of the Tax, have a defect in short-patch BER [Philpott and viral genome and sustain viral replication. More recent Buehring, 1999]. Interestingly, the HPV oncoprotein E6 work has demonstrated that the binding of HBx to UV- has also been proposed to alter the function of DNA poly- DDB is indispensable for productive viral infection and merase b. A recent study demonstrated that HPV E6 the transactivation ability of HBx [Sitterlin et al., 2000]. interacts with XRCC1, a key factor involved in single- In addition to targeting UV-DDB, HBx uses at least strand DNA-break repair [Iftner et al., 2002]. Binding of two additional mechanisms to inhibit NER. p53 plays an E6 to XRCC1 has a negative effect on BER, probably by important role in transcription-coupled DNA repair, and displacing DNA polymerase b from the active damage its interactions with the XPB and XPD helicases of the repair complex. The influence of this event on the viral multisubunit transcription factor TFIIH are required for life cycle is not known, but it may increase availability of this function. It is believed that the association of p53 the DNA polymerase required for replication of the viral with TFIIH normally inhibits trans-lesion replication and genome in terminally differentiated keratinocytes. initiates the assembly of repair complexes at the damaged Possibly the most versatile repair pathway, NER is a sites [Wang et al., 1995b]. HBx blocks the interaction target of Tax, HBx, and the HPV oncoproteins. NER of p53 with XPB and XPD, effectively inhibiting detects helix distortions resulting from ultraviolet irradia- p53-dependent repair [Prost et al., 1998]. Secondly, in tion and carcinogenic agents and recognizes transcription experiments performed in cells containing a mutant complexes stalled at DNA lesions. This repair pathway version of p53, HBx was shown to inhibit NER in a requires DNA polymerases d and e and uses PCNA as a p53-independent mechanism by interacting directly with cofactor [Riedl et al., 2003]. When genomic lesions are XPB and XPD to enhance the helicase activity of the encountered, elevated levels of the cyclin-dependent TFIIH complex [Jia et al., 1999]. Functional p53 is kinase p21waf1/Cip1 interact with PCNA, blocking DNA thought to inhibit the helicase activity of this complex, Impact of Transforming Viruses 317 thereby enabling the assembly of repair complexes [Qadri through an E-box DNA element, but activates its tran- et al., 1996]. scription in resting cells in an NF-kB-dependent manner While gross chromosomal aberrations are the most [Sinha-Datta et al., 2004]. It has been postulated that the common type of genomic alterations found in HPV- interference of Tax with induction of hTERT would result infected cells, high-risk HPV E6 and E7 oncoproteins also in a transient state of genetic instability that is replaced interfere with specific DNA repair pathways resulting in by induction of telomerase transcription in unstimulated single or small nucleotide changes. A limited number of cells to promote long-term proliferation and prevent telo- studies have investigated the effect of HPV oncoproteins mere attrition. Similarly, HPV E6 activates hTERT on NER. Work done in primary keratinocytes immorta- expression by an unknown mechanism, which is probably lized with HPV16 found increased mutation frequencies required to maintain telomere length in the rapidly divid- in both the transcribed and untranscribed strands of a ing neoplastic cells [Veldman et al., 2001]. transgene, demonstrating a failure to repair UV-induced As discussed in the previous sections, aneuploidy is a DNA damage and identifying a defect in general genome general characteristic of cancer cells and is commonly repair and transcription-coupled NER [Rey et al., 1999]. found in ATL, HCC, and UCC. Alterations in chromo- The mechanism of this defect is still unknown, but does some number arise as a result of mitotic perturbations and not appear to involve the viral oncoprotein E6, which was are generally considered to be the cause, rather than a not detected in the system used by the authors. In con- consequence, of transformation [Rasnick, 2002]. To trast, Wani et al. [2002] showed that expression of E6 but ensure the correct partitioning of replicated chromosomes not E7 inhibited the removal of bulky DNA adducts by during mitosis, cells use the mitotic spindle assembly depleting cellular p53, thereby antagonizing its function checkpoint (MSC) as a surveillance mechanism to arrest in global genome repair. The E6 protein was also shown the progression from metaphase to anaphase in the pre- to be responsible for degradation of O6-methylguanine- sence of spindle damage or segregation errors. Several DNA methyltransferase (MGMT), an enzyme that func- genes identified in genetic screens have been shown to tions in a stochiometric reaction to reverse DNA lesions contribute to proper function of the MSC complex, produced by endogenous mutagens and alkylating agents including monopolar spindle 1 (MPS1), budding uninhib- [Srivenugopal and Ali-Osman, 2002]. Together, these data ited by benzimidazole (BUB) genes, and mitotic arrest- suggest that HPV infection induces a mutator phenotype deficient (MAD) 1, 2, and 3 [Jallepalli and Lengauer, that is at least partially due to E6-mediated degradation of 2001]. Several HTLV-1-transformed cell lines are defi- DNA repair proteins, which may contribute to virally cient in MSC integrity following exposure to nocodazole induced transformation. [Kasai et al., 2002]. Consistent with this observation, Tax Currently, there is no indication that the viral oncopro- binds and inactivates hsMAD1 and sequesters both teins discussed in this review affect recombinational MAD1 and -2 in the cytoplasm, preventing the latter from repair. However, several lines of evidence suggest that properly localizing at the kinetocores [Jin et al., 1998]. Tax may interfere with the repair of DNA double-strand Therefore, the ability of Tax to disable an important pro- breaks. As previously discussed, Tax-expressing cells tective mechanism that protects against chromosomal mis- form MN containing whole chromosomes, as well as cen- segregation during mitosis provides a potential tric and acentric fragments, indicating the presence of mechanism for the high incidence of aneuploidy in ATL unresolved chromosomal breaks [Majone et al., 1993]. cells. Secondly, in situ labeling of DNA ends showed that Chromosomal defects resulting from multipolar mitoses HTLV-1-transformed cells as well as HeLa cells expres- have long been recognized as a hallmark of high-risk sing Tax had increased numbers of unprotected DNA HPV-associated cervical lesions. Such aberrant cell divi- ends when compared to controls [Majone and Jeang, sions are prompted by an abnormal number of mitotic 2000]. Recent findings demonstrating that Tax can repress spindle poles formed by the centrosomes. Initial observa- the expression of the human telomerase gene (hTERT) has tions of keratinocytes expressing high-risk HPV E6 and been suggested as a possible explanation for these obser- E7 showed that the two oncoproteins cooperate to induce vations, since DNA ends are stabilized by the transient supernumerary centrosomes [Duensing and Munger, 2001, addition of telomeric repeats. Inhibition of telomerase 2002]. Remarkably, this effect has not been observed with activity would also foster persistent telomere dysfunction, low-risk HPV E6 or E7. High-risk HPV E7 can quickly thereby allowing an accumulation of unbalanced chromo- subvert the control of centrosome duplication during mito- somal rearrangements [Gabet et al., 2003]. A more recent sis, leading to the assembly of multipolar spindles and study presents contrasting evidence for the activation of ultimately to aneuploidy [Duensing and Munger, 2001]. hTERT transcription by Tax in primary T-lymphocytes This function of E7 is independent of its ability to bind infected with HTLV-1 in vitro, as well as in ex vivo ATL and inactivate pRB but appears to depend on a domain samples. The authors proposed a model in which Tax that mediates its interaction with p21Cip1/Waf1. Therefore, inhibits hTERT expression in mitogen-stimulated cells alterations in cyclin/CDK2 complexes have been proposed 318 Gatza et al. as a mechanism of E7-induced centrosome duplication Adya N, Zhao L-J, Huang W, Boros I, Giam C-Z. 1994. Expansion of errors [Duensing and Munger, 2003]. 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