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Environ Mol Mutagen. Author manuscript; available in PMC 2010 October 1.
Published in final edited form as:
PMCID: PMC2760603
NIHMSID: NIHMS91916

Viral transformation and aneuploidy

Abstract

Human tumor viruses are associated with a variety of human malignancies, and it is estimated that 15% of all human cancers have a viral etiology. An abnormality in chromosomal ploidy or aneuploidy is a hallmark of cancers. In normal cells, euploidy is governed by several factors including an intact spindle assembly checkpoint (SAC), accurate centrosome duplication, and proper cytokinesis. Viral oncoproteins are suggested to perturb the cellular machineries for chromosomal segregation creating aneuploidy which can lead to the malignant transformation of infected cells. Here we review in brief some of the mechanisms employed by viruses that can cause cellular aneuploidy.

Keywords: Spindle assembly checkpoint, centrosome, aneuploidy, human T-cell leukemia virus type I (HTLV-I), Tax

Introduction

Viruses are one of the major etiologies of human cancers. There are six major human cancer viruses. These include human T-cell leukemia virus type I (HTLV-I), hepatitis B virus (HBV), hepatitis C virus (HCV), human papillomavirus (HPV), Epstein-Barr virus (EBV), and Kaposi’s sarcoma-associated herpesvirus (KSHV). HTLV-I is a retrovirus that causes adult T-cell leukemia (ATL) (Matsuoka and Jeang, 2007). HBV and HCV cause hepatocellular carcinoma (HCC) (Bruix et al., 2006). HPVs induce cervical cancer (Woodman et al., 2007). EBV is associated with Burkitt’s lymphoma, and nasopharyngeal carcinoma (NPC) (Pattle and Farrell, 2006) amongst others; KSHV is causal for Kaposi’s sarcoma in the compromised hosts (Cathomas, 2000).

The number of virus-related malignancies is estimated to encompass 15% of all human cancers worldwide (zur, 1991). Achievements in the research on viral oncogenic mechanisms have contributed to a better understanding of various biological events in the cell. Indeed, emerging discoveries of new viral causes of cancers such as the human xenotrophic murine leukemia virus (MLV)-related virus (XMRV) in human prostate cancer (Urisman et al., 2006) and the human MC-polyomavirus in Merkel cell carcinoma (Feng et al., 2008) raise the hope of elucidating viral explanations for the genesis of many heretofore unexplained cancers.

Mechanisms of aneuploidy

Aneuploidy is a common feature of many cancers (Chi and Jeang, 2007). A normal mammalian somatic cell is diploid. Thus, a human nucleus has 46 chromosomes, which are precisely duplicated and segregated in mitosis with fidelity to two daughter nuclei. An improper loss or gain in chromosomes can occur through the four events described below (Figure 1). Other means for creating aneuploidy are also possible.

Figure 1
Pathways to aneuploidy. Aneuploidy can be caused by a) improper microtubule attachment to kinetochores with a defect in the SAC; b) abnormal BFB events; c) failure by a cell after mitosis to undergo proper cytokinesis; and d) aberrant amplification of ...

a) The aberrant attachment of spindle microtubules to duplicated chromatids coupled with a defect in the spindle assembly checkpoint (SAC)

In a normal mitosis, duplicated chromosomes pair and congress at the metaphase plate during metaphase and are attached via spindle microtubules to bipolar spindle poles. Each chromosome pair is tethered to the two poles with equal tension, and this bilateral attachment results in unbiased segregation of DNA into two daughter nuclei. When an improper attachment of spindle microtubules to the chromatids occurs (such as in a merotelic attachment), this error will produce missegregation. Spontaneous missegregations are censored by the SAC which monitors the correct attachment of the spindle microtubules to kinetochores (Cleveland et al., 2003). The protein constituents of the SAC include the Mad1, Mad2, Mad3/BubR1 (designated Mad3 in yeast and BubR1 in other species), Bub1, Bub3, and Msp1 proteins. A loss of SAC function and the mutation of some of the genes that encode for SAC proteins have been reported in cancer cells (Malmanche et al., 2006). In animal models, knocking out spindle checkpoint proteins in mice has been found to increase cellular aneuploidy and the incidence of in vivo tumor development (Dai et al., 2004;Iwanaga et al., 2007;Kalitsis et al., 2000;Michel et al., 2001); (Chi et al., 2008b); (Schliekelman et al., 2009).

b) Abnormal breakage-fusion-bridge (BFB)

The breakage-fusion-bridge (BFB) is a well-established mechanism for gene amplification. The BFB cycle is initiated when a chromosome undergoes a double-stranded break, replicates, and the sister chromatids fuse at their ends. Due to the presence of two centromeres, the fused sister chromatids are drawn towards both poles and form a bridge during anaphase. During cytokinesis, these dicentric chromosomes are broken unevenly and may fuse again during interphase, resulting in the next BFB cycle. By this type of cycling, the number chromosomes could become abnormally increased or decreased (Murnane, 2006;Fenech, 2006). The rearrangement of chromosomes through BFB cycles may be another possible source of aneuploidy (Gisselsson et al., 2000;Dey, 2004).

c) Failed cytokinesis

In the cell cycle, cytokinesis follows mitosis. While mitosis leads to the production of two daughter nuclei, cytokinesis divides a parent cell into two daughter cells such that each daughter receives a single nucleus. If cytokinesis does not occur, then the undivided cell becomes binucleated and tetraploid (Gisselsson, 2003). Several studies have shown how tetraploid cells can lead to aneuploid progenies in subsequent cell cycles (Fujiwara et al., 2005;Shi and King, 2005).

d) Aberrant duplication of centrosomes

During the cell cycle, a single centrosome is duplicated once in interphase. Each of the two duplicated centrosomes then becomes one of the two bipolar spindle poles during mitosis. When errors in duplication occur to produce more than two centrosomes (supernumerary centrosomes), a multipolar mitosis ensues. Multipolar mitosis with more than two spindle poles invariably results in aneuploidy. Several cellular proteins, including p53, BRCA1, CHK1, CHK2, Ran GTPase, Aurora A, PLK1, Cyclin B1 and CDK1, regulate centrosome duplication and its function (Chi and Jeang, 2007;Kramer et al., 2004). Not surprisingly, aberrant centrosome numbers are common in many types of cancers including breast, lung, bone, pancreas, colorectal, prostate, head, and neck (Saunders, 2005).

An example of virus-cell transformation: HTLV-I and adult T-cell leukemia (ATL)

HTLV-I is the etiological agent of adult T cell leukemia (ATL), a malignancy of the peripheral CD4+ T lymphocytes. ATL cells are morphologically characterized by hyper-lobulated nuclei and are called “flower cells” (Matsuoka and Jeang, 2007) (Figure 2). The reason for the hyper-lobulated nuclei appears to be because most ATL cells have severe chromosomal aberrations including aneuploidy (Itoyama et al., 2001;Tsukasaki et al., 2001). The development of aneuploidy is likely one step in a multistep leukemogenic process in the development of ATL (Yasunaga and Matsuoka, 2003; Grassmann et al., 2005).

Figure 2
An illustration of HTLV-I Tax-induced aneuploidy. Tax interacts with the spindle assembly checkpoint (SAC) protein, hsMAD1, and inhibits its function. Impairment of SAC permits cells to manifest spontaneous occurrence of unbalanced segregations of chromosomes ...

While the precise mechanisms of ATL leukemogenesis have not been fully clarified, it is thought that the HTLV-I encoded Tax oncoprotein plays a central role in cellular transformation (Boxus et al., 2008; Grassmann, Aboud, and Jeang, 2005). Tax can potently activate the transcription of numerous cellular genes, and recent findings suggest that it can also change the expression profile of putatively oncogenic cellular microRNAs (Yeung et al., 2008; Bouzar and Willems, 2008; Pichler et al., 2008; Grassmann and Jeang, 2008). Tax can functionally inactivate many cellular proteins through direct interaction (Boxus, Twizere, Legros, Dewulf, Kettmann, and Willems, 2008; Ramadan et al., 2008). Importantly, expression of Tax-alone can transform rodent cells (Tanaka et al., 1990), immortalize human cord blood and peripheral blood cells (Akagi and Shimotohno, 1993; Grassmann et al., 1989; Grassmann et al., 1992; Rosin et al., 1998), and create tumors in Tax-transgenic mice (Green et al., 1992; Grossman et al., 1995; Hasegawa et al., 2006; Hinrichs et al., 1987).

Above, we noted that aneuploidy is frequently associated with cellular transformation. In studies of HTLV-I biology, it has been shown that the viral Tax oncoprotein can interact with cellular proteins involved in the SAC and in the regulation of centrosome duplication (Figure 2) (Afonso et al., 2007; Merling et al., 2007; Pumfery et al., 2006). Indeed, the hsMAD1 protein (Chi et al., 2008a) is a SAC component which is targeted by Tax for functional inactivation (Haller et al., 2006; Jin et al., 1998). In addition, Tax dysregulates the replication of centrosomes by associating with several cellular factors (Afonso, Zamborlini, Saib, and Mahieux, 2007). Moreover, Tax can interact with RanBP1, resulting in the fragmentation of centrosomes (Peloponese, Jr. et al., 2005), and Tax can bind TAX1BP2 to create the over-amplification of centrosomes (Ching et al., 2006). Furthermore, consistent with these experimental findings, it has been reported that the peripheral blood lymphocytes isolated from ATL patients frequently have an abnormal number of centrosomes (Nitta et al., 2006). Also, it has been shown that the incidence of multinucleated cells is significantly higher in HTLV-I- infected CD4+ T cell clones than in uninfected cells, and this finding is correlated with the expression level of tax mRNA. Since the T cell clones that were used in the reported study were not transformed, the results suggest that aneuploidy induced by Tax occurs prior to cellular transformation (Sibon et al., 2006).

The creation of chromosomal aberrations is censored unless the checkpoints that guard against their manifestation are also inactivated (Kasai et al., 2002). In this regard, Tax inhibits the functions of checkpoint proteins, such as p53 (Reid et al., 1993), pRB (Neuveut et al., 1998), CHK1 (Park et al., 2004), CHK2 (Haoudi et al., 2003) and others (Matsuoka and Jeang, 2007). Thus by creating DNA errors and also attenuating the cellular checks against these mistakes, HTLV-I creates chromosomal instability and aneuploidy, thereby permitting the emergence of downstream cellular transformation events.

Other examples of virus-cell transformation

a) Human papillomavirus (HPV)

Infection with high-risk HPVs, such as HPV-16 and HPV-18, is associated with approximately 70% of cervical and anogenital cancers worldwide (Carrillo-Infante et al., 2007). High-risk HPVs encode two oncoproteins, E6 and E7, and both contribute to HPV-induced cellular transformation. E6 interacts with p53 and promotes its degradation (Scheffner et al., 1993), whereas E7 binds and inactivates the retinoblastoma tumor suppressor gene (pRB) (Dyson et al., 1989) (Table 1). It has been reported that HPV16 E7 rapidly induces an excessive production of centrioles (Duensing et al., 2007;Duensing et al., 2000), and E6 was found to provoke an accumulation of centrosomes (Duensing et al., 2008). Thus, both HPV-16 E6 and E7 can create abnormalities in centrosome numbers which can lead to aneuploid mitoses.

Table 1
Viral proteins associated with aneuploidy

b) Hepatitis B (HBV) and hepatitis C (HCV) virus

More than 85% of HCC cases are associated with HBV or HCV (Forgues et al., 2003). HBV is a DNA virus that encodes the X oncoprotein (HBx). The HBx gene is frequently integrated into the host genome and is expressed during the development of HCC. Since the HBx protein can transform cultured cells (Hohne et al., 1990;Koike et al., 1994) and induce liver cancers in transgenic mice (Kim et al., 1991;Yu et al., 1999), this protein is thought to be critical in virus induced liver carcinogenesis. A cellular factor Crm1 is reported to play a role in maintaining the fidelity of centrosome duplication. HBx has been reported to interact with Crm1 and affect its localization (Table 1). A current notion is that HBx induces supernumerary centrosomes, multipolar spindles, and consequently aneuploidy via a disturbance of Crm1 function (Forgues et al., 2001;Forgues, Difilippantonio, Linke, Ried, Nagashima, Feden, Valerie, Fukasawa, and Wang, 2003). On the other hand, it has also been reported that HBx induces centrosome amplification and mitotic aberration through activation of the Ras-MEK-MAPK pathway (Yun et al., 2004).

HCV is a member of the positive strand RNA viruses. An HCV nonstructural protein, NS5A, is a phosphoprotein which interacts with cellular proteins such as PKR (Gale, Jr. et al., 1997), Cdk1 (Arima et al., 2001) and others. It has been shown that the over expression of NS5A dysregulates the cell cycle and creates aneuploidy in cultured liver cells (Baek et al., 2006). Recently, it was found that NS5A down-regulates the transcription of the mitotic spindle protein Aspm via the PKR-p38 signaling pathway and induces an aberrant mitotic cell cycle (Wu et al., 2008) (Table 1).

c) Kaposi sarcoma-associated herpesvirus (KSHV)

KSHV is a herpesvirus that is associated with Kaposi’s sarcoma, primary effusion lymphoma, and Castleman’s disease. KSHV encodes approximately 90 genes in its genome. Among them, KSHV-encoded cyclin D homolog, K cyclin, is considered to promote viral oncogenesis. It has been reported that K cyclin transgenic mice (-K cyclin) develop lymphoma, and a loss of p53 (-K cyclin/p53−/−) function increases K cyclin-triggered tumor incidence (Verschuren et al., 2004) while enhancing centrosome abnormalities in mouse fibroblasts (Verschuren et al., 2002). Phosphorylation of nucleophosmin (NPM1) was recently identified as a molecular mechanism for centrosome amplification by K cyclin (Cuomo et al., 2008) (Table 1). Moreover, K cyclin activates CDK6, which phosphorylates NPM1. Hence, it is thought that K cyclin-induced NPM1 phosphorylation triggers centrosome amplification. Additionally, two other KSHV-encoded latent proteins, LANA and vFLIP, augment significant accumulation of supernumerary centrosomes in K cyclin expressing cells. Collectively, the evidence shows that KSHV has evolved several means to induce aneuploidy.

d) Epstein-Barr virus (EBV)

EBV is considered to be causal of malignant diseases, such as Burkitt’s lymphoma, nasopharyngeal carcinoma, and some Hodgkin’s disease. EBV’s latent membrane protein 1 (LMP1) has been reported to transform rodent fibroblasts (Wang et al., 1985) and activate the NF-κB signaling pathways. A tumor suppressor gene RASSF1A is known to stabilize cellular microtubules and regulate mitotic events, and its inactivation induces abnormal spindle formation and chromosomal instability (Liu et al., 2003;Rong et al., 2004). EBV LMP1 has been found to down-regulate the expression of RASSF1A through an NF-κB pathway, resulting in aberrant mitotic spindles and aneuploid chromosomes (Man et al., 2007) (Table 1). In addition, latent EBV infection impairs the mitotic SAC and rescues Burkitt’s lymphoma-derived cells from other caspase-dependent cell death when cultured in vitro (Leao et al., 2007).

Concluding remarks

It is still debatable whether aneuploidy is the cause or the consequence of cellular transformation. As described here in brief, there is evidence that some human cancer viruses encode viral oncopoteins that cause cellular aneuploidy. We note with interest that in similarity with human cancer viruses, bacterial Helicobacter pylori infection and its expression of bacterial CagA protein are also reportedly associated with the accumulation of chromosomal aberrations (Williams et al., 2005). Taken together, the findings converge to suggest that infection with many oncogenic pathogens can induce aneuploidy, and that aneuploidy may be the initial trigger for the development of cellular transformation.

To date, the research on viral oncogenesis has clarified many pathogenic etiologies and shed light on several critical cellular regulatory functions. A direct causality between infection, aneuploidy, and cancer remains to be conclusively established. However, increasingly, findings are consistent with these associations. Future research is needed to focus on clarifying better these linkages and their implications for novel therapeutic strategies against viral malignancies.

Acknowledgments

Research in the Jeang laboratory is supported by intramural funding from the National Institute of Allergy and Infectious Diseases, NIH. This brief review is intended to raise selected illustrative examples. We apologize, in view of space and format limitations, for the failure to cover other examples and issues. We thank Christina Bezon for editorial assistance.

Reference List

  • Afonso PV, Zamborlini A, Saib A, Mahieux R. Centrosome and retroviruses: The dangerous liaisons. Retrovirology. 2007;4:27. [PMC free article] [PubMed]
  • Akagi T, Shimotohno K. Proliferative response of Tax1-transduced primary human T cells to anti-CD3 antibody stimulation by an interleukin-2-independent pathway. Journal of Virology. 1993;67:1211–1217. [PMC free article] [PubMed]
  • Arima N, Kao CY, Licht T, Padmanabhan R, Sasaguri Y, Padmanabhan R. Modulation of cell growth by the hepatitis C virus nonstructural protein NS5A. J Biol Chem. 2001;276:12675–12684. [PubMed]
  • Baek KH, Park HY, Kang CM, Kim SJ, Jeong SJ, Hong EK, Park JW, Sung YC, Suzuki T, Kim CM, Lee CW. Overexpression of hepatitis C virus NS5A protein induces chromosome instability via mitotic cell cycle dysregulation. J Mol Biol. 2006;359:22–34. [PubMed]
  • Bouzar AB, Willems L. How HTLV-1 may subvert miRNAs for persistence and transformation. Retrovirology. 2008;5:101. [PMC free article] [PubMed]
  • Boxus M, Twizere JC, Legros S, Dewulf JF, Kettmann R, Willems L. The HTLV-1 Tax interactome. Retrovirology. 2008;5:76. [PMC free article] [PubMed]
  • Bruix J, Hessheimer AJ, Forner A, Boix L, Vilana R, Llovet JM. New aspects of diagnosis and therapy of hepatocellular carcinoma. Oncogene. 2006;25:3848–3856. [PubMed]
  • Carrillo-Infante C, Abbadessa G, Bagella L, Giordano A. Viral infections as a cause of cancer (review) Int J Oncol. 2007;30:1521–1528. [PubMed]
  • Cathomas G. Human herpes virus 8: a new virus discloses its face. Virchows Archiv. 2000;436:195–206. [PubMed]
  • Chi YH, Haller K, Ward MD, Semmes OJ, Li Y, Jeang KT. Requirements for Protein Phosphorylation and the Kinase Activity of Polo-like Kinase 1 (Plk1) for the Kinetochore Function of Mitotic Arrest Deficiency Protein 1 (Mad1) J Biol Chem. 2008a;283:35834–35844. [PMC free article] [PubMed]
  • Chi YH, Jeang KT. Aneuploidy and cancer. J Cell Biochem. 2007;102:531–538. [PubMed]
  • Chi YH, Ward JM, Cheng LI, Yasunaga J, Jeang KT. Spindle assembly checkpoint and p53 deficiencies cooperate for tumorigenesis in mice. Int J Cancer 2008b [PMC free article] [PubMed]
  • Ching YP, Chan SF, Jeang KT, Jin DY. The retroviral oncoprotein Tax targets the coiled-coil centrosomal protein TAX1BP2 to induce centrosome overduplication. Nat Cell Biol. 2006;8:717–724. [PubMed]
  • Cleveland DW, Mao Y, Sullivan KF. Centromeres and Kinetochores From Epigenetics to Mitotic Checkpoint Signaling. Cell. 2003;112:407–421. [PubMed]
  • Cuomo ME, Knebel A, Morrice N, Paterson H, Cohen P, Mittnacht S. p53-Driven apoptosis limits centrosome amplification and genomic instability downstream of NPM1 phosphorylation. Nat Cell Biol. 2008;10:723–730. [PubMed]
  • Dai W, Wang Q, Liu T, Swamy M, Fang Y, Xie S, Mahmood R, Yang YM, Xu M, Rao CV. Slippage of mitotic arrest and enhanced tumor development in mice with BubR1 haploinsufficiency. Cancer Res. 2004;64:440–445. [PubMed]
  • Dey P. Aneuploidy and malignancy: an unsolved equation. J Clin Pathol. 2004;57:1245–1249. [PMC free article] [PubMed]
  • Duensing A, Chin A, Wang L, Kuan SF, Duensing S. Analysis of centrosome overduplication in correlation to cell division errors in high-risk human papillomavirus (HPV)-associated anal neoplasms. Virology. 2008;372:157–164. [PMC free article] [PubMed]
  • Duensing A, Liu Y, Perdreau SA, Kleylein-Sohn J, Nigg EA, Duensing S. Centriole overduplication through the concurrent formation of multiple daughter centrioles at single maternal templates. Oncogene. 2007;26:6280–6288. [PMC free article] [PubMed]
  • Duensing S, Lee LY, Duensing A, Basile J, Piboonniyom S, Gonzalez S, Crum CP, Munger K. The human papillomavirus type 16 E6 and E7 oncoproteins cooperate to induce mitotic defects and genomic instability by uncoupling centrosome duplication from the cell division cycle. Proc Natl Acad Sci U S A. 2000;97:10002–10007. [PubMed]
  • Dyson N, Howley PM, Munger K, Harlow E. The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science. 1989;243:934–937. [PubMed]
  • Fenech M. Cytokinesis-block micronucleus assay evolves into a “cytome” assay of chromosomal instability, mitotic dysfunction and cell death. Mutat Res. 2006;600:58–66. [PubMed]
  • Feng H, Shuda M, Chang Y, Moore PS. Clonal Integration of a Polyomavirus in Human Merkel Cell Carcinoma. Science. 2008;319:1096. [PMC free article] [PubMed]
  • Forgues M, Difilippantonio MJ, Linke SP, Ried T, Nagashima K, Feden J, Valerie K, Fukasawa K, Wang XW. Involvement of Crm1 in hepatitis B virus X protein-induced aberrant centriole replication and abnormal mitotic spindles. Mol Cell Biol. 2003;23:5282–5292. [PMC free article] [PubMed]
  • Forgues M, Marrogi AJ, Spillare EA, Wu CG, Yang Q, Yoshida M, Wang XW. Interaction of the hepatitis B virus X protein with the Crm1-dependent nuclear export pathway. J Biol Chem. 2001;276:22797–22803. [PubMed]
  • Fujiwara T, Bandi M, Nitta M, Ivanova EV, Bronson RT, Pellman D. Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature. 2005;437:1043–1047. [PubMed]
  • Gale MJ, Jr, Korth MJ, Tang NM, Tan SL, Hopkins DA, Dever TE, Polyak SJ, Gretch DR, Katze MG. Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5A protein. Virology. 1997;230:217–227. [PubMed]
  • Gisselsson D. Chromosome instability in cancer: how, when, and why? Adv Cancer Res. 2003;87:1–29. [PubMed]
  • Gisselsson D, Pettersson L, Hoglund M, Heidenblad M, Gorunova L, Wiegant J, Mertens F, Dal CP, Mitelman F, Mandahl N. Chromosomal breakage-fusion-bridge events cause genetic intratumor heterogeneity. Proc Natl Acad Sci U S A. 2000;97:5357–5362. [PubMed]
  • Grassmann R, Aboud M, Jeang KT. Molecular mechanisms of cellular transformation by HTLV-1 Tax. Oncogene. 2005;24:5976–5985. [PubMed]
  • Grassmann R, Berchtold S, Radant I, Alt M, Fleckenstein B, Sodroski JG, Haseltine WA, Ramstedt U. Role of human T-cell leukemia virus type 1 X region proteins in immortalization of primary human lymphocytes in culture. Journal of Virology. 1992;66:4570–4575. [PMC free article] [PubMed]
  • Grassmann R, Dengler C, Muller-Fleckenstein I, Fleckenstein B, McGuire K, Dokhelar MC, Sodroski JG, Haseltine WA. Transformation to continuous growth of primary human T lymphocytes by human T-cell leukemia virus type I X-region genes transduced by a Herpesvirus saimiri vector. Proc Natl Acad Sci U S A. 1989;86:3351–3355. [PubMed]
  • Grassmann R, Jeang KT. The roles of microRNAs in mammalian virus infection. Biochim Biophys Acta. 2008;1779:706–711. [PMC free article] [PubMed]
  • Green JE, Baird AM, Hinrichs SH, Klintworth GK, Jay G. Adrenal medullary tumors and iris proliferation in a transgenic mouse model of neurofibromatosis. American Journal of Pathology. 1992;140:1401–1410. [PubMed]
  • Grossman WJ, Kimata JT, Wong FH, Zutter M, Ley TJ, Ratner L. Development of leukemia in mice transgenic for the tax gene of human T-cell leukemia virus type I. Proc Natl Acad Sci U S A. 1995;92:1057–1061. [PubMed]
  • Haller K, Kibler KV, Kasai T, Chi YH, Peloponese JM, Yedavalli VS, Jeang KT. The N-terminus of rodent and human MAD1 confers species-specific stringency to spindle assembly checkpoint. Oncogene. 2006;25:2137–2147. [PubMed]
  • Haoudi A, Daniels RC, Wong E, Kupfer G, Semmes OJ. Human T-cell leukemia virus-I tax oncoprotein functionally targets a subnuclear complex involved in cellular DNA damage-response. J Biol Chem. 2003;278:37736–37744. [PubMed]
  • Hasegawa H, Sawa H, Lewis MJ, Orba Y, Sheehy N, Yamamoto Y, Ichinohe T, Tsunetsugu-Yokota Y, Katano H, Takahashi H, Matsuda J, Sata T, Kurata T, Nagashima K, Hall WW. Thymus-derived leukemia-lymphoma in mice transgenic for the Tax gene of human T-lymphotropic virus type I. Nat Med. 2006;12:466–472. [PubMed]
  • Hinrichs SH, Nerenberg M, Reynolds RK, Khoury G, Jay G. A transgenic mouse model for human neurofibromatosis. Science. 1987;237:1340–1343. [PubMed]
  • Hohne M, Schaefer S, Seifer M, Feitelson MA, Paul D, Gerlich WH. Malignant transformation of immortalized transgenic hepatocytes after transfection with hepatitis B virus DNA. EMBO J. 1990;9:1137–1145. [PubMed]
  • Itoyama T, Chaganti RSK, Yamada Y, Tsukasaki K, Atogami S, Nakamura H, Tomonaga M, Ohshima K, Kikuchi M, Sadamori N. Cytogenetic analysis and clinical significance in adult T-cell leukemia/lymphoma: a study of 50 cases from the human T-cell leukemia virus type-1 endemic area, Nagasaki. Blood. 2001;97:3612. [PubMed]
  • Iwanaga Y, Chi YH, Miyazato A, Sheleg S, Haller K, Peloponese JM, Jr, Li Y, Ward JM, Benezra R, Jeang KT. Heterozygous deletion of mitotic arrest-deficient protein 1 (MAD1) increases the incidence of tumors in mice. Cancer Res. 2007;67:160–166. [PubMed]
  • Jin DY, Spencer F, Jeang KT. Human T cell leukemia virus type 1 oncoprotein Tax targets the human mitotic checkpoint protein MAD1. Cell. 1998;93:81–91. [PubMed]
  • Kalitsis P, Earle E, Fowler KJ, Choo KH. Bub3 gene disruption in mice reveals essential mitotic spindle checkpoint function during early embryogenesis. Genes Dev. 2000;14:2277–2282. [PubMed]
  • Kasai T, Iwanaga Y, Iha H, Jeang KT. Prevalent loss of mitotic spindle checkpoint in adult T-cell leukemia confers resistance to microtubule inhibitors. J Biol Chem. 2002;277:5187–5193. [PubMed]
  • Kim CM, Koike K, Saito I, Miyamura T, Jay G. HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature. 1991;351:317–320. [PubMed]
  • Koike K, Moriya K, Yotsuyanagi H, Iino S, Kurokawa K. Induction of cell cycle progression by hepatitis B virus HBx gene expression in quiescent mouse fibroblasts. J Clin Invest. 1994;94:44–49. [PMC free article] [PubMed]
  • Kramer A, Lukas J, Bartek J. Checking out the centrosome. Cell Cycle. 2004;3:1390–1393. [PubMed]
  • Leao M, Anderton E, Wade M, Meekings K, Allday MJ. Epstein-barr virus-induced resistance to drugs that activate the mitotic spindle assembly checkpoint in Burkitt’s lymphoma cells. J Virol. 2007;81:248–260. [PMC free article] [PubMed]
  • Liu L, Tommasi S, Lee DH, Dammann R, Pfeifer GP. Control of microtubule stability by the RASSF1A tumor suppressor. Oncogene. 2003;22:8125–8136. [PubMed]
  • Malmanche N, Maia A, Sunkel CE. The spindle assembly checkpoint: preventing chromosome mis-segregation during mitosis and meiosis. FEBS Lett. 2006;580:2888–2895. [PubMed]
  • Man C, Rosa J, Lee LT, Lee VH, Chow BK, Lo KW, Doxsey S, Wu ZG, Kwong YL, Jin DY, Cheung AL, Tsao SW. Latent membrane protein 1 suppresses RASSF1A expression, disrupts microtubule structures and induces chromosomal aberrations in human epithelial cells. Oncogene. 2007;26:3069–3080. [PubMed]
  • Matsuoka M, Jeang KT. Human T-cell leukaemia virus type 1 (HTLV-1) infectivity and cellular transformation. Nat Rev Cancer. 2007;7:270–280. [PubMed]
  • Merling R, Chen C, Hong S, Zhang L, Liu M, Kuo YL, Giam CZ. HTLV-1 Tax mutants that do not induce G1 arrest are disabled in activating the anaphase promoting complex. Retrovirology. 2007;4:35. [PMC free article] [PubMed]
  • Michel LS, Liberal V, Chatterjee A, Kirchwegger R, Pasche B, Gerald W, Dobles M, Sorger PK, Murty VV, Benezra R. MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells. Nature. 2001;409:355–359. [PubMed]
  • Murnane JP. Telomeres and chromosome instability. DNA Repair (Amst) 2006;5:1082–1092. [PubMed]
  • Neuveut C, Low KG, Maldarelli F, Schmitt I, Majone F, Grassmann R, Jeang KT. Human T-cell leukemia virus type 1 Tax and cell cycle progression: role of cyclin D-cdk and p110Rb. Mol Cell Biol. 1998;18:3620–3632. [PMC free article] [PubMed]
  • Nitta T, Kanai M, Sugihara E, Tanaka M, Sun B, Nagasawa T, Sonoda S, Saya H, Miwa M. Centrosome amplification in adult T-cell leukemia and human T-cell leukemia virus type 1 Tax-induced human T cells. Cancer Sci. 2006;97:836–841. [PubMed]
  • Park HU, Jeong JH, Chung JH, Brady JN. Human T-cell leukemia virus type 1 Tax interacts with Chk1 and attenuates DNA-damage induced G2 arrest mediated by Chk1. Oncogene. 2004;23:4966–4974. [PubMed]
  • Pattle SB, Farrell PJ. The role of Epstein-Barr virus in cancer. Expert Opin Biol Ther. 2006;6:1193–1205. [PubMed]
  • Peloponese JM, Jr, Haller K, Miyazato A, Jeang KT. Abnormal centrosome amplification in cells through the targeting of Ran-binding protein-1 by the human T cell leukemia virus type-1 Tax oncoprotein. Proc Natl Acad Sci U S A. 2005;102:18974–18979. [PubMed]
  • Pichler K, Schneider G, Grassmann R. MicroRNA miR-146a and further oncogenesis-related cellular microRNAs are dysregulated in HTLV-1-transformed lymphocytes. Retrovirology. 2008;5:100. [PMC free article] [PubMed]
  • Pumfery A, de la FC, Kashanchi F. HTLV-1 Tax: centrosome amplification and cancer. Retrovirology. 2006;3:50. [PMC free article] [PubMed]
  • Ramadan E, Ward M, Guo X, Durkin SS, Sawyer A, Vilela M, Osgood C, Pothen A, Semmes OJ. Physical and in silico approaches identify DNA-PK in a Tax DNA-damage response interactome. Retrovirology. 2008;5:92. [PMC free article] [PubMed]
  • Reid RL, Lindholm PF, Mireskandari A, Dittmer J, Brady JN. Stabilization of wild-type p53 in human T-lymphocytes transformed by HTLV-I. Oncogene. 1993;8:3029–3036. [PubMed]
  • Rong R, Jin W, Zhang J, Sheikh MS, Huang Y. Tumor suppressor RASSF1A is a microtubule-binding protein that stabilizes microtubules and induces G2/M arrest. Oncogene. 2004;23:8216–8230. [PubMed]
  • Rosin O, Koch C, Schmitt I, Semmes OJ, Jeang KT, Grassmann R. A human T-cell leukemia virus Tax variant incapable of activating NF-kappaB retains its immortalizing potential for primary T-lymphocytes. J Biol Chem. 1998;273:6698–6703. [PubMed]
  • Saunders W. Centrosomal amplification and spindle multipolarity in cancer cells. Seminars in Cancer Biology. 2005;15:25–32. [PubMed]
  • Scheffner M, Huibregtse JM, Vierstra RD, Howley PM. The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell. 1993;75:495–505. [PubMed]
  • Schliekelman M, Cowley DO, O’Quinn R, Oliver TG, Lu L, Salmon ED, Van DT. Impaired Bub1 function in vivo compromises tension-dependent checkpoint function leading to aneuploidy and tumorigenesis. Cancer Res. 2009;69:45–54. [PubMed]
  • Shi Q, King RW. Chromosome nondisjunction yields tetraploid rather than aneuploid cells in human cell lines. Nature. 2005;437:1038–1042. [PubMed]
  • Sibon D, Gabet AS, Zandecki M, Pinatel C, Thete J, fau-Larue MH, Rabaaoui S, Gessain A, Gout O, Jacobson S, Mortreux F, Wattel E. HTLV-1 propels untransformed CD4 lymphocytes into the cell cycle while protecting CD8 cells from death. J Clin Invest. 2006;116:974–983. [PMC free article] [PubMed]
  • Tanaka A, Takahashi C, Yamaoka S, Nosaka T, Maki M, Hatanaka M. Oncogenic transformation by the tax gene of human T-cell leukemia virus type I in vitro. Proc Natl Acad Sci U S A. 1990;87:1071–1075. [PubMed]
  • Tsukasaki K, Krebs J, Nagai K, Tomonaga M, Koeffler HP, Bartram CR, Jauch A. Comparative genomic hybridization analysis in adult T-cell leukemia/lymphoma: correlation with clinical course. Blood. 2001;97:3875. [PubMed]
  • Urisman A, Molinaro RJ, Fischer N, Plummer SJ, Casey G, Klein EA, Malathi K, Magi-Galluzzi C, Tubbs RR, Ganem D. Identification of a novel gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. PLoS Pathog. 2006;2:e25. [PMC free article] [PubMed]
  • Verschuren EW, Hodgson JG, Gray JW, Kogan S, Jones N, Evan GI. The role of p53 in suppression of KSHV cyclin-induced lymphomagenesis. Cancer Res. 2004;64:581–589. [PubMed]
  • Verschuren EW, Klefstrom J, Evan GI, Jones N. The oncogenic potential of Kaposi’s sarcoma-associated herpesvirus cyclin is exposed by p53 loss in vitro and in vivo. Cancer Cell. 2002;2:229–241. [PubMed]
  • Wang D, Liebowitz D, Kieff E. An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells. Cell. 1985;43:831–840. [PubMed]
  • Williams L, Jenkins GJ, Doak SH, Fowler P, Parry EM, Brown TH, Griffiths AP, Williams JG, Parry JM. Fluorescence in situ hybridisation analysis of chromosomal aberrations in gastric tissue: the potential involvement of Helicobacter pylori. Br J Cancer. 2005;92:1759–1766. [PMC free article] [PubMed]
  • Woodman CB, Collins SI, Young LS. The natural history of cervical HPV infection: unresolved issues. Nat Rev Cancer. 2007;7:11–22. [PubMed]
  • Wu SC, Chang SC, Wu HI, Liao PJ, Chang MF. Hepatitis C virus NS5A protein down-regulates the expression of spindle gene Aspm through PKR-p38 signaling pathway. J Biol Chem 2008 [PMC free article] [PubMed]
  • Yasunaga J, Matsuoka M. Leukemogenesis of Adult T-Cell Leukemia. International Journal of Hematology. 2003;78:312–320. [PubMed]
  • Yeung ML, Yasunaga J, Bennasser Y, Dusetti N, Harris D, Ahmad N, Matsuoka M, Jeang KT. Roles for microRNAs, miR-93 and miR-130b, and TP53INP1 tumor suppressor in cell growth dysregulation by HTLV-1. Cancer Res. 2008 in press. [PMC free article] [PubMed]
  • Yu DY, Moon HB, Son JK, Jeong S, Yu SL, Yoon H, Han YM, Lee CS, Park JS, Lee CH, Hyun BH, Murakami S, Lee KK. Incidence of hepatocellular carcinoma in transgenic mice expressing the hepatitis B virus X-protein. J Hepatol. 1999;31:123–132. [PubMed]
  • Yun C, Cho H, Kim SJ, Lee JH, Park SY, Chan GK, Cho H. Mitotic aberration coupled with centrosome amplification is induced by hepatitis B virus X oncoprotein via the Ras-mitogen-activated protein/extracellular signal-regulated kinase-mitogen-activated protein pathway. Mol Cancer Res. 2004;2:159–169. [PubMed]
  • zur HH. Viruses in human cancers. Science. 1991;254:1167–1173. [PubMed]