Human T cell leukemia virus type-1 (HTLV-1) is the only retrovirus known to be the etiologic agent of a human cancer, adult T-cell leukemia/lymphoma (ATLL), a highly aggressive cancer of mature T cells. Epidemiological reports suggest that 10 to 20 million people throughout the world are infected with HTLV-1, which is endemic in parts of sub-Saharan Africa, the Caribbean, Japan, and South America . HTLV-1 encodes a regulatory protein, Tax, which is essential for virus replication and plays a significant role in the oncogenic potential of HTLV-1. This chapter will summarize the effects of Tax on cellular processes including transcription, cell cycle checkpoints, and DNA repair, and will discuss how these activities may contribute to its transforming potential.
2. HTLV-1 epidemiology and pathogenesis
HTLV-1 is a type C, complex, enveloped retrovirus belonging to the family
ATLL, a rapidly progressing cancer of mature CD4+ T cells, has been classified into four clinical subtypes:, smoldering, chronic, lymphoma, and acute . Leukemic cells from ATLL patients have a phenotype of CD2+, CD3+, CD4+, CD8-, and HLA-DR+, express high levels of interleukin 2 (IL-2) and its receptor (IL-2R), and frequently have lobulated nuclei, causing them to be referred to as flower cells. Interestingly, these cells are only moderately responsive to IL-2, and HTLV-1 infected T cells proliferate continuously in the absence of exogenous IL-2, a characteristic associated with late stage T-cell transformation . Other members of the deltaretrovirus family have also been linked to proliferative diseases. For instance, sheep infected with BLV develop B-cell leukemia/lymphoma, and the simian counterpart of HTLV-1, STLV-1, induces an ATLL like disease in African green monkeys [15,16]. In contrast, HTLV-2 has not been definitively linked to human cancer and the disease potentials of the newly discovered HTLV-3 and -4 viruses remain unknown [17,18].
2.1. HTLV-1 genome
The HTLV-1 proviral genome is approximately 9 kb in length including flanking long terminal repeats (LTR) composed of U3, R, and U5 regions. HTLV-1 encodes structural (
2.2. Transformation by HTLV-1
Multiple studies have demonstrated that Tax is sufficient for cellular transformation and is important for HTLV-1 mediated tumorigenesis [32-38]. Acute transforming retroviruses rapidly induce tumors by expressing a viral oncogene . In contrast, chronic transforming retroviruses induce tumors at a much slower rate by aberrantly regulating genes upstream or downstream of the proviral insertion site . Neither of these models explains HTLV-1 mediated transformation since no cellular homologue of Tax has been identified and HTLV-1 integration is random. The oncogenic potential of Tax has been extensively characterized in rodent fibroblast cell culture systems, transgenic mouse models, and immortalization and transformation studies in primary human T cells.
One of the first studies to show that Tax could independently transform human T cells used a transformation–defective but replication competent
3. Characterization of Tax-induced tumors in transgenic mouse models
To determine whether Tax plays a role in HTLV-1 induced leukemia/lymphoma, first generation transgenic mouse models expressing Tax under the control of the HTLV-1 LTR were developed, resulting in broad expression of Tax in tissues including thymus, lung, and brain . Interestingly, these mice developed neurofibromas and mesenchymal tumors with visual tumors on the ears, feet, and tail, instead of T cell derived lymphoid tumors, indicating that Tax expression driven by the HTLV-1 promoter leads to neurotropic associated tumor development in this model . To generate a mouse model that more closely recapitulates ATLL, second generation transgenic mice expressed Tax under control of the human granzyme B (GzmB) promoter, which limits transgene expression to CD4+ and CD8+ T lymphocytes (T), natural killer (NK), and lymphokine-activated killer cells . These GzmB-Tax mice developed T-cell lymphomas that expressed high levels of nuclear factor kappa B (NF-κB) . Antisense inhibition of NF-κB expression resulted in tumor regression suggesting that Tax-dependent tumor formation and regression correlate with NF-κB expression . Although GzmB-Tax mice presented with hepatosplenomegaly similar to ATLL patients, they developed large granulocytic leukemia (LGL) indicative of infiltrating neutrophils, basophils, and eosinophils . LGL tumor cells exhibited antibody-dependent cellular cytotoxicity, a primary function of NK-cells, and did not express T-lymphocyte markers, thus these tumors were derived from malignant NK cells [42,44]. Although GzmB-Tax mice did not develop T-cell leukemia/lymphoma, this model demonstrated that limiting Tax expression to the lymphoid compartment could drive lymphomagenesis.
Third generation transgenic mice expressed Tax under the control of the Lck promoter, which restricts expression to developing thymocytes . At 10 months of age, Lck-Tax transgenic mice developed swollen and enlarged spleens, livers, and lymph nodes, recapitulating clinical features observed in patients with ATLL, and presented with large mesenteric tumors . These mice displayed skin ulcerations involving infiltration of leukemic cells in to the dermis, and lymphoma cells from these tumors had a “flower-like” morphology consistent with ATLL cells . Engraftment of these tumor cells into SCID mice led to the development of an aggressive and rapidly progressing leukemia resulting in death within 28 days, similar to the aggressive nature of ATLL . Although Lck-Tax mice recapitulate the clinical features of ATLL, isolated tumor cells were CD25+, CD44+, CD69+, but CD4-/CD8- double negative, indicating that the lymphomas were derived from malignant transformation of immature T cells . In this model restriction of Tax expression to the T cell compartment produced transgenic mice having clinical features of ATLL however, the absence of CD4+ lymphomas and continued expression of Tax in the tumor cells does not precisely model ATLL in these mice.
HTLV-1 humanized SCID mice (HTLV-1-Hu-SCID) were generated by reconstituting hematopoiesis in non-obese SCID mice using human CD34+ hematopoietic progenitor stem cells (HPSCs) infected with HTLV-1 . Within 12-20 weeks of reconstitution, the Hu-SCID mice developed CD4+ T cell lymphomas with clinical and histopathological features similar to ATLL and Lck-Tax transgenic mice [45,46]. Isolated tumor cells expressed HTLV-1 Gag, CD25, CD4, and CD8 proteins, demonstrating that the tumor cells originated from malignant transformation of mature T cells . Additionally, Hu-SCID mice generated using HPSCs infected with a lentiviral vector expressing Tax (Tax-Hu-SCID) developed monoclonal CD4+ tumors suggesting that reconstituting mice with a human hematopoietic system drives Tax-mediated lymphomagenesis of mature T cells . The HTLV-1 infected Hu-SCID mouse model provides a promising tool with which to assess the development and progression of HTLV-1-induced CD4+ T cell lymphomas.
4. Molecular mechanisms of Tax mediated transformation
4.1. Regulation of CREB and NFκB pathways by Tax
Since multiple studies have shown that Tax is sufficient for cellular transformation and is important for HTLV-1 mediated lymphomagenesis [32-38] much effort has been invested into understanding the molecular mechanisms that drive Tax-mediated transformation and tumorigenesis. Microarray analysis of HTLV-1 infected and Tax transfected cells demonstrated genome-wide changes in cellular gene expression patterns including changes in the expression of genes that control proliferation, cell cycle checkpoints, apoptosis, and transcription, suggesting potential pathways through which Tax might function to modulate normal cellular responses [47,48]. Extensive mutational analysis of Tax revealed the presence of a nuclear localization signal, nuclear export signal, and activation domains specific for the NF-κB and cAMP-responsive element binding protein (CREB) pathways [49-51]. Tax does not bind DNA but, interacts with cellular proteins to modulate at least three major transcription factor pathways NF-κB, CREB, and serum response factor (SRF) pathways, of which the CREB and NF-κB pathways have been most extensively studied [52-62] and shown to be essential for Tax-mediated transformation.
Modulation of the CREB pathway by Tax is important for transcriptional activation of the HTLV-1 promoter (LTR). The HTLV-1 LTR contains three non-palindromic 21-bp repeats called Tax responsive elements (TRE). Each TRE contains a core CRE sequence flanked by GC-rich sequences, which are required for Tax-mediated transactivation. Under normal physiological conditions, CREB activation is initiated by growth factor stimulated phosphorylation of the kinase inducible domain (KID) of CREB followed by CREB dimerization and recruitment of the CREB binding protein (CBP) through its KID interaction KIX domain [63,64]. The CBP-CREB complex then binds to palindromic CREs to activate transcription of CREB-dependent genes. In Tax expressing cells, Tax interacts with CREB to enhance CREB dimerization and selectively increase the binding affinity of CREB for the viral TRE, which is mediated by the flanking GC rich regions [65-67]. Tax also interacts with the KIX domain of CBP and its homologue p300 to enhance their recruitment to the Tax-CREB-TRE ternary complex, thereby stabilizing the complex and activating viral gene expression in the absence of CREB phosphorylation [67-71]. Thus, Tax can bypass cAMP signaling mediated activation of CREB and induce preferential binding of CREB to the viral LTR rather than to cellular CREs. These results emphasize the importance of the CREB pathway for viral gene expression [54,66,70,70,71,71]
Tax regulation of cellular gene expression through the NF-κB pathway results in cell proliferation, resistance to apoptosis, and maintenance of malignant transformation. In a resting cell, NF-κB is sequestered in the cytoplasm in an inactive complex with inhibitor of kappa B (IκB), which prevents activation of NF-κB -dependent genes . External growth factor stimulation initiates a signaling cascade that induces phosphorylation of IκB by IκB kinase (IKK), resulting in ubiquitination, and subsequent degradation of IκB, which then releases NF-κB to translocate to the nucleus and activate NF-κB-dependent gene expression. Tax disrupts NF-κB regulation by several mechanisms. First, cytoplasmic Tax increases phosphorylation and subsequent degradation of IκBα by forming a ternary complex containing NF-κB essential modulator (NEMO), IKKγ, Tax, and PP2A that blocks deactivation of IKK [73-76]. Constitutively active IKK results in persistent IκB degradation and translocation of NF-κB to the nucleus. Second, nuclear Tax interacts with NF-κB on promoters resulting in constitutive activation of NF-κB dependent genes [77,78]. Persistent degradation of IκB and constitutive activation of NF-κB dependent genes leads to persistent activation of the NF-κB pathway in HTLV-1 infected, and Tax-expressing cells . Upregulation of NF-κB-dependent genes including, but not limited to key T cell activators (IL-2, high affinity IL-2R alpha subunit, and IL-15) is required for immortalization and survival of HTLV-1 transformed cells, setting the stage for neoplastic conversion of a normal T cell [53,60,80]
4.2. CREB and NF-κB pathways in Tax-mediated transformation
A Tax mutant (M47) that is defective for activation of CREB-dependent genes did not induce loss of contact inhibition or anchorage independent growth in Rat 2 cells and failed to induce tumors in nude mice , suggesting that activation of the CREB pathway is required to establish Tax-induced tumors. In the same study, a Tax mutant (M22) that is defective for NF-κB activation did transform Rat 2 cells in vitro and induce tumors in athymic mice similar to wild-type Tax, indicating that NF-κB activation is not required to initiate Tax-mediated tumorigenesis . In a different study, a
5. Effect of Tax on genome stability
5.1. Disruption of DNA repair pathways by Tax
DNA repair and cell cycle progression are tightly linked and involve multiple overlapping pathways that ensure error-free inheritance of genetic material. If a cell incurs extensive DNA damage that cannot be repaired, it will undergo apoptosis or enter a state of replicative senescence. Tax disrupts DNA repair by modulating the functions of key DNA repair enzymes and disrupting the DNA damage response (DDR), resulting in an increased mutation frequency in Tax-expressing cells [83,84]. Cellular DNA damage is repaired by four functionally overlapping pathways that respond to different types of DNA alterations; mismatch repair (MMR) base excision repair (BER), nucleotide excision repair (NER), and double strand break repair (DSBR) . The suppression or disruption of BER, NER or DSBR by Tax appears to contribute to its cellular transformation activity.
BER is initiated by a glycosylase that recognizes helical distortions and flips out the base promoting recruitment of a major repair enzyme, DNA polymerase beta (pol β) [86,87]. Tax has been shown to repress pol β transcription [88,89]. The decreased availability of pol β would reduce the efficient repair of DNA lesions that arise from reactive oxygen species and depurination events consistent with increased mutagenesis of the host genome.
The NER pathway preserves genome stability by scanning for and repairing UV- and chemically-induced bulky adducts . Proliferating cell nuclear antigen (PCNA) is a trimeric sliding clamp that assists in DNA synthesis during DNA replication and repair, by increasing the processivity of DNA polymerase delta (pol δ) to fill in the gap after lesion excision [85,90,91]. In the presence of DNA lesions, elevated levels of p21Cip1/waf1 interact with PCNA to block DNA replication without blocking PCNA-dependent DNA repair . Tax activates PCNA gene expression , which may allow Tax-expressing cells to overwhelm the p21Cip1/waf1-induced replication block and continue DNA replication in the presence of damage, resulting in misincorporation of DNA nucleotides [94,95]. Thus, Tax appears to suppress NER and promote genome instability by increasing the cellular mutation rate.
Unlike NER and BER, less is known about effects of Tax on the DSBR pathway. Double strand DNA breaks (DSBs) are sensed by ataxia telangiectasia mutated (ATM) kinase, which phosphorylates downstream DNA damage checkpoint regulators such as H2AX, Chk2, p53, Nbs1 and MDC1 that function together to arrest the cell cycle and repair DNA . ATM signaling also promotes the recruitment of Ku70 and Ku80 hetereodimers to free DNA ends to facilitate DNA end joining. Tax has been shown to repress Ku80 gene expression, which may impact the cell’s ability to recognize and repair free DNA ends [97,98]. In addition, the phosphorylation of ATM targets (H2AX, Chk2 and Nsb1) and ATM autophosphorylation is reduced in Tax-expressing cells, which attenuates the DDR, causing these cells to be released from the S-phase checkpoint while DSBs remain [99-101]. Cells that undergo mitosis in the presence of DSBs frequently form micronuclei (MN), which are markers of genome instability and interestingly, Tax-expressing cells exhibit significantly more micronuclei than control cells . Since, the response to DNA damage and the initiation of DNA repair are tightly linked, the effect of Tax on early cellular processes such as ATM-mediated DNA damage signaling, translates to defects in later processes including cell cycle checkpoints and DNA repair, creating an environment that promotes cellular transformation as shown in Figure 1.
5.2. Impact of Tax on cell cycle regulation
Under normal conditions, eukaryotic cells undergo growth and division resulting in the passage of genetic information, which is essential for survival. Eukaryotic cell division is controlled by four distinct phases: cell growth (G1, and G2), DNA synthesis (S), and mitosis (M). Critical cell cycle checkpoints (G1/S, G2/M, and M) can be activated to block cell cycle progression and ensure accurate DNA replication and chromosome distribution. Specific complexes containing cyclins, cyclin-dependent kinases (CDK), CDK inhibitors (CKIs), and tumor suppressor proteins work together to maintain genome integrity and prevent uncontrolled proliferation.
Prior to entering G1, mitogenic stimulation increases the levels of type D (D1, D2, and D3) and E (E1, E2) cyclins. During early G1 of a normal cell, active D-CDK4/6 complexes phosphorylate the tumor suppressor retinoblastoma (Rb), allowing release of transcription factor E2F and subsequent activation of S phase genes . At this stage, cells are committed to entering S phase where the E-CDK2 complex phosphorylates substrates needed for S phase. Tax expression accelerates progression through G1 by activating the transcription of genes encoding D cyclins, which directly interact with D-CDK4/6 to enhance Rb phosphorylation [103-105]. Following its release and translocation to the nucleus, E2F interacts with Tax to transcribe E2F-dependent S phase genes . These transcriptional effects, and modulation of CDK complexes propel Tax-expressing cells through G1 and force early entry into S phase [104-106].
During the transition from G1 to S, cells pass through a checkpoint regulated by p53. The tumor suppressor p53 protects cells from transformation by activating the expression of cell cycle control proteins  that mediate cell cycle arrest or apoptosis in response to various cellular stresses, including DNA damage. In the presence of DNA damage, p53 arrests the cell cycle by activating the CKI p21waf1/cip1, which binds and inactivates CDK2. Therefore, overexpression of p21waf1/cip1 induces cell cycle arrest and prevents progression into S-phase until DNA is repaired. p21waf1/cip1 also binds to and stabilizes the cyclin D-CDK4/6 complex, leading to increased kinase activity and cell cycle progression, which is consistent with p21waf1/cip1 overexpression in Tax-transfected and HTLV-1 transformed cells [108,109]. In addition, Tax-expressing cells display a shortened G1 phase followed by early S-phase entry, suggesting that the G1/S checkpoint is deregulated to avoid p21waf1/cip1 induced cell cycle arrest . Tax mediated overexpression of p21waf1/cip1 may contribute to transformation by accelerating the progression of cells through G1 and disrupting the DNA damage-induced G1/S checkpoint [108,111,112].
Further disruption of the G1/S checkpoint occurs by Tax-mediated inactivation of p53. Tax and p53 have been shown to directly compete for binding to the coactivator CBP/p300, thus p53-dependent transcription could be compromised in Tax-expressing cells [113-115]. Tax has also been shown to suppress p53 function by inducing hyperphosphorylation of p53 at Ser15 and Ser392, preventing p53 from interacting with the basal transcription machinery [116,117]. In supporting studies, Tax mutants defective in NF-κB activation failed to suppress p53-mediated transcription [117,118]. Thus, the transcriptional activity of Tax affects p53 regulation of cell cycle checkpoints, DDR and DNA repair, thereby altering the cell’s response to internal and external stress stimuli.
Although p53 and p21waf1/cip1 prevent unchecked proliferation and genome stability, additional CKIs prevent replication of damaged DNA by inhibiting cyclin-CDK interactions [119,120]. Tax regulates the function of cyclin-CDK complexes by disrupting the inhibitory activities of CDK4 (INK4) inhibitors p15INK4b (p15), p16INK4a (p16), p18INK4c (p18), and p19INK4d (p19), which share overlapping functions to regulate G1 entry and progression. Before entering G1 external anti-growth factors such as transforming growth beta (TGF-β) can stimulate cell cycle exit by inducing the binding of p15 to D-CDK4/6 complexes, thereby promoting the degradation of D cyclins . Because a decrease in active D-CDK4/6 complexes prevents cell cycle progression, cellular mechanisms to promote cyclin D overexpression could antagonize p15-mediated arrest. Specifically, the overexpression of D-cyclins and p21waf1/cip1 in Tax expressing cells correlates with increased cell proliferation, consistent with cell cycle progression in the presence of genome instability. Tax also binds to p16 and suppresses its inhibitory function by allowing cyclin D1 to form active complexes with CDK4/6. Inhibition of p15 and p16 by Tax increases the pool of active D-CDK4/6 complexes resulting in continuous Rb phosphorylation and leading to S phase entry [122,123]. Lastly, Tax represses transcription of p18INK4c, and p19INK4d, again linking Tax-mediated transcription with cell cycle deregulation [112,122-125]. Cumulative effects of Tax on the G1 and the G1/S checkpoints contribute to Tax mediated transformation by continuously promoting cell growth and proliferation in the absence of growth factors.
During S phase, cyclin A-CDK2 begins to accumulate after the G1/S transition, and is required both to complete S phase and to enter and exit from M phase. HTLV-1 infected cells express low levels of cyclin A because Tax represses cyclin A transcription in a CREB-ATF-dependent manner . Reduced cyclin A levels also promote early egress from mitosis and disrupt the G2/M checkpoint, producing the types of chromosomal abnormalities observed in ATLL and HTLV-1 transformed cells [127-135].
When cells sense DNA-damage prior to mitosis the G2/M DNA-damage checkpoint is activated through two DNA damage sensors ATM and ATR, which phosphorylate downstream effectors such as p53, and checkpoint kinases 1 and 2 (Chk1 and Chk2). These downstream effectors phosphorylate downstream substrates to induce cell cycle arrest. Following DNA damage, phosphorylation of Cdc25A by Chk1 targets it for proteasomal degradation, thereby inhibiting activation of the Cdk1/2 complex, which is required to progress through the S and G2/M checkpoints. Chk1 also phosphorylates p53 and CDC25A/C to induce G1 and G2/M arrest, respectively. In response to gamma irradiation, Tax interacts with Chk1 and inhibits its kinase activity, thereby disrupting the G1 and G2/M checkpoints and allowing cells to proceed to mitosis in the presence of DNA damage . Interestingly, Tax prevents the release of Chk2 from chromatin after activation by ATM/ATR, thereby preventing phosphorylation of downstream effectors like p53 . Tax disruption of cell cycle regulation and abrogation of the DNA damage response contributes to the proliferation of cells containing DNA damage.
After transiting the G2/M checkpoint, the cell encounters one last critical checkpoint known as the mitotic spindle checkpoint (MSC). The MSC regulates cell cycle transition from metaphase to anaphase, and its disruption is associated with altered chromosome structures and numbers . HTLV-1 infected/transformed cells and ATLL cells display chromosomal abnormalities including deletions, insertions, rearrangements and translocations, suggesting that Tax disrupts the MSC [127-135,139,140]. The direct interaction of Tax with MAD-1 and APC interferes with proper chromosome alignment along the metaphase plate resulting in the potential loss or gain of genetic material and early exit from mitosis [141,142]. The intimate linkage between the DDR and DNA repair expands the effects of Tax on normal cell proliferation by targeting cell modulators, such as p53, that function in multiple cellular processes.
6. Conclusions and perspectives
The progression from HTLV-1 infection to the development of ATLL is complicated and not fully understood. The long clinical latency between infection and disease progression makes HTLV-1 an interesting and useful model in which to study multistep oncogenesis . After initial infection, viral proteins including Tax promote viral replication and aid in virus dissemination. HTLV-1 manipulates normal cellular processes to ensure successful replication of the viral genome, which requires entry into and completion of S phase of the cell cycle. Tax inactivates tumor suppressors, interacts with cellular proteins to deregulate cellular gene expression and cell cycle regulation, and inhibits the DDR and apoptosis, all in an effort to disable cell cycle checkpoints and promote cell cycle progression regardless of long-term consequences to the cell (Figure 1). Although the virus remains integrated into the host genome for the life of the host, the virus can successfully replicate and disseminate to other host cells in a matter of days. Thus, accumulation of genetic insults is of little consequence to the virus. Indeed, these insults can be considered an unintended consequence of successful viral replication and dissemination. The ability of Tax to increase the overall cellular mutation rate sets the stage for the development of ATLL. While the effects of Tax on cellular processes are well studied, gaps remain in our understanding of how Tax influences cellular functions due to the interconnectedness of these functions. Advances in animal model systems and experimental systems to study Tax function will help to reveal the complex effects of Tax on interplay between cellular function networks and will increase our ability to identify the key steps involved in HTLV-1 induced leukemogenesis.
Global epidemiology of HTLV-I infection and associated diseases. Oncogene Proietti F. A Carneiro-proietti A. B Catalan-soares B. C Murphy E. L 2005 24 6058 6068
Adult T-cell leukemia: antigen in an ATL cell line and detection of antibodies to the antigen in human sera. Proc Natl Acad Sci U S A Hinuma Y Nagata K Hanaoka M et al 1981 78 6476 6480
Isolation and characterization of retrovirus from cell lines of human adult T-cell leukemia and its importance in the disease. Proc Natl Acad Sci USA Yoshida M Miyoshi I Hinuma Y 1982 79 2031 2035
Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci U S A Poiesz B. J Ruscetti F. W Gazdar A. F et al 1980 77 7415 7419
Antibodies to human T-lymphotropic virus type I in patients with tropical spastic paraparesis. Lancet Gessain A Barin F Vernant J. C et al 1985 2 407 409
HTLV-I associated myelopathy, a new clinical entity. Lancet Osame M Usuku K Izumo S et al 1986 1031 1032
Intrafamilial transmission of adult T-cell leukemia virus. J Infect Dis Kajiyama W Kashiwaga S Ikematsu H et al 1986 154 851 857
Male-to-female transmission of human T-cell lymphotropic virus types I and II: association with viral load. The Retrovirus Epidemiology Donor Study Group. J Acquir Immune Defic Syndr Hum Retrovirol Kaplan J. E Khabbaz R. F Murphy E. L et al 1996 12 193 201
Sexual transmission of human T-lymphotropic virus type I (HTLV-I). Ann Intern Med Murphy E. L Figueroa J. P Gibbs W. N et al 1989 111 555 560
10 Immunological risks of adult T-cell leukemia at primary HTLV-I infection. Trends Microbiol Kannagi M Ohashi T Harashima N et al 2004 12 346 352
Mother-to-child transmission of human T-cell-leukemia/lymphoma virus type I: implication of high antiviral antibody titer and high proviral load in carrier mothers. Int J Cancer Ureta-vidal A Angelin-duclos C Tortevoye P et al 1999 82 832 836
Mother-to-child transmission of human T-cell lymphotropic virus type 1 (HTLV-1) in Jamaica: association with antibodies to envelope glycoprotein (gp46) epitopes. J Acquir Immune Defic Syndr Hum Retrovirol Wiktor S. Z Pate E. J Murphy E. L et al 1993 6 1162 1167
The human T-cell leukemia virus type 1 (HTLV-1): new insights into the clinical aspects and molecular pathogenesis of adult T-cell leukemia/lymphoma (ATLL) and tropical spastic paraparesis/HTLV-associated myelopathy (TSP/HAM). Microsc Res Tech Shuh M Beilke M 2005 68 176 196
Human T cell leukemia/lymphoma virus type I infection of a CD4+ proliferative/cytotoxic T cell clone progresses in at least two distinct phases based on changes in function and phenotype of the infected cells. J Immunol Yssel H Duc DMD, De Waal M. R et al 1989 142 2279 2289
Simian T cell leukemia virus type I-induced malignant adult T cell leukemia-like disease in a naturally infected African green monkey: implication of CD8+ T cell leukemia. AIDS Res Hum Retroviruses Akari H Ono F Sakakibara I et al 1998 14 367 371
Mechanisms of leukemogenesis induced by bovine leukemia virus: prospects for novel anti-retroviral therapies in human. Retrovirology Gillet N Florins A Boxus M et al 2007
HTLV-3/STLV-3 and HTLV-4 viruses: discovery, epidemiology, serology and molecular aspects. Viruses Mahieux R Gessain A 2011 3 1074 1090
Ancient origin and molecular features of the novel human T-lymphotropic virus type 3 revealed by complete genome analysis. J Virol Switzer W. M Qari S. H Wolfe N. D et al 2006 80 7427 7438
Human T Lymphotropic Virus Type 1 (HTLV-1): Molecular Biology and Oncogenesis. Viruses Kannian P Green P. L 2010 2 2037 2077
Molecular mechanisms of human T-cell leukemia/lymphotropic virus type I infection. Blood Franchini G 1995 86 3619 3639
Orf-I and orf-II-encoded proteins in HTLV-1 infection and persistence. Viruses Edwards D Fenizia C Gold H et al 2011 3 861 885
Functional role of pX open reading frame II of human T-lymphotropic virus type 1 in maintenance of viral loads in vivo. J Virol JID- 0113724 Bartoe J. T Albrecht B Collins N. D et al 2000 74 1094 1100
Selective ablation of human T-cell lymphotropic virus type 1 Collins N. D Newbound G. C Albrecht B et al 12Ireduces viral infectivity in vivo. Blood JID- 7603509 1998
Human T-cell leukemia virus type 1 pX-I and pX-II open reading frames are dispensable for the immortalization of primary lymphocytes. J Virol Robek M. D Wong F. H Ratner L 1998 72 4458 4462
Human T-cell lymphotropic virus type 1 open reading frame II-encoded Silverman L. R Phipps A. J Montgomery A et al 30IIis required for in vivo replication: evidence of in vivo reversion. J Virol 2004
Human T-cell leukemia virus type 1 expressing nonoverlapping tax and rex genes replicates and immortalizes primary human T lymphocytes but fails to replicate and persist in vivo. J Virol Younis I Yamamoto B Phipps A Green P. L 2005 79 14473 14481
Cellular transformation by the HTLV-I Tax protein, a jack-of-all-trades. Oncogene Gatza M. L Watt J. C Marriott S. J 2003 22 5141 5149
A deletion in the proximal untranslated pX region of human T-cell leukemia virus type II decreases viral replication but not infectivity in vivo. Blood JID- 7603509 Cockerell G. L Rovnak J Green P. L Chen I. S 1996 87 1030 1035
The Rex regulatory protein of human T-cell lymphotropic virus type 1 binds specifically to its target site within the viral RNA. Proc Natl Acad Sci USA Unge T Solomin L Mellini M et al 1991 88 7145 7149
The complementary strand of the human T-cell leukemia virus type 1 RNA genome encodes a bZIP transcription factor that down-regulates viral transcription. J Virol Gaudray G Gachon F Basbous J et al 2002 76 12813 12822
Human T-cell leukemia virus type-1 antisense-encoded gene, Hbz, promotes T-lymphocyte proliferation. Blood Arnold J Zimmerman B Li M et al 2008 112 3788 3797
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 USA Grassmann R Dengler C Muller-fleckenstein I et al 1989 86 3551 3355
Role of human T-cell leukemia virus type I X region proteins in immortalization of primary human lymphocytes in culture. J Virol Grassmann R Berchtold S Radant I et al 1992 66 4570 4575
A transgenic mouse model for human neurofibromatosis. Science Hinrichs S. H Nerenberg M Reynolds R. K et al 1987 237 1340 1343
The tat gene of human T-lymphotropic virus type I induces mesenchymal tumors in transgenic mice. Science Nerenberg M Hinrichs S. H Reynolds R. K et al 1987 237 1324 1329
Type I human T cell leukemia virus Tax protein transforms rat fibroblasts through the cyclic adenosine monophosphate response element binding protein/activating transcription factor pathway. J Clin Invest Smith M. R Greene W. C 1991 88 1038 1042
Oncogenic transformation by the tax gene of human T cell leukemia virus type I in vitro. Proc Natl Acad Sci USA Tanaka A Takahashi G Yamaoka S et al 1990 87 1071 1075
Tax protein of human T-cell leukemia virus type I is required for maintenance of the transformed phenotype. Oncogene Yamaoka S Tobe T Hatanaka M 1992 7 433 437
Identification of a transformation-specific antigen induced by an avian sarcoma virus. Nature Bruge J. S Erickson R. L 1977 269 346 348
A common site for immortalizing proviral integrations in Friend erythroleukemia: molecular cloning and characterization. J Virol Paul R Schuetze S Kozak S. L Kabat D 1989 63 4958 4961
The human T lymphotropic virus I tax gene can cooperate with the ras oncogene to induce neoplastic transformation of cells. Mol Cell Biol Pozzati R Vogel J Jay G 1990 10 413 417
Development of leukemia in mice transgenic for the tax gene of human T-cell leukemia virus type I. Proc Natl Acad Sci USA Grossman W. J Kimata J. T Wong F. H et al 1995 92 1057 1061
Ablation of transplanted HTLV-I Tax-transfoprmed tumors in mice by antisense inhibition of NF-kB. Science Kitajima I Shinohara T Bilakovics J et al 1992 258 1792 1795
Cytokine expression and tumorigenicity of large granular lymphocytic leukemia cells from mice transgenic for the tax gene of human T-cell leukemia virus type I. Blood Grossman W. J Ratner L 1997 90 783 794
Thymus-derived leukemia-lymphoma in mice transgenic for the Tax gene of human T-lymphotropic virus type I. Nat Med Hasegawa H Sawa H Lewis M. J et al 2006 12 466 472
Adult T-cell leukemia/lymphoma development in HTLV-1-infected humanized SCID mice. Blood Banerjee P Tripp A Lairmore M. D et al 2010 115 2640 2648
Ng PWPIha H, Iwanaga Y, et al. Genome-wide expression changes induced by HTLV-1 Tax: evidence for MLK-3 mixed lineage kinase involvement in Tax-mediated NF-kappa B activation. Oncogene 2001 20 4484 4496
Human T-lymphotropic virus type I Tax protein utilizes distinct pathways for Pise-masison C. A Mahieux R Radonovich M et al 53inhibition that are cell type-dependent. J Biol Chem 2001
Definition of a minimal activation domain in human T-cell leukemia virus type I Tax. J Virol Semmes O. J Jeang K-T 1995 69 1827 1833
Identification of HTLV-I tax trans-activator mutants exhibiting novel transcriptional phenotypes. Genes Dev Smith M. R Greene W. C 1990 4 1875 1885
Characterization of a novel nuclear localization signal in the HTLV-I tax transactivator protein. Virology Smith M. R Greene W. C 1992 187 316 320
Distinct regions in human T-cell lymphotropic virus type I Tax mediate interactions with activator protein CREB and basal transcription factors. J Virol Adya N Giam C. Z 1995 69 1834 1841
HTLV-1 Tax induces cellular proteins that activate the kB element in the IL-2 receptor gene. Science Ballard D. W Bohnlein E Lowenthal J. W et al 1988 241 1652 1655
Transactivation by the human T-cell leukemia virus Tax protein is mediated through enhanced binding of ATF-2 and CREB. J Biol Chem Franklin A. A Kubik M. F Uittenbogaard M. N et al 1993 268 21225 21231
HTLV-I Tax induces expression of various immediate early serum responsive genes. Oncogene Fujii M Niki T Mori T et al 1991 6 1023 1029
HTLV-I Tax has distinct but overlapping domains for transcriptional activation and for enhancer specificity. Oncogene Fujii M Tsuchiya H Seiki M 1991 6 2349 2352
Interaction of HTLV-I Tax1 with Fujii M Tsuchiya H Chuhjo T et al 67SRFcauses the aberrant induction of cellular immediate early genes through CArG boxes. Genes Dev 1992
Kinetic analysis of human T-cell leukemia virus type I tax- mediated activation of NF-kappaB. Mol Cell Biol Kanno T Brown K Franzoso G Siebenlist U 1994 14 6443 6451
Novel interactions between human T-cell leukemia virus type I Tax and activating transcription factor 3 at a cyclic AMP-responsive element. Mol Cell Biol Low K. G Chu H. M Tan Y et al 1994 14 4958 4974
Cellular transcription factors and regulation of IL-2 receptor gene expression by HTLV-I tax gene product. Science Ruben S Poteat H Tan T et al 1988 241 89 92
Human T-cell leukemia virus type 1 Tax enhances serum response factor DNA binding and alters site selection. J Virol Winter H. Y Marriott S. J 2007 81 6089 6098
Multiple viral strategies of HTLV-1 for dysregulation of cell growth control. Annu Rev Immunol Yoshida M 2001 19 475 96
Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell Gonzalez G. A Montminy M 1989 59 675 680
Kwok RPS, Lamb N, et al. Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature Chrivia J. C 1993 365 855 859
Expansion of CREB’s DNA recognition specificity by Tax results from interaction with Ala-Ala-Arg at positions 282-284 near the conserved DNA-binding domain of CREB. Proc Natl Acad Sci USA Adya N Zhao L. J Huang W et al 1994 91 5642 5646
Kwok RPSLaurance ME, Lundblad JR, et al. Control of cAMP-regulated enhancers by the viral transactivator Tax through CREB and the co-activator CBP. Nature 1996 380 642 646
A molecular mechanism for human T-cell leukemia virus latency and Tax transactivation. J Biol Chem Brauweiler A Garl P Franklin A. A et al 1995 270 12814 12822
Differential transcriptional activation by human T-cell leukemia virus type 1 Tax mutants is mediated by distinct interactions with CREB binding protein and Bex F Yin M. J Burny A Gaynor R. B 300Mol Cell Biol 1998
Regulation of gene expression by HTLV-I Tax protein. Methods: a companion to Methods in Enzymology Bex F Gaynor R 1998 16 83 94
Anchoring of CREB binding protein to the human T-cell leukemia virus type 1 promoter: A molecular mechanism of tax transactivation. Mol Cell Biol Giebler H. A Loring J. E Van Orden K et al 1997 17 5156 5164
An exposed KID-like domain in human T-cell lymphotropic virus type 1 Tax is responsible for the recruitment of coactivators CBP/ Harrod R Tang Y Nicot C et al 300Mol Cell Biol 1998
Shaping the nuclear action of NF-kappaB. Nat Rev Mol Cell Biol Chen L. F Greene W. C 2004 5 392 401
Tax protein of HTLV-1 destabilizes the complexes of NF-kappa B and I kappa B-alpha and induces nuclear translocation of NF-kappa B for transcriptional activation. Oncogene Suzuki T Hirai H Murakami T Yoshida M 1995 10 1199 1207
DiDonato JK, Hawiger J, Ballard DW. The tax oncoprotein of human T-cell leukemia virus type 1 associates with and persistently activates IkappaB kinases containing IKKÃ and IKKÃ¡. J Biol Chem Chu Z. L 1998 273 15891 15894
IKKgamma mediates the interaction of cellular IkappaB kinases with the tax transforming protein of human T cell leukemia virus type 1. J Biol Chem Chu Z. L Shin Y. A Yang J. M et al 1999 274 15297 15300
Human T-lymphotropic virus type I Tax activates I-kappa B kinase by inhibiting I-kappa B kinase-associated serine/threonine protein phosphatase 2A. J Biol Chem Fu D. X Kuo Y. L Liu B. Y et al 2003 278 1487 1493
Coupling of a signal response domain in I kappa B alpha to multiple pathways for NF-kappa B activation. Mol Cell Biol Brockman J. A Scherer D. C Mckinsey T. A et al 1995 15 2809 2818
HTLV-I encoded Tax in association with NF-kappaB precursor Watanabe M Muramatsu M Hirai H et al 105enhances nuclear localization of NF-kappaB p50 and p65 in transfected cells. Oncogene 1993
NF-kappa B activity in T cells stably expressing the Tax protein of human T cell lymphotropic virus type I. Virology Lacoste J Cohen L Hiscott J 1991 184 553 562
Immortalization of CD4 + and CD8 + T lymphocytes by human T- cell leukemia virus type 1 Tax mutants expressed in a functional molecular clone. J Virol Robek M. D Ratner L 1999 73 4856 4865
A human T-cell leukemia virus Tax variant incapable of activating NF- K B retains its immortalizing potential for primary T-lymphocytes. J Biol Chem Rosin O Koch C Schmitt I et al 1998 273 6698 6703
Constitutive activation of NF-kB is essential for transformation of rat fibroblasts by the human T-cell leukemia virus type I Tax protein. EMBO J Yamaoka S Inoue H Sakurai M et al 1996 15 873 887
Suppression of DNA Repair by HTLV-I Tax correlates with Tax transactivation of PCNA gene expression. AIDS Res Hum Retroviruses Lemoine F. J Kao S. Y Marriott S. J 2000 16 1623 1627
Trans-activator Tax of human T-cell leukemia virus type 1 enhances mutation frequency of the cellular genome. Virology Miyake H Suzuki T Hirai H Yoshida M 1999 253 155 161
MOLECULAR MECHANISMS OF MAMMALIAN DNA REPAIR AND THE DNA DAMAGE CHECKPOINTS. Annu Rev Biochem Sancar A Lindsey-boltz L. A Unsal-kaccmaz K Linn S 2004 73 39 85
Requirement of mammalian DNA polymerase-beta in base-excision repair. Nature Sobol R. W Horton J. K Kuhn R et al 1996 379 183 186
Which DNA polymerases are used for DNA-repair in eukaryotes? Carcinogenesis Wood R. D Shivji M. K 1997 18 605 610
Defective DNA repair in cells with human T-cell leukemia bovine leukemia viruses: Role of tax gene. J Natl Cancer Inst Philpott S. M Buehring G. C 1999 91 933 942
HTLV-I trans-activator protein, Tax, is a trans-repressor of the human β-polymerase gene. Science Jeang K. T Widen S. G Semmes O. J Wilson S. H 1990 247 1082 1084
Proliferating cell nuclear antigen facilitates excision in long- patch base excision repair. J Biol Chem Gary R Kim K Cornelius H. L et al 1999 274 4354 4363
Excision of deoxyribose phosphate residues by DNA polymerase beta during DNA repair. Science Matsumoto Y Kim K 1995 269 699 702
Differential effects by the Li R Waga S Hannon G. J et al 21CDK inhibitor on PCNA-dependent DNA replication and repair. Nature 1994
Human T-cell leukemia virus type 1 Tax transactivates the human proliferating cell nuclear antigen promoter. J Virol Ressler S Morris G. F Marriott S. J 1997 71 1181 1190
Disruption of nucleotide excision repair by the human T-cell leukemia virus type 1 Tax protein. J Virol Kao S. Y Marriott S. J 1999 73 4299 4304
Suppression of DNA Repair by HTLV-I Tax correlates with Tax transactivation of PCNA gene expression. AIDS Res Hum Retroviruses Lemoine F. J Kao S. Y Marriott S. J 2000 16 1623 1627
PA. The role of double-strand break repair- insights from human genetics. Nat Rev Genet O Driscoll M Jeggo 2006 7 45 54
The HTLV-1 Tax oncoprotein represses Ku80 gene expression. Virology Ducu R. I Dayaram T Marriott S. J 2011 416 1 8
Ku protein as a potential human T-cell leukemia virus type 1 (HTLV-1) Tax target in clastogenic chromosomal instability of mammalian cells. Retrovirology Majone F Luisetto R Zamboni D et al 2005
Human T-cell leukemia virus type 1 tax attenuates the ATM-mediated cellular DNA damage response. J Virol Chandhasin C Ducu R. I Berkovich E et al 2008 82 6952 6961
Clastogenic effect of the human T-cell leukemia virus type I tax oncoprotein correlates with unstabilized DNA breaks. J Biol Chem Majone F Jeang K. T 2000 275 32906 32910
Induction of micronuclei by HTLV-I Tax: a cellular assay for function. Virology Majone F Semmes O. J Jeang K-T 1993 193 456 459
phase progression: cycling on cue. Cell Sherr C. J. G 1994 79 551 555
Activation of E2F-mediated transcription by human T-cell leukemia virus type I Tax protein in a Lemasson I Thebault S Sardet C et al 16INK4A)-negative T-cell line. J Biol Chem 1998
Physical interaction of human T-cell leukemia virus type 1 tax with cyclin-dependent kinase 4 stimulates the phosphorylation of retinoblastoma protein. Mol Cell Biol Haller K Wu Y Derow E et al 2002 22 3327 3338
Cell type-specific E2F activation and cell cycle progression induced by the oncogene product Tax of human T-cell leukemia virus type I. J Biol Chem JID- 2985121R Ohtani K Iwanaga R Arai M et al 2000 275 11154 11163
Thâ€šbault S, Sardet C, et al. Activation of E2F-mediated transcription by human T-cell leukemia virus type I tax protein in a Lemasson I 16INK4A-negative T-cell line. J Biol Chem 1998
the cellular gatekeeper for growth and division. Cell Levine A. J. p 1997 88 323 331
Expression of cell-cycle regulatory genes in HTLV-I infected T- cell lines: Possible involvement of Tax1 in the altered expression of cyclin D2, Akagi T Ono H Shimotohno K 18Ink4 and p21 Waf1/Cip1/Sdi1. Oncogene 1996
Waf1/Cip1/Sdi1) prevents apoptosis as well as stimulates growth in cells transformed or immortalized by human T-cell leukemia virus type 1-encoded tax. J Virol Kawata S Ariumi Y Shimotohno K. p 2003 77 7291 7299
phase progression induced by the human T cell leukemia virus type I (HTLV-I) Tax oncoprotein. J Biol Chem Lemoine F. J Marriott S. J Accelerated G 2001 276 31851 31857
Cereseto A Diella F Mulloy J. C et al 53functional impairment and high p21waf1/cip1 expression in human T-cell lymphotropic/leukemia virus type I-transformed T cells. Blood 1996
Role of tumor suppressor genes in the development of adult T cell leukemia/lymphoma (ATLL). Leukemia Hatta Y Koeffler H. P 2002 16 1069 1085
HTLV-1 tax oncoprotein represses the Ariumi Y Yamaoka S Lin J. Y et al 53trans-activation function through coactivator CBP sequestration. Oncogene 2000
Tax protein of HTLV-1 inhibits CBP/ Suzuki T Uchida-toita M Yoshida M 300transcription by interfering with recruitment of CBP/p300 onto DNA element of E-box or p53 binding site. Oncogene 1999
Binding of Van Orden K Giebler H. A Lemasson I et al 53to the KIX domain of CREB binding protein. A potential link to human T-cell leukemia virus type I-associated leukemogenesis. J Biol Chem 1999
Phosphorylation of Pise-masison C. A Radonovich M Sakaguchi K et al 53a novel pathway for p53 inactivation in human T-cell lymphotropic virus type 1-transformed cells. J Virol 1998
Inactivation of Pise-masison C. A Mahieux R Jiang H et al 53by human T-cell lymphotropic virus type 1 Tax requires activation of the NF-kB pathway and is dependent on p53 phosphorylation. Mol Cell Biol 2000
Pise Masison CA. HTLV-I Tax induces a novel interaction between Jeong S. J Radonovich M Brady J. N 65RelA and p53 which results in inhibition of p53 transcriptional activity. Blood 2004
Joining the complex: cyclin-dependent kinase inhibitory proteins and the cell cycle. Cell Peter M Herskowitz I 1994 79 181 184
Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev Sherr C Roberts J. M 1995 9 1149 1163
INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature JID- 0410462 Hannon G. J Beach D. p 1994 371 257 261
Human T-cell leukemia virus type 1 tax releases cell cycle arrest induced by Low K. G Dorner L. F Fernando D. B et al 16INK4a. J Virol 1997
HTLV-1 Tax protein interacts with cyclin-dependent kinase inhibitor Suzuki T Kitao S Matsushime H Yoshida M 16INK4Aand counteracts its inhibitory activity towards CDK4. EMBO J 1996
Molecular mechanism of cell cycle progression induced by the oncogene product Tax of human T-cell leukemia virus type I. Oncogene Iwanaga R Ohtani K Hayashi T Nakamura M 2001 20 2055 2067
Down-regulation of the INK4 family of cyclin-dependent kinase inhibitors by tax protein of HTLV-1 through two distinct mechanisms. Virology Suzuki T Narita T Uchida-toita M Yoshida M 1999 259 384 391
CREB/ATF-dependent repression of cyclin a by human T-cell leukemia virus type 1 Tax protein. J Virol Kibler K. V Jeang K. T 2001 75 2161 2173
DelMistro A, et al. Chromosome damage induced in cord blood T-lymphocytes infected in vitro by HTLV-I. Leukemia Chieco-bianchi L Saggioro D 1988s-232s.
High rate of chromosomal abnormalities in HTLV-I-infected T-cell colonies derived from prodromal phase of adult T-cell leukemia: A study of IL-2-stimulated colony formation in methylcellulose. Cancer Genet Cytogenet Fujimoto T Hatta T Itoyama T et al 1999 109 1 13
Cytogenetic studies of human T-cell leukemia virus type I carriers. A family study. Cancer Genet Cytogenet Itoyama T Sadamori N Tokunaga S et al 1990 49 157 163
Chromosome abnormalities in adult T-cell leukemia/lymphoma: a karyotype review committee report. Cancer Res Kamada N Sakurai M Miyamoto K et al 1992 52 1482 1493
Chromosome and gene rearrangements in immortalized human lymphocytes infected with human T-lymphotropic virus type I. Cancer Res Maruyama K Fukushima T Kawamura K Mochizuki S 1990s-5702s.
Chromosome abnormalities of leukemia cells in adult aptients with T-cell leukemia. J Natl Can Instit Miyamoto K Tomita N Ishii A et al 1984 73 353 362
Chromosome patterns in cells from patients positive for human T-cell leukemia/lymphoma virus. Human T-cell leukemia/lymphoma virus. New York: Cold Spring Harbor Laboratory, Rowley J. D Haren J. M Wong-staal F Franchini G Gallo R. C Blattner W et al 1984 1984 85 89
Cytogenetic implication in adult T-cell leukemia. A hypothesis of leukemogenesis. Cancer Genet Cytogenet Sadamori N 1991 51 131 136
Chen YMA, Knutsen T, et al. Chromosome studies in HTLV-I,-II, and HTLV-1,-2 cell lines infected in vivo and in vitro. J Acquir Immune Defic Syndr Hum Retrovirol Whang-peng J 1993 6 930 940
Human T-cell leukemia virus type 1 Tax interacts with Chk1 and attenuates DNA-damage induced G2 arrest mediated by Chk1. Oncogene Park H. U Jeong J. H Chung J. H Brady J. N 2004 23 4966 4974
Human T-cell leukemia virus type 1 tax oncoprotein prevents DNA damage-induced chromatin egress of hyperphosphorylated Chk2. J Biol Chem Gupta S. K Guo X Durkin S. S et al 2007 282 29431 29440
Emerging roles of DNA tumor viruses in cell proliferation: new insights into genomic instability. Oncogene Lavia P Mileo A. M Giordano A Paggi M. G 2003 22 6508 6516
Comparison of tests for aneuploidy. Mutation Research Parry J. M Parry E. M 1987 181 267 287
The identification of micronucleated chromosomes: a possible assay for aneuploidy. Mutagenesis Thompson E. J Perry P. E 1988 3 415 418
Human T cell leukemia virus type 1 oncoprotein tax targets the human mitotic checkpoint protein MAD1. Cell Jin D. Y Spencer F Jeang K. T 1998 93 81 91
Human T-lymphotropic virus type 1 oncoprotein tax promotes unscheduled degradation of Pds1p/securin and Clb2p/cyclin B1 and causes chromosomal instability. Mol Cell Biol Liu B Liang M. H Kuo Y. L et al 2003 23 5269 5281
Human T-cell leukemia virus type I induces adult T-cell leukemia: from clinical aspects to molecular mechanisms. Cancer Control Yasunaga J Matsuoka M 2007 14 133 140