Introduction

The nonstructural regulatory Tax proteins are unique characteristics of delta retroviruses, a subgroup of retroviruses, which confers long-term persistent infection to mammalian lymphocytes. These proteins are crucial for productive viral replication, and they stimulate the proliferation of host lymphocytic cells. Infection of T cells with the prototype of this group, human T-cell leukemia virus type 1 (HTLV-1) causes a severe and fatal lymphoproliferative disease of helper T-cell origin, the adult T-cell leukemia (ATL) and a separate neurodegenerative disease termed tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM) (Poiesz et al., 1980; Yoshida et al., 1984; Gessain et al., 1985; Osame et al., 1986). A proportion of 1–3% of HTLV-1-infected individuals develop these diseases after prolonged viral persistence (i.e. usually after two decades of infection for ATL). Even in patients who do not develop frank leukemia, virus-infected T-lymphocytes appear to be growth-stimulated, since such cells expand clonally and persist over many years (Etoh et al., 1997; Gabet et al., 2000). In vivo infected cells are frequently capable of indefinite proliferation when propagated in tissue culture in the presence of interleukin (IL)-2. Similarly, it is also possible to generate immortal CD4⁺ and CD8⁺ T-cell lines by infecting primary blood lymphocytes with HTLV-1 ex vivo. Since HTLV-1 spreads very inefficiently via cell-free viral particles (Manel, Battini, Taylor and Sitbon, this issue), a critical reason for this virus to encode a cell-growth stimulatory function is to amplify its cell-associated integrated proviral genome.

HTLV-1's capacity to stimulate T-cell growth suggests that the virus encodes gene function(s) involved in clonal expansion of cells. Other than its structural genes, gag, pol and env, HTLV-1 contains several open reading frames in a pX region at the 3' end of its genome. The pX region has the potential to encode essential regulatory proteins (Tax, Rex) and three accessory proteins, p12, p13 and p30 which are important for viral infectivity and replication by influencing cellular signaling and gene expression (Bartoe et al., 2000; Nicot et al., 2001; Johnson et al., 2001; D'Agostino et al., 2002; Ding et al., 2002; Lefebvre et al., 2002). The proteins p12, p13 and p30 are dispensable for the immortalization of primary lymphocytes (Derse et al., 1997; Robek et al., 1998). Our current understanding is that Tax is the primary HTLV-1-encoded factor used by the virus to modulate cellular proliferation.

Structure–function features of Tax for transcriptional activation

During virus replication, the Tax protein is a transcriptional activator of the viral long terminal repeat (LTR). Tax is predominantly a nuclear phosphoprotein with a small amount distributed in the cytoplasm of cells. Recent evidence suggests that Tax is post-translationally modified by ubiquitination (Chiari et al., 2004; Peloponese Jr et al., 2004), and this modification attenuates Tax's transcriptional activity. Several major cellular signal transduction pathways including the transcription factors NF-B, CREB, SRF and AP-1 are induced by Tax (Jeang, 2001; Azran et al., 2004). These Tax functions are detailed elsewhere in this issue, and are here only briefly summarized.

The HTLV-1 LTR is a cyclic-AMP-responsive promoter (Jeang et al., 1988). Tax does not directly bind DNA, but associates through its N-terminus with the CREB protein (Baranger et al., 1995; Adya and Giam, 1995), which docks at the LTR's cyclic-AMP responsive (CRE)-motifs. Tax also recruits transcriptional coactivators, CBP and p300 (Giebler et al., 1997; Bex et al., 1998; Harrod et al., 2000), and in a less-defined manner, P/CAF (Okada and Jeang, 2002). The C-terminal activation domain of Tax (Semmes and Jeang, 1995) is thought to directly contact the TATA-box-bound TBP protein (Caron et al., 1993) thereby promoting transcriptional initiation and RNA polymerase elongation (Ching et al., 2004).

A second major function of Tax is to activate NF-B. This activation likely involves cytoplasmic and nuclear interactions. Tax and NF-B proteins have been shown by immunomicroscopy to colocalize (Semmes and Jeang, 1996) within nuclear bodies that contain RNA polymerase II and other transcription factors (Bex et al., 1997). Recently, evidence suggests that the assembly of a transcriptionally competent 'nuclear' Tax–NF-B–CBP complex likely first occurs in the cytoplasm (Azran et al., 2005). One prevailing view is that Tax binds the IKK/NEMO molecule in the cytoplasm to influence the activity of the IKK/IKK/IKK complex (Chu et al., 1999; Harhaj and Sun, 1999; Jin et al., 1999a). Activated IKK/IKK/IKK complexes then phosphorylate IKK/ leading to a cascade of events (reviewed elsewhere in this issue by Sun and Yamaoka) which result in nuclear migration of NF-B (Iha et al., 2003).

In vitro transforming potential of Tax

Transformation and immortalization of rodent fibroblasts

Tax has many features of an oncogene including the capacity to immortalize primary rodent cells. Expression of Tax along with a selectable marker in early-passage rat embryo fibroblasts produces immortalization without morphological changes. However, when coexpressed with Ras, Tax leads to the formation of cellular foci. Such cells are producing tumors when injected into nude mice (Pozzatti et al., 1990). In rodent fibroblasts such as NIH 3T3 and Rat1, Tax-alone is sufficient to stimulate cells to grow beyond contact-inhibited saturation density, induce anchorage-independent growth in soft agar, and confer tumorigenicity to cells when introduced into nude mice (Tanaka et al., 1990). Compared to rat fibroblasts transformed by classical cellular nuclear oncogenes, Tax-transformed cells also have an apparently higher resistance to the induction of apoptosis (Fujita and Shiku, 1995).

Immortalization of human T-lymphocytes

In contrast to rodent cells, primary human cells are comparatively resistant to Tax-mediated transformation. Indeed, the transformed phenotype in rat fibroblasts can be suppressed by normal human fibroblasts when the two cell types are fused, suggesting the existence of a dominant suppressor gene activity in human cells (Inoue et al., 1994). To date, evidence suggests that Tax can immortalize primary human T-cells derived from peripheral blood or cord blood. This has been demonstrated by transducing cells with Tax expressed from rhadinoviral (Grassmann et al., 1989, 1992) or retroviral (Akagi and Shimotohno, 1993) vectors. The resulting immortalized lymphocytes resemble closely the phenotype of HTLV-1-transformed T-cells, including dependence on exogenous interleukin (IL-) 2 for growth (Akagi et al., 1995; Rosin et al., 1998; Schmitt et al., 1998). Thus, in these primary cells, a mechanism different from the previously proposed IL-2 autocrine model seems to be triggered by Tax in its dysregulation of T-cell proliferation.

Roles for CREB, NF-B and SRF in cellular immortalization

Tax mutants have been used to characterize the structure–function correlate for transformation in rodent cells. Initially, only two Tax functions (NF-B- or CREB- activation) were considered. Surprisingly, depending on the cells, Tax mutants individually deficient in either CREB- (Smith and Greene, 1991) or NF-B- (Yamaoka et al., 1996; Matsumoto et al., 1997) activation remained competent for immortalizing rodent fibroblasts. Separately, it was reported that Tax stimulation of CArG Box function through SRF was also needed to transform primary rat fibroblasts (Matsumoto et al., 1997). In the context of human lymphocytes, activation of the CREB/ATF and/or SRF pathways was required for the clonal expansion of CD4⁺ and CD8⁺ T cells (Akagi et al., 1997a; Rosin et al., 1998), and recently, CREB has been assigned a role as a proto-oncogene in its promotion of abnormal proliferation/survival of haematopoetic cells (Shankar et al., 2005). Primary human lymphocytes transduced with a Tax mutant defective for NF-B activation, nevertheless, still could increase NF-B activity, albeit at a level reduced compared to wild-type Tax (Rosin et al., 1998). This suggests that increased NF-B function in transformed cells emanates from cellular signaling and need not be a direct consequence of Tax. If correct, this would reconcile findings seen in some ATL cells, in which NF-B activity is elevated even when Tax is low to undetectable. On the other hand, it cannot be excluded that activation of the NF-B pathway by Tax is important for growth response to IL-2 (Akagi et al., 1997a) or to the immortalization of CD4⁺ and CD8⁺ T-lymphocytes by an HTLV-1 molecular clone (Robek and Ratner, 2000).

Stimulation of cell growth through signal transduction

Comparison of gene expression profiles between HTLV-infected versus uninfected T-cells revealed numerous differences in expression of signaling molecules including cytokine receptors and cytokines (Ruckes et al., 2001; Pise-Masison et al., 2002). These changes include several factors with growth promoting and/or antiapoptotic functions whose expression patterns are modulated by Tax (Ng et al., 2001). Below, we summarize some salient examples (Figure 1).

Figure 1.

Cytoplasmic signaling of Tax-stimulated regulatory proteins. Tax by transactivation stimulates the gene expression of receptors Ox40, IL2R, IL15 R1 (blue), ligands (yellow) OX40L, IL-13 and IL-15. Receptor ligand binding results in the activation of growth and survival controlling signaling cascades and activation of transcription factors

Full figure and legend (72K)

IL-2 and IL-15

The -chain of the IL-2 receptor (IL-2R) was the first cellular gene reported to be upregulated by Tax (Ballard et al., 1988; Ruben et al., 1988). Together with - and a common - chain, IL-2R forms the high-affinity IL-2 receptor, which permits signaling at low IL-2 concentrations. A complementary observation that the promoter for the IL-2 gene is also activated by Tax (Hoyos et al., 1989; McGuire et al., 1993; Good et al., 1996) led to an unifying hypothesis of T-cell proliferation through an autocrine IL-2/IL-2R loop. Actually, this hypothesis insufficiently explains ATL biology and transformed growth in culture since most Tax or HTLV-1-immortalized T-cells still require exogenous IL-2 and do not detectably express either IL-2 mRNA or protein (Akagi and Shimotohno, 1993; Schmitt et al., 1998; Chung et al., 2003). In parallel, IL-15, a relative of IL-2, uses the - and -chains of the IL-2 receptor for signaling. IL-15 mRNA expression is increased three- to fourfold by Tax in HTLV-I-infected T-cells compared to normal lymphocytes (Azimi et al., 1998). IL-15R, the IL-15-specific binding receptor chain, is also elevated by Tax in HTLV-1-infected cells (Mariner et al., 2001). Therefore, it has been suggested that an IL-15 autocrine loop may also contribute to HTLV-1 pathogenesis (Azimi et al., 1999).

Interleukin-13

Stimulatory signals via the IL-4R chain are provided by the IL-4/IL-13 receptor complex. Whereas IL-4 is mostly absent, IL-13 is upregulated and secreted in HTLV-transformed cells, and in cultured ATL-cells derived from patients (Chung et al., 2003; Wäldele et al., 2004). In HTLV-cells, IL-13 expression is upregulated by Tax transactivation of the NF-AT and AP-1 elements in the promoter (Wäldele et al., 2004). IL-13 is linked to leukemogenesis, since in both Hodgkin's lymphoma cells and HTLV-1-transformed cells, it appears to be operative through an autocrine mechanism.

OX40/OX40L

OX40, a member of the TNF-receptor family, is the only costimulatory T-cell molecule known to be specifically upregulated in HTLV-1-infected cells. Surface expression of OX40 is induced by Tax through OX40 promoter upregulation via two NF-B-like elements (Pankow et al., 2000). OX40 ligand (OX40L/gp34) is a type II transmembrane molecule belonging to the tumor necrosis factor family (Baum et al., 1994); it is constitutively expressed on HTLV-1-producing cells but not uninfected resting T-cells. The presence of both, ligand and receptor on the HTLV-transformed cell suggest that costimulatory signals delivered from Ox40 contribute to a transformed phenotype.

Cytokine receptor signals including Jak/STAT

In response to ligand-binding, the IL-2/IL-15 receptor associated Janus tyrosine kinase (JAK3) phosphorylates signal transducer of activated T cells (Stat5a,b) transcription factors that then enter the nucleus and stimulate target gene transcription. Stat5a and Stat5b, essential for the proliferation of normal T cells, are hyper-activated in both HTLV-1-transformed human T-cell lines and lymphocytes from HTLV-1 patients (Migone et al., 1995). In IL-2-independent HTLV cell lines (i.e. HuT-102 and MT-2), this pathway may be functionally redundant since its disruption with AG-490 failed to inhibit cellular proliferation (Kirken et al., 2000). It is of interest that many genes upregulated in HTLV-transformed cells including cyclin D2 and several cytokines are IL-2 target genes and contain Stat5 binding sites in their promoters (Fung et al., 2005).

Tax also stimulates the expression of a growth-inhibiting protein, the transforming growth factor beta 1 (TGF-1). The protein is also overexpressed in ATL cells (Kim et al., 1990) and may function to limit cytotoxicity. However, Tax represses TGF-1 signaling by reducing the DNA-binding activity of transcription factors Smad 3 and Smad 4 (Mori et al., 2001; Arnulf et al., 2002; Lee et al., 2002).

Kinase-cascades

Phosphoinositide 3-kinase (PI3K) and its downstream target Akt are activated in response to cytokine receptors (Kelly-Welch et al., 2003) and the T-cell receptor activation; this pathway provides growth stimulatory and antiapoptotic signals. PI3K-Akt was found activated in HTLV-transformed Rat-1 cells and to be involved in cell transformation (Liu et al., 2001). Currently, it remains unclear how Tax stimulates this pathway.

The ERK-JNK cascade is constitutively activated in Tax-transformed murine fibroblasts, in human lymphocytes transformed in vitro by HTLV-1, and in leukocytes isolated from ATL patients. However, this activation is not induced by Tax alone, and may represent an important late event when infected lymphocytes become IL-2-independent (Xu et al., 1996; Jin et al., 1997).

Stimulation of cell growth through cell cycle dysregulation

A major mitogenic activity of Tax is reflected in its stimulation of G1- to S-phase transition (Neuveut et al., 1998; Schmitt et al., 1998; Neuveut and Jeang, 2002; Liang et al., 2002). In mammalian cells, G1-progression is controlled by the sequential activation of several cyclin-dependent kinases (Cdks), starting with Cdk4, Cdk6 and Cdk2. Tax activates Cdk4, Cdk6 and Cdk2 leading to phosphorylation of the retinoblastoma (Rb) tumor suppressor family proteins and freeing E2F (Schmitt et al., 1998; Iwanaga et al., 2001). Tax can also increase E2F (Ohtani et al., 2000) in part through upregulation of the E2F-1 promoter via an ATF binding site (Lemasson et al., 1998). Several mechanisms may account for Tax's G1-S phase stimulatory action including (1) transcriptional upregulation of cyclin D2, (2) activation of kinases by direct binding of the kinase holoenzyme complex, and (3) repression of Cdk inhibitors (Figure 2).

Figure 2.

Effects of Tax on checkpoint factors at various points of the cell cycle are diagrammed. Tax is shown to affect p53, pRB, E2F, INK4, MAD1, Securin, CDC20, Chk1, p21^Waf1/Cip1, CDK4 and CDK2/cyclin E

Full figure and legend (58K)

Cyclin D binding and upregulation

HTLV-1-infected T-cell lines and patient cells contain increased levels of the early G (1) cyclin, cycD2. (Akagi et al., 1996; Santiago et al., 1999; Iwanaga et al., 2001). The cycD2 expression is also upregulated by IL-2 receptor signals and in part accounts for the T-cell proliferation stimulated by IL-2. The IL-2 receptor induces cycD2 by activating transcription factor Stat5, which binds directly to a cognate site in the cyclin D2 promoter (Martino et al., 2001; Moon et al., 2004; Fung et al., 2005). Tax may cooperate with IL-2-signaling either indirectly through stimulating the expression of IL2R or directly by activating the cycD2 promoter (Huang et al., 1997; Santiago et al., 1999).

Direct binding to Cdk4/6

A further mechanistic explanation for the Cdk4 and Cdk6 activation is provided by the direct and specific interaction of these protein with Tax (Haller et al., 2000; Haller et al., 2002). It has been found that the N-terminus of Tax interacts with Cdk4 (Li et al., 2003). Binding-deficient Tax mutants failed to activate Cdk4, indicating that direct association with Tax is required for enhanced kinase activity. The Tax/Cdk complexes represent active holoenzymes that capably phosphorylate the Rb protein in vitro and are resistant to repression by the p21^Waf1/Cip1 inhibitor. Tax also interacts with the cycD component of the Cdk4/6 holoenzyme leading possibly to hyperphosphorylation of cycD3 (Neuveut et al., 1998; Haller et al., 2002; Neuveut and Jeang, 2002).

Inhibition of CKI function

The expression of p18^INK4c (Akagi et al., 1996), p19^INK4d (Iwanaga et al., 2001) and p27^Kip1 (Iwanaga et al., 2001) is reduced in the presence of Tax. Expression of p18^INK4c is transcriptionally repressed by Tax through the E-box element of the promoter (Suzuki et al., 1999a). By contrast, p21 is strongly upregulated (Akagi et al., 1996; Cereseto et al., 1996). Tax activates the p21^Waf1/Cip1 promoter in p53 null cells, and increases p21^Waf1/Cip1 expression in Jurkat T cells. These findings suggest that Tax is at least partially responsible for the p53-independent expression of p21^Waf1/Cip1 in HTLV-I-infected cells (Cereseto et al., 1996; Chowdhury et al., 2003). p21^Waf1/Cip1 expression may enhance cell survival through its role in the antiapoptotic machinery (Kawata et al., 2003). Separate from transcriptional activation, Tax also binds p16INK4A and p15INK4B, but not p21^Waf1/Cip1 nor p27^Kip1 (Suzuki et al., 1996; Low et al., 1997). Through direct binding, Tax is thought to interfere with CKI's inhibitory roles on Cdk4 and Cdk6 (Suzuki et al., 1999a).

Effects of Tax on tumor suppressors and cellular apoptosis

To transform cells, oncoproteins must defeat the actions of cellular tumor suppressors. HTLV-1 Tax has evolved various strategies to negate at least three cellular tumor suppressors, p53, Rb and hDLG, and their abilities to dictate apoptosis in primary cells.

Tax and p53

p53 is a DNA-binding transcription factor that guards against cellular DNA damage and transformation. The gene for p53 is mutated in roughly 50% of all cancers. Curiously, unlike most other cancers, only a small fraction of ATL cells have p53 mutation. This paradox was elegantly resolved by independent findings that p53 function is inactivated by Tax (Reid et al., 1993; Akagi et al., 1997b; Mulloy et al., 1998; Pise-Masison et al., 1998; Ariumi et al., 2000; Van et al., 2001). What remains incompletely answered is how Tax inactivates p53. Some findings support that Tax abrogates p53 function by competing with it for binding the p300/CBP transcriptional coactivator (Van Orden et al., 1999; Ariumi et al., 2000). An alternative notion is that Tax acts through an NF-B/RelA(p65) pathway to perturb p53 function (Pise-Masison et al., 2000a, 2000b). Two recent papers suggest that neither the NF-B pathway nor the p300/CBP route fully explains Tax's inactivation of p53 (Jeong et al., 2005; Miyazato et al., 2005).

Tax and Rb

In conjunction with p53, Rb is a major tumor suppressor that regulates G1 to S progression. Rb is epigenetically and genetically inactivated in many cancers (Scrable et al., 1990). In cell cycle studies, many have found that Tax accelerate G1 to S transition (Neuveut et al., 1998; Schmitt et al., 1998; Kehn et al., 2004), providing initial clues that HTLV-1 may inactivate Rb function (Hangaishi et al., 1996; Hatta and Koeffler, 2002). There may be two explanations for how HTLV-1 inactivates Rb. First, Tax can directly bind Cdk4 (Haller et al., 2002) and promote the hyperphosphorylation of Rb to inactivate its function (Neuveut et al., 1998). Second, Tax may also directly bind Rb leading to its proteosomal degradation (Kehn et al., 2005).

Tax and DLG

Lee et al. (1997) first demonstrated that the C-terminus of Tax (ETEV-COOH) contains a consensus motif (PBM; i.e. T/SXV-COOH), which binds the PDZ domains of several cellular proteins (Rousset et al., 1998). One of the proteins bound by Tax is human DLG, a homologue of the Drosophila discs large PDZ-containing tumor suppressor. Comparing HTLV-1 and HTLV-2 Tax proteins revealed that the reduced ability of Tax2 to transform cells correlated with a loss of the PBM in its C-terminus (Semmes et al., 1996; Endo et al., 2002). Tax1's interaction with hDLG correlates with its ability to induce colony formation in rat fibroblasts, suggesting a relevant role of this interplay in cellular transformation (Suzuki et al., 1999b; Hirata et al., 2004). A more extensive discussion of the PDZ-binding properties of Tax is found in an accompanying article in this issue (Hall and Fujii, this issue).

Proliferation versus apoptosis

A long-standing cancer paradox is, that over-expression of oncoproteins provide proliferative advantages to cells but can also trigger cellular apoptosis. Oncogenes such as Myc, E1A and E2F-1 all demonstrate such duality, and Tax may share this property. There is evidence that Tax protects cells from stress-induced cell cycle arrest or apoptosis (Copeland et al., 1994; Brauweiler et al., 1997; Torgeman et al., 2001; Kasai and Jeang, 2004), but can also sensitize cells to stress-induced apoptosis (Chlichlia et al., 1995, 1997, 2002; Kao et al., 2000; Kasai and Jeang, 2004). This duality may be because transforming insults induce countervailing responses by the cell's tumor suppressors, which often manifest as cell cycle arrest and/or apoptosis. To transform a cell, an oncoprotein must disable the cell's apoptotic response, and this would explain why Tax exerts antiapoptotic activity perhaps through activation of NF-B (Kawakami et al., 1999). The antiapoptotic effect of Tax may also be mediated by the transcriptional transactivation of cellular regulators of apoptosis such as Bcl-XL, Bfl1 (Bcl-2A1) (Tsukahara et al., 1999; Nicot et al., 2000; De La et al., 2003) and HIAP-1 (Wäldele and Grassmann, unpublished observation). Likely, the choice between proliferation and death is influenced by cellular environment, cell background, and whether the cell's tumor suppressor functions have been defeated (see above). In ATL, these multiple intricacies may account for the long duration required by HTLV-1 to transform cells.

Tax and genetic damage in cells

Cancer cells can have more than 100 000 mutations (Perucho, 1996), some essential to initiating transformation and others for malignant progression. Genetic alterations initiated by Tax could be the trigger for malignant conversion in HTLV infected cells. Below, we summarize how Tax can harm the cell's genomic integrity by inducing structural DNA damage or alter chromosomal stability (Figure 2) (Loeb and Loeb, 2000).

Tax and DNA structural damage

Structurally damaged DNA is frequent in HTLV-1-transformed cells (Marriott et al., 2002; see also Marriott and Semmes, this issue), suggesting the loss of checkpoint and repair functions which normally sense and eliminate such lesions. Indeed, Tax impairs the DNA-damage-induced checkpoint normally operative during G2/M transition (Liang et al., 2002; Haoudi and Semmes, 2003). Tax also represses the expression of DNA polymerase , an enzyme involved in base-excision repair, BER (Jeang et al., 1990). Reduced BER activity is seen in HTLV-1, HTLV-2 and bovine leukemia virus transformed cells (Philpott and Buehring, 1999). Further, Tax independently suppresses a second repair process, nucleotide excision repair (NER), which is normally utilized by cells following UV irradiation (Kao et al., 2001). Finally, chromosomal end-to-end fusion, a mistake common in cancers is also prevalent in HTLV-1 transformed cells. An explanation for the last finding may reside with the role played by telomeric repeats normally added to chromosomal ends and DNA breaks to guard against end-to-end fusions and exonucleolytic degradation. Provocatively, Tax suppresses the expression of human telomerase (hTert; (Gabet et al., 2003)), thus reducing the cell's capacity to add telomeric repeats to double-stranded breaks (DSB) and chromosomal ends (Wilkie et al., 1990; Morin, 1991; Flint et al., 1994). Loss of hTert function can destabilize the repair of DSB (Majone and Jeang, 2000). Consistent with its repression of cell endogenous telomerase, we recently observed that Tax cannot immortalize primary human cells unless exogenous hTert is coexpressed (Sheleg and Jeang, unpublished observation).

Tax and chromosomal instability

Cancers fall into two groups (Loeb and Loeb, 2000): those with structurally damaged chromosomes and those with aberrant chromosome numbers (i.e. aneupoidy and/or polyploidy). Most cancers are aneuploid (Cahill et al., 1998), although it remains arguable whether aneuploidy is a cause, or a consequence, of transformation (Rasnick, 2002). Thus while normal peripheral blood lymphocytes are always diploid, ATL cells are ubiquitously aneuploid (Marriott et al., 2002). The high correlation of ATL cells with aneuploidy, hints at a viral mechanism effectively subverting the cellular checkpoint(s) which guards against chromosomal instability (CIN).

The mitotic spindle assembly checkpoint (SAC; (Musacchio and Hardwick, 2002)) is a guardian of cellular euploidy. Two SAC proteins, MAD1 and MAD2, function as a MAD1–MAD2 heterodimer at kinetochores (Musacchio and Hardwick, 2002) in monitoring for proper chromosomal segregation during mitosis. In a knockout mouse model, it was found that heterozygous loss of just a single MAD2 allele (Michel et al., 2001) heightened the risk for cellular transformation. Although knockout mouse data for MAD1 have yet to be described, there is clinical evidence obtained from two large acute myeloid leukemia (AML) studies that loss of a single MAD1 allele through monosomy of chromosome 7 holds elevated risk for human cancers (Jin et al., 1999b) (Grimwade et al., 1998; Byrd et al., 2002). Although monosomy of the MAD1-encoding chromosome 7 (Jin et al., 1999b) is uncommon in ATL cells, HTLV-1 Tax was found to bind directly MAD1 and repress its function (Jin et al., 1998; Iwanaga et al., 2002). Hence, the direct protein–protein interaction between a viral oncoprotein and a cellular checkpoint protein accomplishes a functional scenario equivalent to monosomy 7. Consistent with their aneuploid status, several ATL cell lines when tested ex vivo demonstrate defective SAC function (Kasai et al., 2002).

SAC loss is a recessive change, which explains cellular tolerance of aneuploidy, but such loss in itself cannot create chromosomal mistakes. The following findings suggest that Tax may trigger chromosomal separation errors in several ways. (1) We find that Tax, like the HPV E7 oncoprotein (Duensing and Munger, 2003), can induce abnormal amplification of cellular centrosomes (Peloponese, Haller and Jeang, unpublished). Centrosomal amplification is seen in diverse tumors, and is considered a frequent first step shared by many cancers in developing CIN (Storchova and Pellman, 2004). Aberrant centrosomal amplification can directly initiate chromosomal missegregation. (2) Tax can promote unscheduled degradation of securin and cyclin B1 most likely through the premature activation of the CDC20-associated anaphase promoting complex (Liu et al., 2005). This can lead to faulty chromosomal segregation and ensuing aneuploidy. (3) There is a paradigm that polyploidy is the precursor to aneuploidy (Margolis et al., 2003). Tax expression frequently engenders multinucleated polyploid cells (Jin et al., 1998; Liang et al., 2002). Additionally, because Tax also inactivates p53 and Rb (Akagi et al., 1997a; Neuveut et al., 1998; Pise-Masison et al., 1998; Takemoto et al., 2000; Van et al., 2001), two factors essential to a G1 tetraploid/polypoid checkpoint (Margolis et al., 2003), it is reasonable that the polyploidy to aneuploidy mechanism can contribute to ATL transformation.

Conclusion

This article summarizes our current, albeit incomplete, understanding of how HTLV-1 transforms cells. In vitro cell transformation assays have clearly assigned a fundamental role to Tax in several important correlates of transformation. Conceptually, it is important to note that initiation and maintenance of transformation are separate processes, which require different biological events. Currently, based on the absence of Tax expression in many late-stage ATL cells, this viral oncoprotein is likely to be needed only for the former but not for the latter. Transformation initiation may start with mitogenic activation by Tax of lymphocytes in G1 with concomitant interference with tumor suppressor function and enhanced survival function (Figure 3). Initiation of transformation then transits to the maintenance of a committed ATL-transformed phenotype, which likely arises from the cell's imprinted damaged genetic content. In this regards, we also propose that Tax plays a role in the creation of damaged DNA in cells. We note that two discrete requirements must be met for damaged DNA to manifest and persist. First, DNA damage must be created, either as a consequence of ambient errors or because Tax induces centrosomal amplification and/or premature APC-degradation of mitotic cyclins. Second, tolerance of created DNA errors must also occur. Tolerance can only happen if checkpoints that monitor and repair errors are extinguished. Thus, initiation of mitogenesis, creation of DNA errors, and inactivation of checkpoints represent a series of linked events overcome by Tax for cellular transformation. The requirement that HTLV-1 surmounts several biological barriers may explain the long latency period required for the virus to engender ATL.

Figure 3.

Progression of T-lymphocytes from immortalization and clonal expansion to transformation. Various changes in the cell during the different stages are listed in the shaded boxes. As shown, virus-infected cells can also go into apoptosis

Full figure and legend (139K)

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Acknowledgements

This work was supported in part by DFG (Grant SFB466-TPC3) and Wilhelm Sander-Stiftung (to RG). We thank Anthony Elmo for assistance with manuscript preparation.