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Viruses. Jun 2011; 3(6): 714–749.
Published online Jun 10, 2011. doi:  10.3390/v3060714
PMCID: PMC3131208
NIHMSID: NIHMS303405
Human T-Cell Lymphotropic Virus: A Model of NF-κB-Associated Tumorigenesis
Zhaoxia Qu1,2* and Gutian Xiao1,2*
1Cancer Institute, Medical Center, University of Pittsburgh, Pittsburgh, PA 15213, USA;
2Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
*Authors to whom correspondence should be addressed; E-Mails: quz/at/upmc.edu (Z.Q.); xiaog2/at/upmc.edu (G.X.); Tel.: +1-412-623-5410; Fax: +1-412-623-1415.
Received April 2, 2011; Revised May 13, 2011; Accepted June 1, 2011.
Human T-cell lymphotropic virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATL), whereas the highly related HTLV-2 is not associated with ATL or other cancers. In addition to ATL leukemogenesis, studies of the HTLV viruses also provide an exceptional model for understanding basic pathogenic mechanisms of virus-host interactions and human oncogenesis. Accumulating evidence suggests that the viral regulatory protein Tax and host inflammatory transcription factor NF-κB are largely responsible for the different pathogenic potentials of HTLV-1 and HTLV-2. Here, we discuss the molecular mechanisms of HTLV-1 oncogenic pathogenesis with a focus on the interplay between the Tax oncoprotein and NF-κB pro-oncogenic signaling. We also outline some of the most intriguing and outstanding questions in the fields of HTLV and NF-κB. Answers to those questions will greatly advance our understanding of ATL leukemogenesis and other NF-κB-associated tumorigenesis and will help us design personalized cancer therapies.
Keywords: ATL, IKK, HTLV, immune escape, NF-κB, PDLIM2, Tax, transformation, tumorigenesis, virus-host interaction, WWOX
Human T-cell leukemia virus type 1 (HTLV-1) and type 2 (HTLV-2) are closely related human retroviruses that were originally discovered in the early 1980s [1]. They have a similar genome structure with approximately 70% nucleotide homology (Figure 1). They also share a common mechanism of replication and transmission. But the pathogenic potentials and clinical manifestations of these two highly related viruses differ significantly [2]. HTLV-1 is the etiological agent of adult T-cell leukemia/lymphoma (ATL), an aggressive and lethal malignancy of CD4+ T lymphocytes, as well as a variety of autoimmune and inflammatory diseases including the neurodegenerative disorder tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM). However, no significant association of HTLV-2 with human malignancies has been demonstrated. Unfortunately, there is still no cure for HTLV-1-associated malignancies and no means of assessing the risk of disease or prognosis in infected people [35]. In addition to the direct clinical problems caused by HTLV-1 infection, studies of HTLV-1 particularly in comparison with HTLV-2, provide important models for understanding basic pathogenic mechanisms of host-virus interaction, human oncogenesis, and inflammatory and autoimmune disorders.
Figure 1.
Figure 1.
The Human T-cell lymphotropic virus (HTLV) proviral genome. Gag, Pol, and Env are viral structural proteins, others are viral regulatory/accessory proteins. Except the hbz gene, which is encoded by the minus strand of the HTLV proviral genome from 3′-LTR, (more ...)
Unlike animal oncoretroviruses, HTLV-1 does not carry a host-derived oncogene or activate a cellular oncogene through proviral integration [6]. Instead, HTLV-1 encodes a regulatory protein Tax that serves as the primary oncogenic mediator [79]. Tax not only transforms rodent fibroblasts but also immortalizes human primary T cells in vitro [1013]. Compared to cells transformed by many cellular oncogenes, Tax-transformed cells have an apparently higher resistance to the induction of apoptosis [14]. In addition, Tax-transformed lymphoid cells and fibroblasts induce tumors when introduced into immunodeficient mice (nude mice or SCID mice) [10,13,15]. More importantly, the HTLV-1 genome without Tax loses its original transforming ability [16], whereas Tax transgenic mice develop various tumors depending on the type of the promoters used to drive Tax expression [1723]. A more recent study shows that Tax-transduced human hematopoietic stem cells, a preferential HTLV-1 reservoir in vivo, acquire the ability to develop CD4+ T-cell lymphomas in SCID mice [24]. Of note, Tax-immortalized lymphocytes in vitro and Tax-mediated T-cell lymphoma in animals closely resemble the phenotype of HTLV-1-transformed T-cells and HTLV-1-induced ATL, respectively [2325]. Tax is a pleiotropic protein that exploits various cellular machinery and signaling pathways to mediate cellular transformation as well as viral replication (Figure 2). Among those host machineries, NF-κB signaling plays a pivotal role in Tax-mediated transformation and ATL leukemogenesis.
Figure 2.
Figure 2.
Cellular targets of the Tax viral oncoprotein. NF-κB, PI3K/AKT and SRF are well-known for their roles in various cellular functions, particularly cell survival and cell proliferation. The JAK/STAT signaling pathway is activated indirectly through (more ...)
2.1. The NF-κB Family
NF-κB, nuclear factor-κB, is a family of transcription factors that plays a central role in the regulation of diverse biological processes, including immune responses, development, cell proliferation and survival [26]. Deregulated NF-κB has been linked to a variety of human diseases, particularly cancers [27]. The NF-κB family consists of five closely related DNA binding proteins: RelA (p65), RelB, c-Rel, NF-κB1/p50 and NF-κB2/p52, which function as various homodimers and heterodimers to regulate transcription of genes containing κB motifs in their promoters [26]. NF-κB members share a highly conserved 300-amino acid-long N-terminal Rel homology domain (RHD), which is responsible for their dimerization, nuclear translocation, DNA binding and also interaction with the inhibitors of NF-κB (IκBs) (Figure 3). However, NF-κB family members exhibit major differences in their C-terminal sequences as well as in their modes of synthesis. RelA, RelB and c-Rel have transactivating domains (TAD) at their C-termini and are synthesized directly as mature forms, whereas p50 and p52 lack a TAD and are generated from large precursor proteins, p105 and p100, respectively. Interestingly, p105 and p100 contain IκB-like sequences in their C-terminal portions and function as NF-κB inhibitors [28,29]. Processing of p105 and p100 (selective degradation of their C-terminal IκB-like sequences) thus has two functions: to disrupt their IκB-like function and to generate mature NF-κB subunits. Since p105 is constitutively processed to p50 and is usually completely degraded upon NF-κB stimulation [30,31], it can be simply considered as a “typical” IκB. On the other hand, p100 processing is tightly controlled and its induction is highly signal-dependent [32,33].
Figure 3.
Figure 3.
Schematic representation of members of NF-κB and IκB families. ARD: ankyrin repeat domain; DD: death domain; GRR: glycine-rich region; LZ: leucine zipper; NES: nuclear export sequence; NLS: nuclear localization sequences; PEST: PEST containing (more ...)
2.2. Pathways Leading to NF-κB Activation
In unstimulated cells, NF-κB dimers are usually sequestered in the cytoplasm by IκBs such as IκBα and p100. NF-κB nuclear translocation and subsequent transcription activation require degradation of IκBs or processing of p100 to generate p52, which represent two major mechanisms of NF-κB activation [26]. Due to the fundamental difference between inducible IκB degradation and p100 processing in their signal transduction and biological outcomes, the two mechanisms leading to NF-κB activation are termed as the canonical (classical) and non-canonical (non-classical) NF-κB pathways, respectively (Figure 4).
Figure 4.
Figure 4.
NF-κB signaling pathways. Although the canonical and non-canonical signaling pathways primarily activate the RelA/p50 and RelB/p52 dimers, respectively, all NF-κB members may be activated by either pathway or both. In fact, the RelA/p50 (more ...)
Canonical NF-κB pathway:
The canonical pathway can be rapidly activated by a plethora of stimuli from either outside or inside cells, such as extracellular antigens and inflammation cytokines (e.g., tumor necrosis factor, TNF, a prototypic NF-κB stimulus), cytoplasmic oxidative stress and nuclear DNA damage [34]. These stimuli induce assembly of a multimolecular complex that includes the RING-finger E3 ubiquitin ligase TNF receptor associated factor 6 (TRAF6) or other TRAF proteins, leading to K63-linked auto-polyubiquitination of TRAF6 [35,36]. The ubiquitinated TRAF6 recruits and catalyzes K63-linked ubiquitination of the transforming growth factor-β-activated kinase 1 (TAK1) and the IκB kinase (IKK) complex (the IKK complex consists of two catalytic components, IKK1 (IKKα) and IKK2 (IKKβ), and a regulatory component, NEMO (NF-κB essential modulator, IKKγ)), so that TAK1 can phosphorylate and activate IKK [37]. Once activated, IKK phosphorylates specific serines within IκBs (e.g., IκBα, S32 and S36; IκBβ, S19 and S23; p105, S927 and S932), triggering their K48-linked ubiquitination by the E3 ubiquitin ligase β-transducin repeat-containing protein (β-TrCP) and subsequent degradation by the 26S proteasome [26,27]. NF-κB released from IκBs then translocates into the nucleus to regulate expression of a wide range of genes, particularly those involved in cell proliferation, survival, adhesion and migration [34]. In addition to IκB degradation, many other regulatory mechanisms are also important for canonical NF-κB activation, such as phosphorylation, prolyl isomerization and acetylation of RelA [26,27]. These post-translational modifications prevent RelA from binding to IκBα, facilitate RelA to recruit the transcriptional coactivators CBP/p300, and/or increase the DNA binding activity and protein stability of RelA [3841].
Non-canonical NF-κB pathway:
In contrast to the canonical pathway, the noncanonical NF-κB pathway is induced only by a handful of stimuli including B-cell activating factor (BAFF), lymphotoxin β (LTβ), CD40 ligand (CD40L), TNF-like weak inducer of apoptosis (TWEAK), and receptor activator of NF-κB ligand (RANKL) [26]. In addition, activation of the noncanonical NF-κB pathway is slow and depends on protein synthesis of NF-κB-inducing kinase (NIK) [32,42]. Although its mRNA expression is relatively abundant, the level of NIK protein is normally very low because it is constitutively degraded via a TRAF3-dependent mechanism [42,43]. TRAF3 functions as a scaffold between NIK and TRAF2, which in turn recruits cellular inhibitors of apoptosis 1 and 2 (c-IAP1/2) into the NIK complex. Within the complex, c-IAP1 or c-IAP2 acts as the E3 ubiquitin ligase to mediate NIK polyubiquitination and proteolysis, thereby keeping its abundance below the threshold required for its function [44]. In response to noncanonical NF-κB stimuli, either TRAF2 and TRAF3 or c-IAP1 and c-IAP2 are degraded by the proteasome, resulting in stabilization and accumulation of the newly synthesized NIK, thereby allowing NIK proteins to form oligomers and cross-phosphorylate each other for their activation [42,43,4551]. Self-activated NIK in turn activates the IKK complex and specifically recruits IKK1 into the p100 complex to phosphorylate p100, leading to p100 ubiquitination by the β-TrCP E3 ubiquitin ligase and processing by the proteasome to generate p52 [32,5254]. The processed p52 product, together with its NF-κB binding partner, translocates into the nucleus to induce or repress gene expression. Moreover, NIK-activated IKK may also induce IκBα degradation to activate the canonical NF-κB pathway [55].
2.3. Termination of NF-κB Activation
Activation of the NF-κB pathways is tightly regulated and rapidly curtailed following the initial activating stimulus. Transient activation of NF-κB is physiologically important because persistent activation can result in deleterious or even fatal conditions, such as acute inflammation, septic shock or at a cellular level, inappropriate cell growth and survival leading to cancer [26]. It is therefore not surprising that feedback inhibition mechanisms to terminate NF-κB activation occur at almost all steps in the leading to activation.
Consistent with the central role of IKK in the activation of both canonical and non-canonical NF-κB pathways, several mechanisms are employed to inactivate IKK. Once activated, IKK phosphorylates itself and its upstream activators, such as RIP in the canonical NF-κB pathway and NIK in the non-canonical NF-κB pathway, in addition to the IκB proteins. The autophosphorylation of the IKK catalytic components at their multiple C-terminal serines is supposed to cause conformational alteration of IKK and phosphatase recruitment, resulting in dephosphorylation of the IKK activation loops and IKK inactivation [56]. Phosphorylation of RIP and NIK, similar to IκB phosphorylation, leads to K48-linked ubiquitination and degradation of these IKK activators [57,58]. The ubiquitination of RIP is mediated by A20 (TNFAIP3, TNFα-induced protein 3), a known target of NF-κB activation [59], providing a distinct feedback inhibition mechanism. In addition to functioning as an E3 ubiquitin ligase for RIP K48-linked ubiquitination and degradation, A20 exerts at least two additional functions to terminate NF-κB activation. First it can function as a deubiquitinase (DUB) to remove K63-linked ubiquitin chains from multiple NF-κB signaling molecules such as TRAF2/6, RIP, MALT1 and NEMO. Alternatively, it can block continuous K63-linked ubiquitination of these key NF-κB regulators by disrupting the interaction between the K63 ubiquitin ligases TRAF2/6 and their E2 ubiquitin conjugating enzymes Ubc13 and UbcH5c [58,6063]. As stated above and shown in Figure 4, K63-linked ubiquitination of NF-κB signaling molecules is critical for the assembly of signaling complexes and subsequent activation of IKK/NF-κB. Interestingly, A20 is also a target of IKK activation for phosphorylation. In this case, IKK-mediated phosphorylation increases the K63-specific DUB activity of A20, suggesting another feedback inhibition mechanism of IKK/NF-κB activation [64]. Besides A20, another deubiquitinase termed cylindromatosis (CYLD) also plays an important role in the termination of IKK/NF-κB activation [65]. Like A20, CYLD is a target gene of NF-κB activation and can remove K63-linked ubiquitin chains from multiple activated IKK/NF-κB signaling molecules, including TRAF2/6, RIP, TAK1, NEMO and Bcl-3 [6668].
Given the role of RelA posttranslational modifications in its transcriptional activity, several mechanisms have been reported to reverse these modifications for NF-κB termination. For example, phosphorylation and acetylation of RelA are reversibly regulated by different phosphatases and histone deacetylases (HDACs) [38,39,41,6972]. Moreover, RelA phosphorylation induced by pro-inflammatory cytokines is blocked by a protein called SINK and the DNA binding activity of RelA can be prevented by the basic helix-loop-helix (bHLH) transcription factor Twist or RelA-associated inhibitor (RAI) through their associations with RelA in the nucleus [7375]. Interestingly, SINK and Twist are known target genes of NF-κB activation [73,74], suggesting that feedback inhibition is a common mechanism for NF-κB termination at different levels.
The best known and most critical feedback inhibition mechanism is to replenish the pool of IκB proteins via NF-κB activation. Similar to other NF-κB repressors, all IκB family members except IκBβ are direct targets of NF-κB. In particular, newly synthesized IκBα enters the nucleus to bind to and transport NF-κB dimers back to the cytoplasm to reconstitute the status quo ante [76].
Recent studies indicate that this feedback inhibition mechanism is neither sufficient nor necessary to turnoff NF-κB activation, at least in certain situations [77]. Instead, ubiquitination-mediated degradation of nuclear NF-κB provides a more rapid and essential mechanism for NF-κB termination. In this context, PDZ-LIM domain-containing protein 2, PDLIM2, a ubiquitously expressed nuclear protein with a strong cytoplasmic-nuclear shuttling activity, is particularly important. PDLIM2 terminates NF-κB activation using two distinct but related mechanisms: it not only functions as an E3 ubiquitin ligase to promote nuclear RelA ubiquitination but also shuttles RelA to the nuclear matrix for the proteasome-mediated degradation [78,79]. Importantly, PDLIM2 knockout mice are more sensitive to septic shock due to enhanced p65 activation and subsequently augmented production of inflammatory cytokines [78].
Although tightly controlled in normal cells including T cells, NF-κB is constitutively activated in both transformed and untransformed HTLV-1-infected cells [80]. Given the association of NF-κB activation with tumorigenesis and the oncogenic ability of Tax [27], much effort has been devoted to elucidating the mechanism by which Tax persistently activates NF-κB. In fact, Tax is the first pathogenic agent shown to activate NF-κB, and the studies on Tax have greatly advanced our understanding of both physiological and pathogenic activations of NF-κB.
3.1. Tax-Mediated NF-κB Activation
Activation of the canonical NF-κB pathway by Tax:
The initial clue suggesting a role of the Tax oncoprotein in NF-κB activation came from the findings that Tax is able to activate the κB element in the promoter of the interleukin 2 (IL2) receptor alpha (IL-2Rα) gene and in the long terminal repeat (LTR) of the human immunodeficiency virus type 1 (HIV-1) [8184]. Since then, our knowledge of Tax activation of NF-κB has increased significantly. We now know that Tax intervenes at multiple levels to activate NF-κB. In the cytoplasm, Tax directly binds to the IKK regulatory component NEMO, via the leucine-repeat motif of Tax and two homologous leucine zipper domains within NEMO, and recruits the IKK complex to the perinuclear compartment where IKK is phosphorylated and activated [8588]. The activated IKK in turn phosphorylates IκBs (by IKK2) and also RelA (by IKK1), resulting in ubiquitination and proteasomal degradation of IκBs and subsequent nuclear translocation of NF-κB including the phosphorylated RelA [89]. In the nucleus, Tax recruits RelA as well as other cellular transcriptional components into interchromatin granules to form discrete transcriptional hot spots termed ‘Tax nuclear bodies’ for full NF-κB transcriptional activation [90,91].
Currently, the detailed mechanism of how the Tax-IKK interaction activates IKK remains largely unknown. Tax does not have kinase activity and cannot directly phosphorylate IKK for its activation. Given the dimerization ability of Tax [92,93], one possibility is that through self-dimerization, Tax brings different IKK complexes together so that they can cross-phosphorylate and activate each other. In support of the hypothesis, fusion of Tax, but not its M22 mutant that is defective in self-dimerization, to IKK1 or IKK2 is sufficient for their catalytic activation [94]. Tax may also act as an adaptor protein to recruit the IKK complex and its upstream kinase to the perinuclear compartment to form a new complex for IKK phosphorylation and activation. In this regard, the mitogen-activated protein kinase kinase kinases (MAP3Ks), MEKK1, NIK, Tpl2, and TAK1, have been shown to interact with Tax and enhance Tax-mediated IKK activation when over-expressed [9598]. However, other studies suggest that none of these kinases is required for Tax-mediated IKK activation [99101]. Instead, Tax may activate these MAP3Ks for activation of signaling pathways other than IKK/NF-κB. Another debated issue is the subcellular locations for Tax-mediated IKK activation. Some suggest it is the centrosome [102], while others imply endoplasmic reticulum or Golgi-associated structures [103106].
Interestingly, the critical cytoplasmic and nuclear steps of NF-κB activation seem to involve two distinct posttranslational modifications of Tax protein, K63-linked ubiquitination and sumoylation, respectively [107,108]. While the K63-linked ubiquitination of Tax is mediated by the E2 ubiquitin conjugating enzyme Ubc13 and E3 ubiquitin ligase TRAF2, 5 or 6 [95,109], the E3 sumo ligase for Tax sumoylation has not yet been identified. Both ubiquitination and sumoylation of Tax involve the same C-terminal lysines, suggesting exclusive mechanisms for the two modifications [102,107,108]. Currently, it remains unclear whether the same Tax proteins undergo two different modifications for cytoplasmic-nuclear shuttling to exert their cytoplasmic and nuclear functions in the IKK/NF-κB activation, or whether different Tax proteins are involved in the different modifications and functions. A recent study suggests that the same Tax molecule alternatively undergoes ubiquitination at the centrosome or sumoylation at Tax nuclear bodies, and shuttles between these cytoplasmic and nuclear compartments [110]. Interestingly, the same study suggests that the ubiquitination and sumoylation of Tax also controls the shuttling of NEMO proteins among the centrosome and different Tax nuclear bodies and facilitates NEMO sumoylation in Tax nuclear bodies when over-expressed. Nuclear shuttling and sumoylation of NEMO are key steps for nuclear initiated IKK/NF-κB activation such as by DNA damage, an event particularly important for cancer biology and cancer treatment [111]. NEMO sumoylation induced by DNA damage triggers NEMO phosphorylation and monoubiquitination, which in turn leads to the relocation of NEMO back to the cytoplasm where the IKK-activating kinase TAK1 is recruited to phosphorylate IKK for its catalytic activation [111]. Thus, it is interesting to examine whether nuclear sumoylation of NEMO happens under HTLV-1 pathogenic conditions and whether Tax-induced NEMO sumoylation is also involved in the induction of NEMO ubiquitination, TAK1 recruitment and IKK catalytic activation. This idea may be challenged by previous studies showing that fusion of the NEMO N-terminus, which is responsible for the NEMO/IKK1/2 interaction but lacks the sumoylation or ubiquitination sites [112], to Tax is sufficient to activate IKK/NF-κB in NEMO deficient cells [94]. In light of this, some studies suggest that Tax-mediated IKK activation is independent of NEMO K63-linked ubiquitination and IKK upstream kinases including TAK1 [99,100]. Furthermore, Tax-induced NEMO sumoylation actually reduces the ubiquitination of NEMO proteins [110]. Those studies strongly argue against the role of NEMO nuclear sumoylation in Tax-mediated IKK activation. Alternatively, Tax-induced NEMO sumoylation may prevent the nuclear function of NEMO and therefore contribute to the transcriptional activation of NF-κB. In this regard, it has been reported that NEMO can translocate into the nucleus to repress NF-κB-mediated gene transcription by competing with RelA for the transcriptional co-activator CBP [113].
Besides the ubiquitin and sumo modifications, Tax also undergoes phosphorylation and acetylation [114116]. Although the kinase(s) responsible for Tax phosphorylation remain to be identified and the involved phosphorylation sites are still controversial [114,116], Tax phosphorylation seems to be important for NF-κB activation, possibly by contributing to Tax nuclear translocation, and subsequent sumoylation and acetylation in the Tax nuclear bodies [115]. Furthermore, the phosphorylation of Tax may be involved in Tax binding to the prolyl isomerase Pin1 and subsequent Tax protein stabilization [117,118]. Previous studies have shown that Pin1 directly interacts with and stabilizes phosphorylated RelA and c-Rel, thereby increasing NF-κB activity and promoting oncogenesis [40,119]. Thus, it is of interest to examine whether Tax recruitment of Pin1 stabilizes RelA and other NF-κB members, besides Tax itself.
Activation of the noncanonical NF-κB pathway by Tax:
In addition to activation of the canonical NF-κB pathway, Tax induces the processing of p100 to yield p52 for the activation of the noncanonical NF-κB pathway [26]. The induction of p100 processing is a hallmark of NF-κB activation by HTLV-1 infection because activation of this alternative pathway usually occurs in B cells and lymphoid stromal cells but not in either resting or activated normal T cells [120]. In contrast to the physiological processing of p100, which requires the NIK kinase but is independent of NEMO, Tax activation of the noncanonical NF-κB pathway requires NEMO but is independent of NIK [120]. NEMO is required in this pathogenic process is because it plays an adaptor role in the assembly of the Tax/IKK complexes [120], a step also required to activate the canonical NF-κB pathway [121,122]. However, unlike the canonical Tax/NEMO/IKK complex, which contains both IKK1 and IKK2, the noncanonical Tax/NEMO/IKK complex only contains IKK1, but not IKK2 [120]. Like the NIK kinase, the physiological stimulator of p100 processing, Tax not only activates IKK1 but also recruits IKK1 (indirectly via NEMO) into the p100 complex. Within the p100 complex, IKK1 phosphorylates p100, leading to p100 ubiquitination and processing by the β-TrCP ubiquitin ligase and the proteasome, respectively [123].
3.2. Tax-Independent NF-κB Activation
Obviously, Tax-mediated IKK activation is a major mechanism contributing to the high NF-κB activation in HTLV-1-infected cells. However, Tax expression is lost in about 60% of all ATLs during the late stages of leukemogenesis because of hypermethylation, deletion of the proviral 5′ LTR, or nonsense or missense mutations of the tax gene [8,124129]. Notably, both canonical and noncanonical NF-κB pathways are still strongly activated in HTLV-1-infected Tax-negative cells, suggesting a Tax-independent mechanism [130132]. Moreover, Tax-independent NF-κB activation also happens in Tax-positive cells. Several mechanisms may be involved in Tax-independent NF-κB activation in HTLV-1-infected T cells. It is conceivable that ligation of the T-cell receptor (TCR) following HTLV-1 infection will lead to canonical NF-κB activation. However, if it exists, this is only a minor and transient mechanism, since the TCR and its proximal signaling molecules are quickly down-regulated after antigen ligation [133]. In fact, loss of antigen receptor and its downstream signaling molecules are characteristic and a contributing factor in malignant transformation of lymphocytes mediated by HTLV-1 or directly by the oncogenic NF-κB member c-Rel [134139]. Possibly, the positive feedback mechanism is the most promising one for Tax-independent NF-κB activation. Largely through NF-κB activation (initially activated by TCR ligation and Tax, and later activated by Tax or Tax-independent mechanisms, see discussion below), HTLV-1 infection induces expression of many NF-κB stimulators and signaling molecules such as TNF, CD40, CD30, and Bcl-3 [140143]. As discussed previously, TNF is the prototypic stimuli of canonical NF-κB activation, while CD40 and CD30 are potent activators of both canonical and noncanonical NF-κB pathways [144,145]. On the other hand, Bcl-3 binds to p50 or p52 homodimers and transforms them from transcription repressors into activators [27]. Interestingly, CD30 upregulation and its resulting NF-κB activation are hallmarks of anaplastic large cell lymphoma (ALCL) and Hodgkin lymphoma (HL) [145,146]. Other mechanisms involved in Tax-independent NF-κB activation in HTLV-1-infected T cells may be attributed to various stress conditions and epigenetic/genetic alterations caused by HTLV-1 infection. For example, DNA damage, a determining factor in tumorigenesis including ATL leukemogenesis [147,148], can lead to strong NF-κB activation [111]. On the other hand, epigenetic up-regulation of NIK expression and genetic deletions of the p100 C-terminus have recently been detected in certain ATL cells [149151]. While NIK is a potent activator of both canonical and noncanonical NF-κB pathways [32,55,96], C-terminal deletions of p100 results in constitutive p100 processing and non-canonical NF-κB activation [32,152,153].
3.3. Persistent NF-κB Activation by HTLV-1
Unlike the rapid but normally transient activation under physiological conditions, NF-κB activation in HTLV-1-infected cells is aberrantly persistent, whether it is Tax-dependent or -independent or whether it is canonical or noncanonical. A main reason for this abnormal activation is the co-existence and cross-activation of different NF-κB and NF-κB-related signaling pathways. In this way, the tightly controlled activation mechanisms of NF-κB are inappropriately unleashed and the normal termination mechanisms are overridden. Again, the Tax oncoprotein is the primary culprit. First, Tax persistently activates IKK through physical interaction, leading to continuous degradation of IκBα, which controls the early-phase of NF-κB activation, IκBβ and p105, which controls the late-phase of NF-κB activation, as well as constant processing of p100, which controls another late-phase of NF-κB activation (noncanonical pathway) [120,154158]. Second, Tax binds to and increases the stability and activity of NF-κB and/or prevents NF-κB from binding to its inhibitors [159167], resulting in a prolonged and elevated activation of NF-κB. Third, Tax directly shuts off the mechanisms that terminate NF-κB activity. For example, Tax prevents nuclear RelA from PDLIM2-mediated ubiquitination and subsequent degradation, although the cost is the sacrifice of Tax itself [168]. Moreover, Tax binds to and recruits NEMO-related protein (NRP/Optineurin) and TAXBP1 to the Golgi-related structures [104]. Although NRP and TAXBP1 are not required for Tax recruit NEMO, the formation of a Tax/NRP/TAXBP1 ternary complex disrupts the A20/TAXBP1 deubiquitinase complex, therefore increasing K63-linked ubiquitination of Tax and possibly also many cellular NF-κB signaling molecules. As discussed previously, K63-linked protein ubiquitination is a key mechanism for signaling complex assembly and NF-κB activation. Fourth, Tax induces expression of NF-κB members, signaling molecules and activators, particularly cytokines, which form a positive feedback loop of NF-κB activation [140143,159,169171]. In this way, different NF-κB pathways can be cross-activated. Canonical NF-κB activation induces expression of p100 as well as p100 processing inducers such as CD40 to persistently activate the non-canonical NF-κB pathway [120,140,159]. Non-canonical NF-κB also facilitates canonical NF-κB activation by repressing transcription of the WW domain-containing oxidoreductase (wwox) tumor suppressor gene, a specific inhibitor of Tax-induced RelA phosphorylation [172]. In addition to NF-κB, Tax induces many other signaling pathways such as the phosphatidylinositol 3-kinase (PI3K)/AKT and DNA damage signaling pathways, leading a reciprocal enhancement of these pro-oncogenic pathways with NF-κB [8,27,111,173,174]. It should be pointed out that most of these mechanisms also apply to the persistent activation of Tax-independent and -dependent NF-κB.
3.4. Differences between Tax-Dependent and Tax-Independent NF-κB Activation by HTLV-1
Both canonical and noncanonical NF-κB signaling pathways are persistently activated in HTLV-1-infected cells regardless of Tax expression. In addition to the common and distinct signaling mechanisms for their activation, Tax-dependent and -independent NF-κB pathways also involve activation of common and distinct NF-κB members. NF-κB members activated in Tax-expressing T cells are predominantly RelA, c-Rel, p50 and p52 [120,159,169], and those in HTLV-1-infected Tax-negative T cells and primary ATL cells are mainly RelA and p50 [131,169]. Consistent with the role of positive feedback mechanisms in persistent NF-κB activation, expression of c-Rel and p100/p52 is induced in Tax-expressing cells while that of p105/p50 mRNA is enhanced in ATL cells [159,169171]. Activation of common and distinct NF-κB members leads to transcriptional changes, which regulate specific stage of ATL leukemogenesis. For example, c-Rel-mediated activation of IL2 and IL2R may play a critical role in growth, particularly the transition from IL2-dependence to IL2-independence, of HTLV-1-infected T cells during the pre-leukemic stage of ATL [175,176]. On the other hand, p50-dependent induction of activation-induced cytidine deaminase (AID) may contribute to genomic mutations and ATL initiation and development [177].
4.1. Significance of NF-κB in Tax-Mediated Cellular Transformation and ATL Leukemogenesis
The significance of NF-κB activation in ATL leukemogenesis has been suggested since it was linked to HTLV-1 induction of the IL2R in the late 1980s [81,83,84]. The requirement of NF-κB for HTLV-1- or Tax-induced immortalization was largely defined using Tax mutants that are deficient in the activation of either NF-κB or CREB/ATF (cyclic-AMP-response element binding protein/activating transcription factor), a transcription factor responsible for Tax-mediated viral gene expression [178,179]. Surprisingly, these Tax mutant analyses have yielded conflicting results as to whether NF-κB or CREB/ATF activation is critical for Tax-mediated cellular transformation [180183]. Regardless of the discrepancy, studies using the Tax mutants suggest that NF-κB is important in Tax-induced IL2-dependent or -independent cell growth as well as in HTLV-1-induced T-cell immortalization [184187]. In addition, inhibition of NF-κB, by silencing NF-κB or its activators IKK and NIK, by over-expressing degradation/processing-resistant forms of IκBα and p100, or by using IKK/NF-κB chemical inhibitors, prevents Tax-mediated cellular transformation and blocks the growth of HTLV-1- or Tax-transformed cells and ATL cells, both in culture and in SCID mice [80,122,132,150,172,180,188193]. Together, those studies suggest that NF-κB plays a crucial role in HTLV-1/Tax-mediated transformation in vitro.
Recently, an in vivo role of NF-κB in HTLV-1-mediated tumorigenesis has been demonstrated in two independent studies using two different Tax transgenic mouse models: lymphocyte-restricted Tax transgenic mice and HTLV-1 LTR Tax transgenic mice. The former mice develop a lethal cutaneous disease that shares several features in common with the skin disease that occurs during the preleukemic stage in HTLV-1-infected patients [194], while the latter mice develop different kinds of soft tissue tumors [17,18]. Notably, mice expressing a Tax mutant defective in the activation of NF-κB, but not CREB/ATF, fail to develop the skin disease or any other diseases [194]. More interestingly, genetic knockout of the nf-kb2 gene alone dramatically delays tumor onset in the HTLV-1 LTR Tax transgenic mice [172]. These in vivo studies also suggest that both canonical and non-canonical NF-κB pathways are involved in Tax-induced cellular transformation and tumorigenesis. In this regard, knockdown of either rela or nf-kb2 reduces Tax-induced T-cell proliferation in vitro [195]. On the other hand, the transforming activity of Tax2, the homologous Tax protein encoded by HTLV-2, which activates the canonical NF-κB pathway as efficiently as Tax but loses the ability to activate the noncanonical NF-κB pathway, is much lower than that of Tax [196]. Induction of p100 processing by expressing the NIK kinase can restore the transforming activity of Tax2 to a level comparable to that of Tax [196].
4.2. Functional Role of NF-κB in Tax-Mediated Cellular Transformation and ATL Leukemogenesis
NF-κB has been suggested to be involved in all stages of ATL leukemogenesis from initiation to invasion and dissemination, through the transcriptional regulation of various tumor-related genes [27]. During the early stages of ATL leukemogenesis, NF-κB induces expression of genes involved in T-cell proliferation and survival such as IL2Rα, IL4, IL6, IL8, IL9, IL13, IL21, IL27, IL15R, CXCR7, MCP-1, CD30, CD40, OX40/OX4OL, miRNA146a, 4-1BB, Bcl-2, Bcl-xL, cIAP, CCD1, CCD2, and CCD6 [81,83,84,140,141,195,197216]. Activated NF-κB also promotes genetic and epigenetic changes that drive the transformation of HTLV-1-infected T cells via several different mechanisms. The first one involves induction of the ‘mutagenic’ enzyme AID and the epigenetic mediator DNA methyltransferase 1 (DNMT1) [177,217]. The second one depends on transcriptional repression of the cell cycle checkpoint regulator p53 and the DNA repair protein β-polymerase. This function of NF-κB occurs indirectly through RelA-mediated sequestration of the transcriptional coactivators CBP/p300, leading to transcriptional repression of the bHLH transcription factor c-Myb and subsequent inactivation of c-Myb-mediated transcription of p53 and β-polymerase [218220]. Since the competition for limited CBP/p300 proteins is an important mechanism for the mutual repression of NF-κB and p53 [221223], CBP/p300 sequestration by RelA may also contribute to the transcriptional inactivation of p53 in HTLV-1-infected cells. Indeed, Tax-induced transcriptional repression of p53 requires IKK-mediated RelA phosphorylation, a modification that is known to promote RelA binding to CBP/p300 [224226]. Tax also induces a physical interaction between RelA and p53, suggesting another mechanism for NF-κB-mediated p53 inactivation [224]. Consistent with the central role of p53 in tumor suppression and the causative role of NF-κB in tumorigenesis, NF-κB also represses p53 at the protein level using two different mechanisms. First, activated IKK directly phosphorylates p53 to trigger p53 ubiquitination by the β-TrCP ubiquitin ligase and degradation by the proteasome and second, activated NF-κB induces expression of MDM2, a ubiquitin ligase well-known for p53 ubiquitination and degradation [227229]. Although it remains unknown whether activation of IKK/NF-κB induces degradation of p53 protein in HTLV-1-infected cells, these findings suggest different mechanisms for NF-κB-mediated suppression of p53 for HTLV-1 pathogenesis. Furthermore, NF-κB may contribute to DNA damage and induction of oncogenic mutations indirectly through inflammation-mediated production of reactive oxygen and nitrogen species (ROS and RNS) [27]. Interestingly, NF-κB also activates many other pro-oncogenic molecules/signaling pathways such as c-Myc and PI3K to induce expression of human telomerase reverse transcriptase (hTERT) for the long-term proliferation and clonal expansion of HTLV-1-infected cells that have acquired chromosomal abnormalities [147,174,230,231]. In addition to its role in the initiation and development of ATL, deregulated NF-κB induces expression of many genes involved in tumor progression and metastasis such as matrix metalloproteinase-9 (MMP-9) [232].
Given the strong oncogenic ability of Tax and its essential role in viral transcription, it is not surprising that this viral oncoprotein is a major target of both humoral and cellular immune responses [233235]. To evade the host immune surveillance, the virus has evolved several mechanisms that allow Tax to be expressed at the proper time and level. During the late stages of ATL leukemogenesis when Tax functions have been completed or taken over by other mechanisms such as constitutive NF-κB activation, its expression is permanently silenced via genetic mutations or epigenetic repression. Thus, understanding how Tax is regulated will provide important insights into the virus-host interaction, viral latency, ATL leukemogenesis as well as health disparities in HTLV-1 infection. This is particularly important, given that the majority of HTLV-1-infected persons remain lifelong asymptomatic carries and it takes decades for ALT to develop in less than 5% virus carriers.
5.1. Repression of Tax by Viral Genes
Besides the tax gene, HTLV-1 also encodes several other regulatory/accessory genes including rex, p12, p13, p30 and hbz (Figure 1). Among these gene products, Rex, p30 and HBZ have been reported to negatively regulate the expression and/or activity of Tax. Rex binds to and exports the unspliced and singly spliced viral RNAs, which encode viral structural proteins (env, gag and pol), from the nucleus into the cytoplasm [236,237]. Rex also inhibits splicing of the viral RNAs [238]. In these two ways, Rex increases the expression of viral structural proteins at the expense of Tax and itself, because the Tax and Rex RNAs are generated by a second splicing event from the singly spliced RNA (Figure 1). The p30 protein, on the other hand, inhibits expression of Tax and Rex by trapping the tax/rex doubly spliced RNAs in the nucleus [239]. Moreover, p30 blocks Tax-dependent viral gene activation by competing for binding to the transcriptional coactivators CBP/p300 [240]. HBZ (HTLV-1 basic leucine zipper factor), which is encoded by the minus strand of the HTLV-1 proviral genome from 3′-LTR, functions in both RNA and protein forms. The hbz RNA promotes T-cell proliferation, and the HBZ protein suppresses Tax-mediated viral transcription by sequestering CREB/ATF, the transcription factor responsible for Tax activation of the HTLV-1 LTR [241243]. More recent studies suggest that the hbz RNA, but not the HBZ protein, increases Tax expression indirectly by down-regulation of p30 RNA [244]. Thus, the hbz gene regulates Tax both positively and negatively, depending on its expression form. It should be pointed out that the hbz gene induces T-cell lymphoma in mice when it is conditionally expressed in CD4+ T cells [245]. Currently, it remains unknown which form (RNA or protein) of the hbz gene drives tumorigenesis in the transgenic mice. Whereas the RNA form, but not the protein form, promotes T-cell proliferation in vitro [241], the function of HBZ protein in Foxp3 regulation in vitro correlates with the increased CD4+ Foxp3+ Treg cells in mice [245]. Thus, it seems that both forms of the hbz gene contribute to tumorigenesis in the transgenic mice. However, hbz RNA may be the main functional form in HTLV-1-infected cells, given that hbz RNA is strongly expressed in ATL cells and human T cells transduced with HTLV-1 molecular clones [246]. In contrast to the high level of its RNA form, the level of HBZ protein may be very low in infected persons due to high human immune responses toward HBZ [247,248]. The main function of the hbz gene in ATL leukemogenesis appears to be maintaining the outgrowth of HTLV-1-transfomed cells [241,243], because it is not required for HTLV-1-mediated T-cell immortalization [249]. Nevertheless, these findings are exciting, as they shed light on the mechanism of how ATL cells maintain the transformed phenotype after Tax is inactivated.
5.2. Repression of Tax by Cellular Genes
Apart from the immune responses towards Tax, the mechanism of how Tax is regulated by cellular factors has been rarely studied. One report showed that histone deacetylase 1 (HDAC1) associates with and prevents Tax from binding to the transcriptional coactivator CBP, thereby suppressing Tax activation of viral gene transcription [250]. However, another study suggested that the Tax-HDAC1 interaction benefits viral gene transcription by removing HDAC1 from the viral promoter [251]. Since those studies were performed with over-expressed proteins and in the absence of HTLV-1 infection, the physiological significance of this finding needs to be examined.
More recently, a negative role of PDLIM2 in Tax regulation has clearly been demonstrated. Through a specific Tax-binding motif, PDLIM2 directly shuttles Tax from its activation sites to the nuclear matrix for ubiquitination-mediated degradation when over-expressed and during HTLV-1 infection [79,168]. Consistently, PDLIM2 expression inversely correlates with the stability and activity of Tax in HTLV-1-transformed T cells [168]. Interestingly, PDLIM2 expression is down-regulated in HTLV-I-transformed T cells and in primary ATL cells partially due to methylation of the pdlim2 promoter [252254]. Notably, PDLIM2 expression blocks constitutive NF-κB activation, and prevents in vitro cell growth and in vivo tumorigenesis of Tax-expressing cells and HTLV-1-transformed T cells, whereas PDLIM2 knockout enhances the pathogenic processes [79,168]. These studies suggest that the balance between PDLIM2 and HTLV-1 may determine ATL leukemogenesis. Given its role in terminating NF-κB/RelA activation [78], PDLIM2 may directly target RelA to suppress ATL, particularly during late stages of leukemogenesis when Tax expression is lost. In support of this, PDLIM2 expression is epigenetically repressed in several tumors such as breast and colon cancers, and expression of exogenous PDLIM2 or re-induction of endogenous PDLIM2 inhibits constitutive NF-κB activation and suppresses in vitro anchorage-independent growth and in vivo tumor formation of those malignant cells [253,254].
Over the past three decades, significant progress has been made toward understanding the molecular mechanism of constitutive NF-κB activation and its functional role in Tax-mediated tumorigenesis and ATL leukemogenesis. These studies have greatly enhanced our knowledge of NF-κB signaling regulation and NF-κB-associated tumorigenesis beyond ATL. However, many key issues have not yet been addressed. First, it is largely unknown how IKK is activated by the Tax-IKK interaction and whether Tax-independent IKK/NF-κB activation in HTLV-1-infected T cells is reminiscent of cellular mechanisms such as those induced by cytokines, oxidative stress and genetic stress. Second, there is still no convincing evidence for a functional role of NF-κB pathways, particularly different NF-κB family members, in Tax-mediated tumorigenesis or ATL leukemogenesis. Most functional studies have focused on the in vitro effects on Tax-induced cell growth and immortalization using IKK or NF-κB inhibitors (most of them not completely NF-κB specific, and IKK has many functions independent of NF-κB activation) or Tax mutants defective in NF-κB but not CREB/ATF activation. However, Tax has many functions beyond NF-κB and CREB/ATF. Moreover, the functions of Tax are highly sensitive to structural changes [178,179]. The loss-of-function studies through Tax mutations may be artificial. Third, it remains largely unknown how NF-κB cooperates with other signaling pathways in tumorigenesis. In this regard, NF-κB is known to crosstalk with many other tumor-related signaling pathways such as autophagy and PI3K signaling pathways [255257]. Fourth, most studies focus on the net effect of NF-κB activation on cell growth and tumor tumorigenesis. As an old Chinese saying goes, everything has yin (negative) and yang (positive), two opposite aspects, and so does NF-κB. Although NF-κB activation contributes to tumorigenesis in general, it may also play a negative role at certain stages of tumorigenesis and even exert a net negative effect on tumorigenesis in certain situations. One mechanism of NF-κB-mediated tumor suppression involves its original function in immunity and immunosurveillance [27]. Moreover, Tax-activated NF-κB may also lead to cell apoptosis [258]. Currently, it is largely unknown how the anti-tumor activity of NF-κB is suppressed and converted to be pro-tumorigenic for ATL development. It is possible that various cytokines/chemokines and other factors involved in immune responses also stimulate growth and migration of pre-tumor and tumor cells, in addition to immune cells [27]. In this regard, HTLV-1-infected T cells are in a unique position, because they are part of the immune system. It is also possible that human immune activation may induce Tax expression and reactivate latent HTLV-1, thereby leading to ATL development or other viral pathogenesis [259]. Fifth, very few downstream targets of NF-κB that play a critical role in tumorigenesis have been clearly and comprehensively identified. Sixth, possibly the most important and interesting question in the HTLV-1 field is how the Tax oncoprotein and the hbz gene cooperate and contribute to the pathogenesis of ATL and other HTLV-1-associated diseases. Finally, there is a lack of a systematic analysis of the correlations between ATL development and viral gene expression, PDLIM2 repression and NF-κB activation. Future genetic studies, particularly those using inducible and conditional transgenic mice, and computational modeling analysis will help to understand the complex and dynamic role of NF-κB in ATL leukemogenesis and other human tumors, and help to design personalized treatments for cancer patients.
Acknowledgments
This study was supported in part by National Institutes of Health/National Cancer Institute (NIH/NCI) grant R01 CA116616, American Cancer Society (ACS) Research Scholar grant RSG-06-066-01-MGO and Hillman Innovative Cancer Research Award to G. Xiao. The authors would like to thank Susan Marriott for critical reading of the manuscript.
1. Gallo R. History of the discoveries of the first human retroviruses: HTLV-1 and HTLV-2. Oncogene. 2005;24:5926–5930. [PubMed]
2. Feuer G, Green PL. Comparative biology of human T-cell lymphotropic virus type 1 (HTLV-1) and HTLV-2. Oncogene. 2005;24:5996–56004. [PMC free article] [PubMed]
3. Oh U, Jacobson S. Treatment of HTLV-I-associated myelopathy/tropical spastic paraparesis: Toward rational targeted therapy. Neurol. Clin. 2008;26:781–797. [PMC free article] [PubMed]
4. Tsukasaki K, Hermine O, Bazarbachi A, Ratner L, Ramos JC, Harrington W, Jr, O'Mahony D, Janik JE, Bittencourt AL, Taylor GP, et al. Definition, prognostic factors, treatment, and response criteria of adult T-cell leukemia-lymphoma: A proposal from an international consensus meeting. J. Clin. Oncol. 2009;27:453–459. [PMC free article] [PubMed]
5. Goncalves DU, Proietti FA, Ribas JG, Araujo MG, Pinheiro SR, Guedes AC, Carneiro-Proietti AB. Epidemiology, treatment, and prevention of human T-cell leukemia virus type 1-associated diseases. Clin. Microbiol. Rev. 2010;23:577–589. [PMC free article] [PubMed]
6. Burmeister T. Oncogenic retroviruses in animals and humans. Rev. Med. Virol. 2001;11:369–380. [PubMed]
7. Sun SC, Yamaoka S. Activation of NF-kappaB by HTLV-I and implications for cell transformation. Oncogene. 2005;24:5952–5964. [PubMed]
8. 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]
9. Higuchi M, Fujii M. Distinct functions of HTLV-1 Tax1 from HTLV-2 Tax2 contribute key roles to viral pathogenesis. Retrovirology. 2009;6:117. [PMC free article] [PubMed]
10. Pozzatti R, Vogel J, Jay G. The human T-lymphotropic virus type I tax gene can cooperate with the ras oncogene to induce neoplastic transformation of cells. Mol. Cell Biol. 1990;10:413–417. [PMC free article] [PubMed]
11. 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. J. Virol. 1992;66:4570–4575. [PMC free article] [PubMed]
12. Akagi T, Shimotohno K. Proliferative response of Tax1-transduced primary human T cells to anti-CD3 antibody stimulation by an interleukin-2-independent pathway. J. Virol. 1993;67:1211–1217. [PMC free article] [PubMed]
13. 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]
14. Fujita M, Shiku H. Differences in sensitivity to induction of apoptosis among rat fibroblast cells transformed by HTLV-I tax gene or cellular nuclear oncogenes. Oncogene. 1995;11:15–20. [PubMed]
15. Oka T, Sonobe H, Iwata J, Kubonishi I, Satoh H, Takata M, Tanaka Y, Tateno M, Tozawa H, Mori S, et al. Phenotypic progression of a rat lymphoid cell line immortalized by human T-lymphotropic virus type I to induce lymphoma/leukemia-like disease in rats. J. Virol. 1992;66:6686–6694. [PMC free article] [PubMed]
16. Yamaoka S, Tobe T, Hatanaka M. Tax protein of human T-cell leukemia virus type I is required for maintenance of the transformed phenotype. Oncogene. 1992;7:433–437. [PubMed]
17. Nerenberg M, Hinrichs SH, Reynolds RK, Khoury G, Jay G. The tat gene of human T-lymphotropic virus type 1 induces mesenchymal tumors in transgenic mice. Science. 1987;237:1324–1329. [PubMed]
18. Hinrichs SH, Nerenberg M, Reynolds RK, Khoury G, Jay G. A transgenic mouse model for human neurofibromatosis. Science. 1987;237:1340–1343. [PubMed]
19. Peebles RS, Maliszewski CR, Sato TA, Hanley-Hyde J, Maroulakou IG, Hunziker R, Schneck JP, Green JE. Abnormal B-cell function in HTLV-I-tax transgenic mice. Oncogene. 1995;10:1045–1051. [PubMed]
20. 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]
21. Iwakura Y, Tosu M, Yoshida E, Saijo S, Nakayama-Yamada J, Itagaki K, Asano M, Siomi H, Hatanaka M, Takeda T, et al. Augmentation of c-fos and c-jun expression in transgenic mice carrying the human T-cell leukemia virus type-I tax gene. Virus Genes. 1995;9:161–170. [PubMed]
22. Hall AP, Irvine J, Blyth K, Cameron ER, Onions DE, Campbell ME. Tumours derived from HTLV-I tax transgenic mice are characterized by enhanced levels of apoptosis and oncogene expression. J. Pathol. 1998;186:209–214. [PubMed]
23. Hasegawa H, Sawa H, Lewis MJ, Orba Y, Sheehy N, Yamamoto Y, Ichinohe T, Tsunetsugu-Yokota Y, Katano H, Takahashi H, et al. 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]
24. Banerjee P, Tripp A, Lairmore MD, Crawford L, Sieburg M, Ramos JC, Harrington W, Jr, Beilke MA, Feuer G. Adult T-cell leukemia/lymphoma development in HTLV-1-infected humanized SCID mice. Blood. 2010;115:2640–2648. [PubMed]
25. Akagi T, Ono H, Shimotohno K. Characterization of T cells immortalized by Tax1 of human T-cell leukemia virus type 1. Blood. 1995;86:4243–4249. [PubMed]
26. Xiao G, Rabson AB, Young W, Qing G, Qu Z. Alternative pathways of NF-kappaB activation: a double-edged sword in health and disease. Cytokine Growth Factor Rev. 2006;17:281–293. [PubMed]
27. Xiao G, Fu J. NF-kappaB and Cancer: A Paradigm of Yin-Yang. Am. J. Cancer Res. 2011;1:192–221. [PMC free article] [PubMed]
28. Rice NR, MacKichan ML, Israel A. The precursor of NF-kappa B p50 has I kappa B-like functions. Cell. 1992;71:243–253. [PubMed]
29. Mercurio F, DiDonato JA, Rosette C, Karin M. p105 and p98 precursor proteins play an active role in NF-kappa B-mediated signal transduction. Genes Dev. 1993;7:705–718. [PubMed]
30. Heissmeyer V, Krappmann D, Hatada EN, Scheidereit C. Shared pathways of IkappaB kinase-induced SCF(betaTrCP)-mediated ubiquitination and degradation for the NF-kappaB precursor p105 and IkappaBalpha. Mol. Cell Biol. 2001;21:1024–1035. [PMC free article] [PubMed]
31. Sriskantharajah S, Belich MP, Papoutsopoulou S, Janzen J, Tybulewicz V, Seddon B, Ley SC. Proteolysis of NF-kappaB1 p105 is essential for T cell antigen receptor-induced proliferation. Nat. Immunol. 2009;10:38–47. [PubMed]
32. Xiao G, Harhaj EW, Sun SC. NF-kappaB-inducing kinase regulates the processing of NF-kappaB2 p100. Mol. Cell. 2001;7:401–409. [PubMed]
33. Qing G, Qu Z, Xiao G. Regulation of NF-kappa B2 p100 processing by its cis-acting domain. J. Biol. Chem. 2005;280:18–27. [PubMed]
34. Pahl HL. Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene. 1999;18:6853–6866. [PubMed]
35. Chen ZJ. Ubiquitin signalling in the NF-kappaB pathway. Nat. Cell Biol. 2005;7:758–765. [PMC free article] [PubMed]
36. Wuerzberger-Davis SM, Miyamoto S. TAK-ling IKK activation: “Ub” the judge. Sci Signal. 2010;3:pe3. [PubMed]
37. Israel A. The IKK complex, a central regulator of NF-kappaB activation. Cold Spring Harb. Perspect. Biol. 2010;2:a000158. [PMC free article] [PubMed]
38. Zhong H, May MJ, Jimi E, Ghosh S. The phosphorylation status of nuclear NF-kappaB determines its association with CBP/p300 or HDAC-1. Mol. Cell. 2002;9:625–636. [PubMed]
39. Ashburner BP, Westerheide SD, Baldwin AS., Jr The p65 (RelA) subunit of NF-kappaB interacts with the histone deacetylase (HDAC) corepressors HDAC1 and HDAC2 to negatively regulate gene expression. Mol. Cell Biol. 2001;21:7065–7077. [PMC free article] [PubMed]
40. Ryo A, Suizu F, Yoshida Y, Perrem K, Liou YC, Wulf G, Rottapel R, Yamaoka S, Lu KP. Regulation of NF-kappaB signaling by Pin1-dependent prolyl isomerization and ubiquitin-mediated proteolysis of p65/RelA. Mol. Cell. 2003;12:1413–1426. [PubMed]
41. Chen LF, Fischle W, Verdin E, Greene WC. Duration of nuclear NF-kappaB action regulated by reversible acetylation. Science. 2001;293:1653–1657. [PubMed]
42. Qing G, Qu Z, Xiao G. Stabilization of basally translated NF-kappaB-inducing kinase (NIK) protein functions as a molecular switch of processing of NF-kappaB2 p100. J. Biol. Chem. 2005;280:40578–40582. [PubMed]
43. Liao G, Zhang M, Harhaj EW, Sun SC. Regulation of the NF-kappaB-inducing kinase by tumor necrosis factor receptor-associated factor 3-induced degradation. J. Biol. Chem. 2004;279:26243–26250. [PubMed]
44. Sun SC, Ley SC. New insights into NF-kappaB regulation and function. Trends Immunol. 2008;29:469–478. [PubMed]
45. Xiao G, Sun SC. Negative regulation of the nuclear factor kappa B-inducing kinase by a cis-acting domain. J. Biol. Chem. 2000;19:1448–1456. [PubMed]
46. Gardam S, Sierro F, Basten A, Mackay F, Brink R. TRAF2 and TRAF3 signal adapters act cooperatively to control the maturation and survival signals delivered to B cells by the BAFF receptor. Immunity. 2008;28:391–401. [PubMed]
47. Grech AP, Amesbury M, Chan T, Gardam S, Basten A, Brink R. TRAF2 differentially regulates the canonical and noncanonical pathways of NF-kappaB activation in mature B cells. Immunity. 2004;21:629–642. [PubMed]
48. He JQ, Zarnegar B, Oganesyan G, Saha SK, Yamazaki S, Doyle SE, Dempsey PW, Cheng G. Rescue of TRAF3-null mice by p100 NF-kappa B deficiency. J. Exp. Med. 2006;203:2413–2418. [PMC free article] [PubMed]
49. Moore CR, Bishop GA. Differential regulation of CD40-mediated TNF receptor-associated factor degradation in B lymphocytes. J. Immunol. 2005;175:3780–3789. [PubMed]
50. Varfolomeev E, Blankenship JW, Wayson SM, Fedorova AV, Kayagaki N, Garg P, Zobel K, Dynek JN, Elliott LO, Wallweber HJ, et al. IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis. Cell. 2007;131:669–681. [PubMed]
51. Vince JE, Wong WW, Khan N, Feltham R, Chau D, Ahmed AU, Benetatos CA, Chunduru SK, Condon SM, McKinlay M, et al. IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis. Cell. 2007;131:682–693. [PubMed]
52. Fong A, Sun SC. Genetic evidence for the essential role of beta-transducin repeat-containing protein in the inducible processing of NF-kappa B2/p100. J. Biol. Chem. 2002;277:22111–22114. [PubMed]
53. Senftleben U, Cao Y, Xiao G, Greten FR, Krahn G, Bonizzi G, Chen Y, Hu Y, Fong A, Sun SC, Karin M. Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway. Science. 2001;293:1495–1499. [PubMed]
54. Xiao G, Fong A, Sun SC. Induction of p100 processing by NF-kappaB-inducing kinase involves docking IkappaB kinase alpha (IKKalpha) to p100 and IKKalpha-mediated phosphorylation. J. Biol. Chem. 2004;279:30099–30105. [PubMed]
55. Zarnegar B, Yamazaki S, He JQ, Cheng G. Control of canonical NF-kappaB activation through the NIK-IKK complex pathway. Proc. Natl. Acad. Sci. U. S. A. 2008;105:3503–3508. [PubMed]
56. Delhase M, Hayakawa M, Chen Y, Karin M. Positive and negative regulation of IkappaB kinase activity through IKKbeta subunit phosphorylation. Science. 1999;284:309–313. [PubMed]
57. Razani B, Zarnegar B, Ytterberg AJ, Shiba T, Dempsey PW, Ware CF, Loo JA, Cheng G. Negative feedback in noncanonical NF-kappaB signaling modulates NIK stability through IKKalpha-mediated phosphorylation. Sci Signal. 2010;3:pe41. [PMC free article] [PubMed]
58. Wertz IE, O'Rourke KM, Zhou H, Eby M, Aravind L, Seshagiri S, Wu P, Wiesmann C, Baker R, Boone DL, et al. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature. 2004;430:694–699. [PubMed]
59. Krikos A, Laherty CD, Dixit VM. Transcriptional activation of the tumor necrosis factor alpha-inducible zinc finger protein, A20, is mediated by kappa B elements. J. Biol. Chem. 1992;267:17971–17976. [PubMed]
60. Shembade N, Ma A, Harhaj EW. Inhibition of NF-kappaB signaling by A20 through disruption of ubiquitin enzyme complexes. Science. 2010;327:1135–1139. [PMC free article] [PubMed]
61. Boone DL, Turer EE, Lee EG, Ahmad RC, Wheeler MT, Tsui C, Hurley P, Chien M, Chai S, Hitotsumatsu O, et al. The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nat. Immunol. 2004;5:1052–1060. [PubMed]
62. Zhang SQ, Kovalenko A, Cantarella G, Wallach D. Recruitment of the IKK signalosome to the p55 TNF receptor: RIP and A20 bind to NEMO (IKKgamma) upon receptor stimulation. Immunity. 2000;12:301–311. [PubMed]
63. Mauro C, Pacifico F, Lavorgna A, Mellone S, Iannetti A, Acquaviva R, Formisano S, Vito P, Leonardi A. ABIN-1 binds to NEMO/IKKgamma and co-operates with A20 in inhibiting NF-kappaB. J. Biol. Chem. 2006;281:18482–18488. [PubMed]
64. Hutti JE, Turk BE, Asara JM, Ma A, Cantley LC, Abbott DW. IkappaB kinase beta phosphorylates the K63 deubiquitinase A20 to cause feedback inhibition of the NF-kappaB pathway. Mol. Cell Biol. 2007;27:7451–7461. [PMC free article] [PubMed]
65. Sun SC. CYLD: a tumor suppressor deubiquitinase regulating NF-kappaB activation and diverse biological processes. Cell Death Differ. 2010;17:25–34. [PubMed]
66. Brummelkamp TR, Nijman SM, Dirac AM, Bernards R. Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB. Nature. 2003;424:797–801. [PubMed]
67. Kovalenko A, Chable-Bessia C, Cantarella G, Israel A, Wallach D, Courtois G. The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination. Nature. 2003;424:801–805. [PubMed]
68. Trompouki E, Hatzivassiliou E, Tsichritzis T, Farmer H, Ashworth A, Mosialos G. CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members. Nature. 2003;424:793–796. [PubMed]
69. Chew J, Biswas S, Shreeram S, Humaidi M, Wong ET, Dhillion MK, Teo H, Hazra A, Fang CC, López-Collazo E, et al. WIP1 phosphatase is a negative regulator of NF-kappaB signalling. Nat. Cell Biol. 2009;11:659–666. [PubMed]
70. Li S, Wang L, Berman MA, Zhang Y, Dorf ME. RNAi screen in mouse astrocytes identifies phosphatases that regulate NF-kappaB signaling. Mol. Cell. 2006;24:497–509. [PMC free article] [PubMed]
71. Yang J, Fang GH, Wadzinski BE, Sakurai H, Richmond A. Protein phosphatase 2A interacts with and directly dephosphorylates RelA. J. Biol. Chem. 2001;276:47828–47833. [PMC free article] [PubMed]
72. Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA, Mayo MW. Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 2004;23:2369–2380. [PubMed]
73. Wu M, Xu LG, Zhai Z, Shu HB. SINK is a p65-interacting negative regulator of NF-kappaB-dependent transcription. J. Biol. Chem. 2003;278:27072–27079. [PubMed]
74. Šošić D, Richardson JA, Yu K, Ornitz DM, Olson EN. Twist regulates cytokine gene expression through a negative feedback loop that represses NF-kappaB activity. Cell. 2003;112:169–180. [PubMed]
75. Yang JP, Hori M, Sanda T, Okamoto T. Identification of a novel inhibitor of nuclear factor-kappaB, RelA-associated inhibitor. J. Biol. Chem. 1999;274:15662–15670. [PubMed]
76. Sun SC, Ganchi PA, Ballard DW, Greene WC. NF-kappa B controls expression of inhibitor I kappa B alpha: evidence for an inducible autoregulatory pathway. Science. 1993;259:1912–1915. [PubMed]
77. Saccani S, Marazzi I, Beg AA, Natoli G. Degradation of promoter-bound p65/RelA is essential for the prompt termination of the nuclear factor kappaB response. J. Exp. Med. 2004;200:107–113. [PMC free article] [PubMed]
78. Tanaka T, Grusby MJ, Kaisho T. PDLIM2-mediated termination of transcription factor NF-kappaB activation by intranuclear sequestration and degradation of the p65 subunit. Nat. Immunol. 2007;8:584–591. [PubMed]
79. Fu J, Yan P, Li S, Qu Z, Xiao G. Molecular determinants of PDLIM2 in suppressing HTLV-I Tax-mediated tumorigenesis. Oncogene. 2010;29:6499–6507. [PMC free article] [PubMed]
80. Watanabe M, Ohsuqi T, Shoda M, Ishida T, Aizawa S, Maruyama-Nagai M, Utsunomiya A, Koga S, Yamada Y, Kamihira S, et al. Dual targeting of transformed and untransformed HTLV-1-infected T cells by DHMEQ, a potent and selective inhibitor of NF-kappaB, as a strategy for chemoprevention and therapy of adult T-cell leukemia. Blood. 2005;106:2462–2471. [PubMed]
81. Ballard DW, Böhnlein E, Lowenthal JW, Wano Y, Franza BR, Greene WC. HTLV-I tax induces cellular proteins that activate the kappa B element in the IL-2 receptor alpha gene. Science. 1988;241:1652–1655. [PubMed]
82. Böhnlein E, Siekevitz M, Ballard DW, Lowenthal JW, Rimsky L, Bogérd H, Hoffman J, Wano Y, Franza BR, Greene WC. Stimulation of the human immunodeficiency virus type 1 enhancer by the human T-cell leukemia virus type I tax gene product involves the action of inducible cellular proteins. J. Virol. 1989;63:1578–1586. [PMC free article] [PubMed]
83. Leung K, Nabel GL. HTLV-1 transactivator induces interleukin-2 receptor expression through an NF-kappa B-like factor. Nature. 1988;333:776–778. [PubMed]
84. Ruben S, Poteat H, Tan TH, Kawakami K, Roeder R, Haseltine W, Rosen CA. Cellular transcription factors and regulation of IL-2 receptor gene expression by HTLV-I tax gene product. Science. 1988;241:89–92. [PubMed]
85. Chu ZL, Shin YA, Yang JM, DiDonato JA, Ballard DW. IKKgamma mediates the interaction of cellular IkappaB kinases with the tax transforming protein of human T cell leukemia virus type 1. J. Biol. Chem. 1999;274:15297–15300. [PubMed]
86. Harhaj EW, Sun SC. IKKgamma serves as a docking subunit of the IkappaB kinase (IKK) and mediates interaction of IKK with the human T-cell leukemia virus Tax protein. J. Biol. Chem. 1999;274:22911–22914. [PubMed]
87. Jin DY, Giordano V, Kibler KV, Nakano H, Jeang KT. Role of adapter function in oncoprotein-mediated activation of NF-kappaB. Human T-cell leukemia virus type I Tax interacts directly with IkappaB kinase gamma. J. Biol. Chem. 1999;274:17402–17405. [PubMed]
88. Xiao G, Harhaj EW, Sun SC. Domain-specific interaction with the I kappa B kinase (IKK)regulatory subunit IKK gamma is an essential step in tax-mediated activation of IKK. J. Biol. Chem. 2000;275:34060–34067. [PubMed]
89. O'Mahony AM, Montanp M, Van Beneden K, Chen LF, Greene WC. Human T-cell lymphotropic virus type 1 tax induction of biologically Active NF-kappaB requires IkappaB kinase-1-mediated phosphorylation of RelA/p65. J. Biol. Chem. 2004;279:18137–18145. [PubMed]
90. Semmes OJ, Jeang KT. Localization of human T-cell leukemia virus type 1 tax to subnuclear compartments that overlap with interchromatin speckles. J. Virol. 1996;70:6347–6357. [PMC free article] [PubMed]
91. Bex F, McDowall A, Burny A, Gaynor R. The human T-cell leukemia virus type 1 transactivator protein Tax colocalizes in unique nuclear structures with NF-kappaB proteins. J. Virol. 1997;71:3484–3497. [PMC free article] [PubMed]
92. Jin DY, Jeang KT. HTLV-I Tax self-association in optimal trans-activation function. Nucleic Acids Res. 1997;25:379–387. [PMC free article] [PubMed]
93. Tie F, Adya N, Greene WC, Giam CZ. Interaction of the human T-lymphotropic virus type 1 Tax dimer with CREB and the viral 21-base-pair repeat. J. Virol. 1996;70:8368–8374. [PMC free article] [PubMed]
94. Xiao G, Sun SC. Activation of IKKalpha and IKKbeta through their fusion with HTLV-I tax protein. Oncogene. 2000;19:5198–5203. [PubMed]
95. Yu Q, Minoda Y, Yoshida R, Yoshida H, Iha H, Kobayashi T, Yoshimura A, Takaesu G. HTLV-1 Tax-mediated TAK1 activation involves TAB2 adapter protein. Biochem. Biophys. Res. Commun. 2008;365:189–194. [PubMed]
96. Uhlik M, Good L, Xiao G, Harhaj EW, Zandi E, Karin M, Sun SC. NF-kappaB-inducing kinase and IkappaB kinase participate in human T-cell leukemia virus I Tax-mediated NF-kappaB activation. J. Biol. Chem. 1998;273:21132–21136. [PubMed]
97. Yin MJ, Christerson LB, Yamamoto Y, Kwak YT, Xu S, Mercurio F, Barbosa M, Cobb MH, Gaynor RB. HTLV-I Tax protein binds to MEKK1 to stimulate IkappaB kinase activity and NF-kappaB activation. Cell. 1998;93:875–884. [PubMed]
98. Babu G, Waterfield M, Chang M, Wu X, Sun SC. Deregulated activation of oncoprotein kinase Tpl2/Cot in HTLV-I-transformed T cells. J. Biol. Chem. 2006;281:14041–14047. [PubMed]
99. Suzuki S, Singhirunnusorn P, Mori A, Yamaoka S, Kitajima I, Saiki I, Sakurai H. Constitutive activation of TAK1 by HTLV-1 tax-dependent overexpression of TAB2 induces activation of JNK-ATF2 but not IKK-NF-kappaB. J. Biol. Chem. 2007;282:25177–25181. [PubMed]
100. Gohda J, Irisawa M, Tanaka Y, Sato S, Ohtani K, Fujisawa J, Inoue J. HTLV-1 Tax-induced NFkappaB activation is independent of Lys-63-linked-type polyubiquitination. Biochem. Biophys. Res. Commun. 2007;357:225–230. [PubMed]
101. Suzuki S, Zhou Y, Refaat A, Takasaki I, Koizumi K, Yamaoka S, Tabuchi Y, Saiki I, Sakurai H. Human T cell lymphotropic virus 1 manipulates interferon regulatory signals by controlling the TAK1-IRF3 and IRF4 pathways. J. Biol. Chem. 2010;285:4441–4446. [PubMed]
102. Kfoury Y, Nasr R, Favre-Bonvin A, El-Sabban M, Renault N, Giron ML, Setterblad N, Hajj HE, Chiari E, Mikati AG, et al. Ubiquitylated Tax targets and binds the IKK signalosome at the centrosome. Oncogene. 2008;27:1665–1676. [PubMed]
103. Harhaj NS, Sun SC, Harhaj EW. Activation of NF-kappa B by the human T cell leukemia virus type I Tax oncoprotein is associated with ubiquitin-dependent relocalization of I kappa B kinase. J. Biol. Chem. 2007;282:4185–4192. [PubMed]
104. Journo C, Filipe J, About F, Chevalier SA, Afonso PV, Brady JN, Flynn D, Tangy F, Israël A, Vidalain PO, et al. NRP/Optineurin Cooperates with TAX1BP1 to potentiate the activation of NF-kappaB by human T-lymphotropic virus type 1 tax protein. PLoS Pathog. 2009;5:e1000521. [PMC free article] [PubMed]
105. Avesani F, Romanelli MG, Turci M, Di Gennaro G, Sampaio C, Bidoia C, Bertazzoni U, Bex F. Association of HTLV Tax proteins with TAK1-binding protein 2 and RelA in calreticulin-containing cytoplasmic structures participates in Tax-mediated NF-κB activation. Virology. 2010;408:39–48. [PubMed]
106. Huang J, Ren T, Guan H, Jiang Y, Cheng H. HTLV-1 Tax is a critical lipid raft modulator that hijacks IkappaB kinases to the microdomains for persistent activation of NF-kappaB. J. Biol. Chem. 2009;284:6208–6217. [PubMed]
107. Lamsoul I, Lodewick J, Lebrun S, Brasseur R, Burny A, Gaynor RB, Bex F. Exclusive ubiquitination and sumoylation on overlapping lysine residues mediate NF-kappaB activation by the human T-cell leukemia virus tax oncoprotein. Mol. Cell Biol. 2005;25:10391–10406. [PMC free article] [PubMed]
108. Nasr R, Chiari E, El-Sabban M, Mahieux R, Kfoury Y, Abdulhay M, Yazbeck V, Hermine O, de Thé H, Pique C, Bazarbachi A. Tax ubiquitylation and sumoylation control critical cytoplasmic and nuclear steps of NF-kappaB activation. Blood. 2006;107:4021–4029. [PubMed]
109. Shembade N, Harhaj NS, Yamamoto M, Akira S, Harhaj EW. The human T-cell leukemia virus type 1 Tax oncoprotein requires the ubiquitin-conjugating enzyme Ubc13 for NF-kappaB activation. J. Virol. 2003;81:13735–13742. [PMC free article] [PubMed]
110. Kfoury Y, Setterblad N, El-Sabban M, Zamborlini A, Dassouki Z, El Hajj H, Hermine O, Pique C, de Thé H, Saïb A, Bazarbachi A. Tax ubiquitylation and SUMOylation control the dynamic shuttling of Tax and NEMO between Ubc9 nuclear bodies and the centrosome. Blood. 2011;117:190–199. [PubMed]
111. Miyamoto S. Nuclear initiated NF-kappa B signaling: NEMO and ATM take center stage. Cell Res. 2011;21:116–130. [PMC free article] [PubMed]
112. Huang TT, Wuerzberger-Davis SM, Wu ZH, Miyamoto S. Sequential modification of NEMO/IKKgamma by SUMO-1 and ubiquitin mediates NF-kappaB activation by genotoxic stress. Cell. 2003;115:565–576. [PubMed]
113. Verma UN, Yamamoto Y, Prajapati S, Gaynor RB. Nuclear role of I kappa B Kinase-gamma/NF-kappa B essential modulator (IKK gamma/NEMO) in NF-kappa B-dependent gene expression. J. Biol. Chem. 2004;279:3509–3515. [PubMed]
114. Bex F, Murphy K, Wattiez R, Burny A, Gaynor RB. Phosphorylation of the human T-cell leukemia virus type 1 transactivator tax on adjacent serine residues is critical for tax activation. J. Virol. 1999;73:738–745. [PMC free article] [PubMed]
115. Lodewick J, Lamsoul I, Polania A, Lebrun S, Burny A, Ratner L, Bex F. Acetylation of the human T-cell leukemia virus type 1 Tax oncoprotein by p300 promotes activation of the NF-kappaB pathway. Virology. 2009;386:68–78. [PMC free article] [PubMed]
116. Durkin SS, Ward MD, Fryrear KA, Semmes OJ. Site-specific phosphorylation differentiates active from inactive forms of the human T-cell leukemia virus type 1 Tax oncoprotein. J. Biol. Chem. 2006;281:31705–31712. [PubMed]
117. Peloponese JM, Jr, Yasunaga J, Kinjo T, Watashi K, Jeang KT. Peptidylproline cis-transisomerase Pin1 interacts with human T-cell leukemia virus type 1 tax and modulates its activation of NF-kappaB. J. Virol. 2009;83:3238–3248. [PMC free article] [PubMed]
118. Jeong SJ, Rya A, Yamamoto N. The prolyl isomerase Pin1 stabilizes the human T-cell leukemia virus type 1 (HTLV-1) Tax oncoprotein and promotes malignant transformation. Biochem. Biophys. Res. Commun. 2009;381:294–299. [PubMed]
119. Fan G, Fan Y, Gupta N, Matsuura I, Liu F, Zhou XZ, Lu KP, Gélinas C. Peptidylprolyl isomerase Pin1 markedly enhances the oncogenic activity of the rel proteins in the nuclear factor-kappaB family. Cancer Res. 2009;69:4589–4597. [PMC free article] [PubMed]
120. Xiao G, Cvijic ME, Fong A, Harhaj EW, Uhlik MT, Waterfield M, Sun SC. Retroviral oncoprotein Tax induces processing of NF-kappaB2/p100 in T cells: Evidence for the involvement of IKKalpha. EMBO J. 2001;20:6805–6815. [PubMed]
121. Harhaj EW, Good L, Xiao G, Uhlik M, Cvijic ME, Rivera-Walsh I, Sun SC. Somatic mutagenesis studies of NF-kappa B signaling in human T cells: evidence for an essential role of IKK gamma in NF-kappa B activation by T-cell costimulatory signals and HTLV-I Tax protein. Oncogene. 2000;19:1448–1456. [PubMed]
122. Yamaoka S, Courtois G, Bessia C, Whiteside ST, Weil R, Agou F, Kirk HE, Kay RJ, Israël A. Complementation cloning of NEMO, a component of the IkappaB kinase complex essential for NF-kappaB activation. Cell. 1998;93:1231–1240. [PubMed]
123. Qu Z, Qing G, Rabson AB, Xiao G. Tax deregulation of NF-kappaB2 p100 processing involves both beta-TrCP-dependent and -independent mechanisms. J. Biol. Chem. 2004;279:44563–44572. [PubMed]
124. Furukawa Y, Kubota R, Tara M, Izumo S, Osame M. Existence of escape mutant in HTLVI tax during the development of adult T-cell leukemia. Blood. 2001;97:987–993. [PubMed]
125. Furukawa Y, Osame M, Kubota R, Tara M, Yoshida M. Human T-cell leukemia virus type-1 (HTLV-1) Tax is expressed at the same level in infected cells of HTLV-1-associated myelopathy or tropical spastic paraparesis patients as in asymptomatic carriers but at a lower level in adult T-cell leukemia cells. Blood. 1995;85:1865–1870. [PubMed]
126. Koiwa T, Hamano-Usami A, Ishida T, Okayama A, Yamaguchi K, Kamihira S, Watanabe T. 5′-long terminal repeat-selective CpG methylation of latent human T-cell leukemia virus type 1 provirus in vitro and in vivo. J. Virol. 2001;76:9389–9397. [PMC free article] [PubMed]
127. Takeda S, Maeda M, Morikawa S, Taniguchi Y, Yasunaga J, Nosaka K, Tanaka Y, Matsuoka M. Genetic and epigenetic inactivation of tax gene in adult T-cell leukemia cells. Int. J. Cancer. 2004;109:559–567. [PubMed]
128. Taniguchi Y, Nosaka K, Yasunaga J, Maeda M, Mueller N, Okayama A, Matsuoka M. Silencing of human T-cell leukemia virus type I gene transcription by epigenetic mechanisms. Retrovirology. 2005;2:64. [PMC free article] [PubMed]
129. Tamiya S, Matsuoka M, Etoh K, Watanabe T, Kamihira S, Yamaguchi K, Takatsuki K. Two types of defective human T-lymphotropic virus type I provirus in adult T-cell leukemia. Blood. 1996;88:3065–3073. [PubMed]
130. Hironaka N, Mochida K, Mori N, Maeda M, Yamamoto N, Yamaoka S. Tax-independent constitutive IkappaB kinase activation in adult T-cell leukemia cells. Neoplasia. 2004;6:266–278. [PMC free article] [PubMed]
131. Mori N, Fujii M, Ikeda S, Yamada Y, Tomonaga M, Ballard DW, Yamamoto N. Constitutive activation of NF-kappaB in primary adult T-cell leukemia cells. Blood. 1999;93:2360–2368. [PubMed]
132. Yan P, Qing G, Qu Z, Wu CC, Rabson AB, Xiao G. Targeting autophagic regulation of NFkappaB in HTLV-I transformed cells by geldanamycin: Implications for therapeutic interventions. Autophagy. 2007;3:600–603. [PubMed]
133. Jang IK, Gu H. Negative regulation of TCR signaling and T-cell activation by selective protein degradation. Curr. Opin. Immunol. 2003;15:315–320. [PubMed]
134. Gupta N, Delrow J, Drawid A, Sengupta AM, Fan G, Gélinas C. Repression of B-cell linker (BLNK) and B-cell adaptor for phosphoinositide 3-kinase (BCAP) is important for lymphocyte transformation by rel proteins. Cancer Res. 2008;68:808–814. [PMC free article] [PubMed]
135. Harhaj EW, Good L, Xiao G, Sun SC. Gene expression profiles in HTLV-I-immortalized T cells: deregulated expression of genes involved in apoptosis regulation. Oncogene. 1999;18:1341–1349. [PubMed]
136. Koga Y, Oh-Hori N, Sato H, Yamamoto N, Kimura G, Nomoto K. Absence of transcription of lck (lymphocyte specific protein tyrosine kinase) message in IL-2-independent, HTLV-I-transformed T cell lines. J. Immunol. 1989;142:4493–4499. [PubMed]
137. Yssel H, de Waal Malefyt R, Duc Dodon MD, Blanchard D, Gazzolo L, de Vries JE, Spits H. 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. 1989;142:2279–2289. [PubMed]
138. de Waal Malefyt R, Yssel H, Spits H, de Vries JE, Sancho J, Terhorst C, Alarcon B. Human T cell leukemia virus type I prevents cell surface expression of the T cell receptor through down-regulation of the CD3-gamma, -delta, -epsilon, and -zeta genes. J. Immunol. 1990;145:2297–2303. [PubMed]
139. Weil R, Levraud J, Dodon MD, Bessia C, Hazan U, Kourilsky P, Israël A. Altered expression of tyrosine kinases of the Src and Syk families in human T-cell leukemia virus type 1-infected T-cell lines. J. Virol. 1999;73:3709–3717. [PMC free article] [PubMed]
140. Harhaj EW, Harhaj NS, Grant C, Mostoller K, Alefantis T, Sun SC, Wigdahl B. Human T cell leukemia virus type I Tax activates CD40 gene expression via the NF-kappaB pathway. Virology. 2005;333:145–158. [PubMed]
141. Higuchi M, Matsuda T, Mori N, Yamada Y, Horie R, Watanabe T, Takahashi M, Oie M, Fujii M. Elevated expression of CD30 in adult T-cell leukemia cell lines: possible role in constitutive NF-kappaB activation. Retrovirology. 2005;2:29. [PMC free article] [PubMed]
142. Cowan EP, Alexander RK, Daniel S, Kashanchi F, Brady JN. Induction of tumor necrosis factor alpha in human neuronal cells by extracellular human T-cell lymphotropic virus type 1 Tax. J. Virol. 1997;71:6982–6989. [PMC free article] [PubMed]
143. Kim YM, Sharma N, Nyborg JK. The proto-oncogene Bcl3, induced by Tax, represses Tax-mediated transcription via p300 displacement from the human T-cell leukemia virus type 1 promoter. J. Virol. 2008;82:11939–11947. [PMC free article] [PubMed]
144. Coope HJ, Atkinson P, Huhse B, Belich M, Janzen J, Holman MJ, Klaus GG, Johnston LH, Ley SC. CD40 regulates the processing of NF-kappaB2 p100 to p52. EMBO J. 2002;21:5375–5385. [PubMed]
145. Wright CW, Rumble JM, Duckett CS. CD30 activates both the canonical and alternative NF-kappaB pathways in anaplastic large cell lymphoma cells. J. Biol. Chem. 2007;282:s10252–s10262. [PubMed]
146. Horie R, Higashihara M, Watanabe T. Hodgkin's lymphoma and CD30 signal transduction. Int. J. Hematol. 2003;77:37–47. [PubMed]
147. Marriott SJ, Semmes OJ. Impact of HTLV-I Tax on cell cycle progression and the cellular DNA damage repair response. Oncogene. 2005;24:5986–5995. [PubMed]
148. Chlichlia K, Khazaie K. HTLV-1 Tax: Linking transformation, DNA damage and apoptotic T-cell death. Chem. Biol. Interact. 2010;188:359–365. [PubMed]
149. Isogawa M, Higuchi M, Takahashi M, Oie M, Mori N, Tanaka Y, Aoyagi Y, Fujii M. Rearranged NF-kappa B2 gene in an adult T-cell leukemia cell line. Cancer Sci. 2008;99:792–798. [PubMed]
150. Saitoh Y, Yamamoto N, Dewan MZ, Sugimoto H, Martinez Bruyn VJ, Iwasaki Y, Matsubara K, Qi X, Saitoh T, Imoto I, et al. Overexpressed NF-kappaB-inducing kinase contributes to the tumorigenesis of adult T-cell leukemia and Hodgkin Reed-Sternberg cells. Blood. 2008;111:5118–5129. [PubMed]
151. Yamamoto M, Ito T, Shimizu T, Ishida T, Semba K, Watanabe S, Yamaguchi N, Inoue J. Epigenetic alteration of the NF-kappaB-inducing kinase (NIK) gene is involved in enhanced NIK expression in basal-like breast cancer. Cancer Sci. 2010;101:2391–2397. [PubMed]
152. Qing G, Qu Z, Xiao G. Endoproteolytic processing of C-terminally truncated NF-kappaB2 precursors at kappaB-containing promoters. Proc. Natl. Acad Sci. U. S. A. 2007;104:5324–5329. [PubMed]
153. Qing G, Xiao G. Essential role of IkappaB kinase alpha in the constitutive processing of NF-kappaB2 p100. J. Biol. Chem. 2005;280:9765–9768. [PubMed]
154. Watanabe M, Muramatsu M, Hirai H, Suzuki T, Fujisawa J, Yoshida M, Arai K, Arai N. HTLV-I encoded Tax in association with NF-kappa B precursor p105 enhances nuclear localization of NF-kappa B p50 and p65 in transfected cells. Oncogene. 1992;8:2949–2958. [PubMed]
155. McKinsey TA, Brockman JA, Scherer DC, Al-Murrani SW, Green PL, Ballard DW. Inactivation of IkappaBbeta by the tax protein of human T-cell leukemia virus type 1: a potential mechanism for constitutive induction of NF-kappaB. Mol. Cell Biol. 1996;16:2083–2090. [PMC free article] [PubMed]
156. Good L, Sun SC. Persistent activation of NF-kappa B/Rel by human T-cell leukemia virus type 1 tax involves degradation of I kappa B beta. J. Virol. 1996;70:2730–2735. [PMC free article] [PubMed]
157. Maggirwar SB, Harhaj EW, Sun SC. Activation of NF-kappa B/Rel by Tax involves degradation of I kappa B alpha and is blocked by a proteasome inhibitor. Oncogene. 1995;11:993–998. [PubMed]
158. Sun SC, Xiao G. Deregulation of NF-kappaB and its upstream kinases in cancer. Cancer Metastasis Rev. 2003;22:405–422. [PubMed]
159. Hirai H, Fujisawa J, Suzuki T, Ueda K, Muramatsu M, Tsuboi A, Arai N, Yoshida M. Transcriptional activator Tax of HTLV-1 binds to the NF-kappa B precursor p105. Oncogene. 1992;7:1737–1742. [PubMed]
160. Suzuki T, Hirai H, Fujisawa J, Fujita T, Yoshida M. A trans-activator Tax of human T-cell leukemia virus type 1 binds to NF-kappa B p50 and serum response factor (SRF) and associates with enhancer DNAs of the NF-kappa B site and CArG box. Oncogene. 1993;8:2391–2397. [PubMed]
161. Suzuki T, Hirai H, Yoshida M. Tax protein of HTLV-1 interacts with the Rel homology domain of NF-kappa B p65 and c-Rel proteins bound to the NF-kappa B binding site and activates transcription. Oncogene. 1994;9:3099–3105. [PubMed]
162. Murakami T, Hirai H, Suzuki T, Fujisawa J, Yoshida M. HTLV-1 Tax enhances NF-kappa B2 expression and binds to the products p52 and p100, but does not suppress the inhibitory function of p100. Virology. 1995;206:1066–1074. [PubMed]
163. Suzuki T, Hirai H, Murakami T, Yoshida M. 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. 1995;10:1199–1207. [PubMed]
164. Petropoulos L, Lin R, Hiscott J. Human T cell leukemia virus type 1 tax protein increases NF-kappa B dimer formation and antagonizes the inhibitory activity of the I kappa B alpha regulatory protein. Virology. 1996;225:52–64. [PubMed]
165. Beraud C, Sun SC, Ganchi P, Ballard DW, Greene WC. Human T-cell leukemia virus type I Tax associates with and is negatively regulated by the NF-kappa B2 p100 gene product: implications for viral latency. Mol. Cell Biol. 1994;14:1374–1382. [PMC free article] [PubMed]
166. Lacoste J, Lanoix J, Pepin N, Hiscott J. Interactions between HTLV-I Tax and NF-kappa B/Rel proteins in T cells. Leukemia. 1994;8:S71–S76. [PubMed]
167. Lanoix J, Lacoste J, Pepin N, Rice N, Hiscott J. Overproduction of NFKB2 (lyt-10) and c-Rel: a mechanism for HTLV-I Tax-mediated trans-activation via the NF-kappa B signalling pathway. Oncogene. 1994;9:841–852. [PubMed]
168. Yan P, Fu J, Qu Z, Li S, Tanaka T, Grusby MJ, Xiao G. PDLIM2 suppresses human T-cell leukemia virus type I Tax-mediated tumorigenesis by targeting Tax into the nuclear matrix for proteasomal degradation. Blood. 2009;113:4370–4380. [PubMed]
169. Arima N, Molitor JA, Smith MR, Kim JH, Daitoku Y, Greene WC. Human T-cell leukemia virus type I Tax induces expression of the Rel-related family of kappa B enhancer-binding proteins: evidence for a pretranslational component of regulation. J. Virol. 1991;65:6892–6899. [PMC free article] [PubMed]
170. Inoue M, Matsuoka M, Yamaguchi K, Takatsuki K, Yoshida M. Characterization of mRNA expression of IkappaB alpha and NF-kappaB subfamilies in primary adult T-cell leukemia cells. Jpn. J. Cancer Res. 1998;89:53–59. [PubMed]
171. Li CC, Ruscetti FW, Rice NR, Chen E, Yang NS, Mikovits J, Longo DL. Differential expression of Rel family members in human T-cell leukemia virus type I-infected cells: transcriptional activation of c-rel by Tax protein. J. Virol. 1993;67:4205–4213. [PMC free article] [PubMed]
172. Fu J, Qu Z, Yan P, Ishikawa C, Aqeilan R, Rabson AB, Xiao G. The tumor suppressor gene wwox links the canonical and non-canonical NF-kappaB pathways in HTLV-I Tax-mediated tumorigenesis. Blood. 2011;117:1652–1661. [PubMed]
173. Jeong SJ, Pise-Masison CA, Radonovich MF, Park HU, Brady JN. Activated AKT regulates NF-kappaB activation, p53 inhibition and cell survival in HTLV-1-transformed cells. Oncogene. 2005;24:6719–6728. [PubMed]
174. Fukuda RI, Tsuchiya K, Suzuki K, Itoh K, Fujita J, Utsunomiya A, Tsuji T. Human T-cell leukemia virus type I tax down-regulates the expression of phosphatidylinositol 3,4,5-trisphosphate inositol phosphatases via the NF-kappaB pathway. J. Biol. Chem. 2009;284:2680–2689. [PubMed]
175. Köntgen F, Grumont RJ, Strasser A, Metcalf D, Li R, Tarlinton D, Gerondakis S. Mice lacking the c-rel proto-oncogene exhibit defects in lymphocyte proliferation, humoral immunity, and interleukin-2 expression. Genes Dev. 1995;9:1965–1977. [PubMed]
176. Liou HC, Jin Z, Tumang J, Andjelic S, Smith KA, Liou ML. c-Rel is crucial for lymphocyte proliferation but dispensable for T cell effector function. Int. Immunol. 1999;11:361–371. [PubMed]
177. Ishikawa C, Nakachi S, Senba M, Sugai M, Mori N. Activation of AID by human T-cell leukemia virus Tax oncoprotein and the possible role of its constitutive expression in ATL genesis. Carcinogenesis. 2011;32:110–119. [PubMed]
178. Smith MR, Greene WC. Identification of HTLV-I tax trans-activator mutants exhibiting novel transcriptional phenotypes. Genes Dev. 1990;4:1875–1885. [PubMed]
179. Semmes OJ, Jeang KT. Mutational analysis of human T-cell leukemia virus type I Tax: regions necessary for function determined with 47 mutant proteins. J. Virol. 1992;66:7183–7192. [PMC free article] [PubMed]
180. Yamaoka S, Inoue H, Sakurai M, Sugiyama T, Hazama M, Yamada T, Hatanaka M. Constitutive activation of NF-kappa B is essential for transformation of rat fibroblasts by the human T-cell leukemia virus type I Tax protein. EMBO J. 1996;15:873–887. [PubMed]
181. Smith MR, Greene WC. 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. 1991;88:1038–1042. [PMC free article] [PubMed]
182. Matsumoto K, Shibata H, Fujisawa JI, Inoue H, Hakura A, Tsukahara T, Fujii M. Human T-cell leukemia virus type 1 Tax protein transforms rat fibroblasts via two distinct pathways. J. Virol. 1997;71:4445–4451. [PMC free article] [PubMed]
183. 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;271:6698–6703. [PubMed]
184. Iwanaga Y, Tsukahara T, Ohashi T, Tanaka Y, Arai M, Nakamura M, Ohtani K, Koya Y, Kannagi M, Yamamoto N, Fujii M. Human T-cell leukemia virus type 1 tax protein abrogates interleukin-2 dependence in a mouse T-cell line. J. Virol. 1999;73:1271–1277. [PMC free article] [PubMed]
185. Akagi T, Ono H, Nyunoya H, Shimotohno K. Characterization of peripheral blood T-lymphocytes transduced with HTLV-I Tax mutants with different trans-activating phenotypes. Oncogene. 1997;14:2071–2078. [PubMed]
186. Robek MD, Ratner L. 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. 1999;73:4856–4865. [PMC free article] [PubMed]
187. Ross TM, Narayan M, Fang ZY, Minella AC, Green PL. Human T-cell leukemia virus type 2 tax mutants that selectively abrogate NFkappaB or CREB/ATF activation fail to transform primary human T cells. J. Virol. 2000;74:2655–2662. [PMC free article] [PubMed]
188. Kitajima I, Shinohara T, Bilakovics J, Brown DA, Xu X, Nerenberg M. Ablation of transplanted HTLV-I Tax-transformed tumors in mice by antisense inhibition of NF-kappa B. Science. 1992;258:1792–1795. [PubMed]
189. Mori N, Yamada Y, Ikeda S, Yamasaki Y, Tsukasaki K, Tanaka Y, Tomonaga M, Yamamoto N, Fujii M. Bay 11–7082 inhibits transcription factor NF-kappaB and induces apoptosis of HTLV-I-infected T-cell lines and primary adult T-cell leukemia cells. Blood. 2002;100:1828–1834. [PubMed]
190. Nasr R, El-Sabban ME, Karam JA, Dbaibo G, Kfoury Y, Arnulf B, Lepelletier Y, Bex F, de Thé H, Hermine O, Bazarbachi A. Efficacy and mechanism of action of the proteasome inhibitor PS-341 in T-cell lymphomas and HTLV-I associated adult T-cell leukemia/lymphoma. Oncogene. 2005;24:419–430. [PubMed]
191. Satou Y, Nosaka K, Koya Y, Yasunaga JI, Toyokuni S, Matsuoka M. Proteasome inhibitor, bortezomib, potently inhibits the growth of adult T-cell leukemia cells both in vivo and in vitro. Leukemia. 2004;18:1357–1363. [PubMed]
192. Sanda T, Asamitsu K, Ogura H, Iida S, Utsunomiya A, Ueda R, Okamoto T. Induction of cell death in adult T-cell leukemia cells by a novel IkappaB kinase inhibitor. Leukemia. 2006;20:590–598. [PubMed]
193. Mitra-Kaushik S, Harding JC, Hess JL, Ratner L. Effects of the proteasome inhibitor PS-341 on tumor growth in HTLV-1 Tax transgenic mice and Tax tumor transplants. Blood. 2004;104:802–809. [PubMed]
194. Kwon H, Ogle L, Benitez B, Bohuslav J, Montano M, Felsher DW, Greene WC. Lethal cutaneous disease in transgenic mice conditionally expressing type I human T cell leukemia virus Tax. J. Biol. Chem. 2005;280:35713–35722. [PubMed]
195. Iwanaga R, Ozono E, Fujisawa J, Ikeda MA, Okamura N, Huang Y, Ohtani K. Activation of the cyclin D2 and cdk6 genes through NF-kappaB is critical for cell-cycle progression induced by HTLV-I Tax. Oncogene. 2008;27:5635–5642. [PubMed]
196. Higuchi M, Tsubata C, Kondo R, Yoshida S, Takahashi M, Oie M, Tanaka Y, Mahieux R, Matsuoka M, Fujii M. Cooperation of NF-kappaB2/p100 activation and the PDZ domain binding motif signal in human T-cell leukemia virus type 1 (HTLV-1) Tax1 but not HTLV-2 Tax2 is crucial for interleukin-2-independent growth transformation of a T-cell line. J. Virol. 2007;81:11900–11907. [PMC free article] [PubMed]
197. Chen J, Petrus M, Bryant BR, Phuc Nguyen V, Stamer M, Goldman CK, Bamford R, Morris JC, Janik JE, Waldmann TA. Induction of the IL-9 gene by HTLV-I Tax stimulates the spontaneous proliferation of primary adult T-cell leukemia cells by a paracrine mechanism. Blood. 2008;111:5163–5172. [PubMed]
198. Jin Z, Nagakubo D, Shirakawa AK, Nakayama T, Shigeta A, Hieshima K, Yamada Y, Yoshie O. CXCR7 is inducible by HTLV-1 Tax and promotes growth and survival of HTLV-1-infected T cells. Int. J. Cancer. 2009;125:2229–2235. [PubMed]
199. Larousserie F, Bardel E, Pflanz S, Arnulf B, Lome-Maldonado C, Hermine O, Brégeaud L, Perennec M, Brousse N, Kastelein R, Devergne O. Analysis of interleukin-27 (EBI3/p28) expression in Epstein-Barr virus- and human T-cell leukemia virus type 1-associated lymphomas: heterogeneous expression of EBI3 subunit by tumoral cells. Am. J. Pathol. 2005;166:1217–1228. [PubMed]
200. Li-Weber M, Giaisi M, Chlichlia K, Khazaie K, Krammer PH. Human T cell leukemia virus type I Tax enhances IL-4 gene expression in T cells. Eur. J. Immunol. 2001;31:2623–2632. [PubMed]
201. Mizuguchi M, Asao H, Hara T, Higuchi M, Fujii M, Nakamura M. Transcriptional activation of the interleukin-21 gene and its receptor gene by human T-cell leukemia virus type 1 Tax in human T-cells. J. Biol. Chem. 2009;284:25501–25511. [PubMed]
202. Mori N, Fujii M, Cheng G, Ikeda S, Yamasaki Y, Yamada Y, Tomonaga M, Yamamoto N. Human T-cell leukemia virus type I tax protein induces the expression of anti-apoptotic gene Bcl-xL in human T-cells through nuclear factor-kappaB and c-AMP responsive element binding protein pathways. Virus Genes. 2001;22:279–287. [PubMed]
203. Pichler K, Schneider G, Grassmann R. MicroRNA miR-146a and further oncogenesis-related cellular microRNAs are dysregulated in HTLV-1-transformed T lymphocytes. Retrovirology. 2008;5:100. [PMC free article] [PubMed]
204. Tomita M, Tanaka Y, Mori N. MicroRNA miR-146a is induced by HTLV-1 tax and increases the growth of HTLV-1-infected T-cells. Int J Cancer. 2009 doi: 10.1002/ijc.25115. [PubMed] [Cross Ref]
205. Tsukahara T, Kannagi M, Ohashi T, Kato H, Arai M, Nunez G, Iwanaga Y, Yamamoto N, Ohtani K, Nakamura M, Fujii M. Induction of Bcl-x(L) expression by human T-cell leukemia virus type 1 Tax through NF-kappaB in apoptosis-resistant T-cell transfectants with Tax. J. Virol. 1999;73:7981–7987. [PMC free article] [PubMed]
206. Akita K, Kawata S, Shimotohno K. p21WAF1 modulates NF-kappaB signaling and induces anti-apoptotic protein Bcl-2 in Tax-expressing rat fibroblast. Virology. 2005;332:249–257. [PubMed]
207. Silbermann K, Schneider G, Grassmann R. Stimulation of interleukin-13 expression by human T-cell leukemia virus type 1 oncoprotein Tax via a dually active promoter element responsive to NF-kappaB and NFAT. J. Gen. Virol. 2008;89:2788–2798. [PubMed]
208. Mariner JM, Lantz V, Waldmann TA, Azimi N. Human T cell lymphotropic virus type I Tax activates IL-15R alpha gene expression through an NF-kappa B site. J. Immunol. 2001;166:2602–2609. [PubMed]
209. Mori N, Mukaida N, Ballard DW, Matsushima K, Yamamoto N. Human T-cell leukemia virus type I Tax transactivates human interleukin 8 gene through acting concurrently on AP-1 and nuclear factor-kappaB-like sites. Cancer Res. 1998;58:3993–4000. [PubMed]
210. Mori N, Ueda A, Ikeda S, Yamasaki Y, Yamada Y, Tomonaga M, Morikawa S, Geleziunas R, Yoshimura T, Yamamoto N. Human T-cell leukemia virus type I tax activates transcription of the human monocyte chemoattractant protein-1 gene through two nuclear factor-kappaB sites. Cancer Res. 2000;60:4939–4945. [PubMed]
211. Pichler K, Kattan T, Gentzsch J, Kress AK, Taylor GP, Bangham CR, Grassmann R. Strong induction of 4–1BB, a growth and survival promoting costimulatory receptor, in HTLV-1-infected cultured and patients' T cells by the viral Tax oncoprotein. Blood. 2008;111:4741–4751. [PubMed]
212. Pankow R, Dürkop H, Latza U, Krause H, Kunzendorf U, Pohl T, Bulfone-Paus S. The HTLV-I tax protein transcriptionally modulates OX40 antigen expression. J. Immunol. 2000;165:263–270. [PubMed]
213. Ohtani K, Tsujimoto A, Tsukahara T, Numata N, Miura S, Sugamura K, Nakamura M. Molecular mechanisms of promoter regulation of the gp34 gene that is trans-activated by an oncoprotein Tax of human T cell leukemia virus type I. J. Biol. Chem. 1998;273:14119–14129. [PubMed]
214. Mori N, Fujii M, Hinz M, Nakayama K, Yamada Y, Ikeda S, Yamasaki Y, Kashanchi F, Tanaka Y, Tomonaga M, Yamamoto N. Activation of cyclin D1 and D2 promoters by human T-cell leukemia virus type I tax protein is associated with IL-2-independent growth of T cells. Int. J. Cancer. 2002;99:378–385. [PubMed]
215. Wäldele K, Silbermann K, Schneider G, Ruckes T, Cullen BR, Grassmann R. Requirement of the human T-cell leukemia virus (HTLV-1) tax-stimulated HIAP-1 gene for the survival of transformed lymphocytes. Blood. 2006;107:4491–4499. [PubMed]
216. Mori N, Shirakawa F, Shimizu H, Murakami S, Oda S, Yamamoto K, Eto S. Transcriptional regulation of the human interleukin-6 gene promoter in human T-cell leukemia virus type I-infected T-cell lines: evidence for the involvement of NF-kappa B. Blood. 1994;84:2904–2911. [PubMed]
217. Liu S, Liu Z, Xie Z, Pang J, Yu J, Lehmann E, Huynh L, Vukosavljevic T, Takeki M, Klisovic RB, et al. Bortezomib induces DNA hypomethylation and silenced gene transcription by interfering with Sp1/NF-kappaB-dependent DNA methyltransferase activity in acute myeloid leukemia. Blood. 2008;111:2364–2373. [PubMed]
218. Nicot C, Mahieux R, Pise-Masison C, Brady J, Gessain A, Yamaoka S, Franchini G. Human T-cell lymphotropic virus type 1 Tax represses c-Myb-dependent transcription through activation of the NF-kappaB pathway and modulation of coactivator usage. Mol. Cell Biol. 2001;21:7391–7402. [PMC free article] [PubMed]
219. Uittenbogaard MN, Armstron AP, Chiaramello A, Nyborg JK. Human T-cell leukemia virus type I Tax protein represses gene expression through the basic helix-loop-helix family of transcription factors. J. Biol. Chem. 1994;269:22466–22469. [PubMed]
220. Uittenbogaard MN, Giebler HA, Reisman D, Nyborg JK. Transcriptional repression of p53 by human T-cell leukemia virus type I Tax protein. J. Biol. Chem. 1995;270:28503–28506. [PubMed]
221. Ravi R, Mookerjee B, van Hensbergen Y, Bedi GC, Giordano A, El-Deiry WS, Fuchs EJ, Bedi A. p53-mediated repression of nuclear factor-kappaB RelA via the transcriptional integrator p300. Cancer Res. 1998;58:4531–4536. [PubMed]
222. Wadgaonkar R, Phelps KM, Haque Z, Williams AJ, Silverman ES, Collins T. CREB-binding protein is a nuclear integrator of nuclear factor-kappaB and p53 signaling. J. Biol. Chem. 1999;274:1879–1882. [PubMed]
223. Webster GA, Perkins ND. Transcriptional cross talk between NF-kappaB and p53. Mol. Cell Biol. 1999;19:3485–3495. [PMC free article] [PubMed]
224. Jeong SJ, Radonovich MF, Brady JN, Pise-Masison CA. HTLV-I Tax induces a novel interaction between p65/RelA and p53 that results in inhibition of p53 transcriptional activity. Blood. 2004;104:1490–1497. [PubMed]
225. Pise-Masison CA, Mahieux R, Jiang H, Ashcroft M, Radonovich MF, Duvall J, Guillerm C, Brady JN. Inactivation of p53 by human T-cell lymphotropic virus type 1 Tax requires activation of the NF-kappaB pathway and is dependent on p53 phosphorylation. Mol Cell Biol. 2000;20:3377–3386. [PMC free article] [PubMed]
226. Jeong SJ, Pise-Masison CA, Radonovich MF, Park HU, Brady JN. A novel NF-kappaB pathway involving IKKbeta and p65/RelA Ser-536 phosphorylation results in p53 Inhibition in the absence of NF-kappaB transcriptional activity. J. Biol. Chem. 2005;280:10326–10332. [PubMed]
227. Xia Y, Padre RC, De Mendoza TH, Bottero V, Tergaonkar VB, Verma IM. Phosphorylation of p53 by IkappaB kinase 2 promotes its degradation by beta-TrCP. Proc. Natl. Acad Sci. U. S. A. 2009;106:2629–2634. [PubMed]
228. Tergaonkar V, Pando M, Vafa O, Wahl G, Verma I. p53 stabilization is decreased upon NFkappaB activation: a role for NFkappaB in acquisition of resistance to chemotherapy. Cancer Cell. 2002;1:493–503. [PubMed]
229. Busuttil V, Droin N, McCormick L, Bernassola F, Candi E, Melino G, Green DR. NF-kappaB inhibits T-cell activation-induced, p73-dependent cell death by induction of MDM2. Proc. Natl. Acad. Sci. U. S. A. 2010;107:18061–18066. [PubMed]
230. Bellon M, Nicot C. Central role of PI3K in transcriptional activation of hTERT in HTLV-I-infected cells. Blood. 2008;112:2946–2955. [PubMed]
231. Sinha-Datta U, Horikawa I, Michishita E, Datta A, Sigler-Nicot JC, Brown M, Kazanji M, Barrett JC, Nicot C. Transcriptional activation of hTERT through the NF-kappaB pathway in HTLV-I-transformed cells. Blood. 2004;104:2523–2531. [PubMed]
232. Mori N, Sato H, Hayashibara T, Senba M, Hayashi T, Yamada Y, Kamihira S, Ikeda S, Yamasaki Y, Morikawa S, et al. Human T-cell leukemia virus type I Tax transactivates the matrix metalloproteinase-9 gene: potential role in mediating adult T-cell leukemia invasiveness. Blood. 2002;99:1341–1349. [PubMed]
233. Okayama A, Chen YM, Tachibana N, Shioiri S, Lee TH, Tsuda K, Essex M. High incidence of antibodies to HTLV-I tax in blood relatives of adult T cell leukemia patients. J. Infect. Dis. 1991;163:47–52. [PubMed]
234. Tochikura T, Iwahashi M, Matsumoto T, Koyanagi Y, Hinuma Y, Yamamoto N. Effect of human serum anti-HTLV antibodies on viral antigen induction in vitro cultured peripheral lymphocytes from adult T-cell leukemia patients and healthy virus carriers. Int. J. Cancer. 1985;36:1–7. [PubMed]
235. Hanon E, Hall S, Taylor GP, Saito M, Davis R, Tanaka Y, Usuku K, Osame M, Weber JN, Bangham CR. Abundant tax protein expression in CD4+ T cells infected with human T-cell lymphotropic virus type I (HTLV-I) is prevented by cytotoxic T lymphocytes. Blood. 2000;95:1386–1392. [PubMed]
236. Inoue J, Seiki M, Yoshida M. The second pX product p27 chi-III of HTLV-1 is required for gag gene expression. FEBS Lett. 1986;209:187–190. [PubMed]
237. Hidaka M, Inoue J, Yoshida M, Seiki M. Post-transcriptional regulator (rex) of HTLV-1 initiates expression of viral structural proteins but suppresses expression of regulatory proteins. EMBO J. 1988;7:519–523. [PubMed]
238. Gröne M, Koch C, Grassmann R. The HTLV-1 Rex protein induces nuclear accumulation of unspliced viral RNA by avoiding intron excision and degradation. Virology. 1996;218:316–325. [PubMed]
239. Nicot C, Dundr M, Johnson JM, Fullen JR, Alonzo N, Fukumoto R, Princler GL, Derse D, Misteli T, Franchini G. HTLV-1-encoded p30II is a post-transcriptional negative regulator of viral replication. Nat. Med. 2004;10:197–201. [PubMed]
240. Zhang W, Nisbet JW, Albrecht B, Ding W, Kashanchi F, Bartoe JT, Lairmore MD. Human T-lymphotropic virus type 1 p30(II) regulates gene transcription by binding CREB binding protein/p300. J. Virol. 2001;75:9885–9985. [PMC free article] [PubMed]
241. Satou Y, Yasunaga J, Yoshida M, Matsuoka M. HTLV-I basic leucine zipper factor gene mRNA supports proliferation of adult T cell leukemia cells. Proc. Natl. Acad. Sci. U. S. A. 2006;103:720–725. [PubMed]
242. Gaudray G, Gachon F, Basbous J, Biard-Piechaczyk M, Devaux C, Mesnard JM. 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. 2002;76:12813–12822. [PMC free article] [PubMed]
243. Arnold J, Zimmerman B, Li M, Lairmore MD, Green PL. Human T-cell leukemia virus type-1 antisense-encoded gene, Hbz, promotes T-lymphocyte proliferation. Blood. 2008;112:3788–3797. [PubMed]
244. Choudhary G, Ratner L. The HTLV-1 hbz antisense gene indirectly promotes tax expression via down-regulation of p30(II) mRNA. Virology. 2011;410:307–315. [PMC free article] [PubMed]
245. Satou Y, Yasunaga J, Zhao T, Yoshida M, Miyazato P, Takai K, Shimizu K, Ohshima K, Green PL, Ohkura N, et al. HTLV-1 bZIP Factor Induces T-Cell Lymphoma and Systemic Inflammation In vivo. PLoS Pathog. 2011;7:e1001274. [PMC free article] [PubMed]
246. Rende F, Cavallari I, Corradin A, Silic-Benussi M, Toulza F, Toffolo GM, Tanaka Y, Jacobson S, Taylor GP, D'Agostino DM, et al. Kinetics and intracellular compartmentalization of HTLV-1 gene expression: Nuclear retention of HBZ mRNA. Blood. 2011;117:4855–4859. [PubMed]
247. Saito M, Matsuzaki T, Satou Y, Yasunaga J, Saito K, Arimura K, Matsuoka M, Ohara Y. In vivo expression of the HBZ gene of HTLV-1 correlates with proviral load, inflammatory markers and disease severity in HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) Retrovirology. 2009;6:19. [PMC free article] [PubMed]
248. Hilburn S, Rowan A, Demontis MA, MacNamara A, Asquith B, Bangham CR, Taylor GP. In vivo expression of human T-lymphotropic virus type 1 basic leucine-zipper protein generates specific CD8+ and CD4+ T-lymphocyte responses that correlate with clinical outcome. J. Infect. Dis. 2011;203:529–536. [PMC free article] [PubMed]
249. Arnold J, Yamamoto B, Li M, Phipps AJ, Younis I, Lairmore MD, Green PL. Enhancement of infectivity and persistence in vivo by HBZ, a natural antisense coded protein of HTLV-1. Blood. 1996;107:3976–3982. [PubMed]
250. Ego T, Ariumi Y, Shimotohno K. The interaction of HTLV-1 Tax with HDAC1 negatively regulates the viral gene expression. Oncogene. 2002;21:7241–7246. [PubMed]
251. Lu H, Pise-Masison CA, Linton R, Park HU, Schiltz RL, Sartorelli V, Brady JN. Tax relieves transcriptional repression by promoting histone deacetylase 1 release from the human T-cell leukemia virus type 1 long terminal repeat. J. Virol. 2004;78:6735–6743. [PMC free article] [PubMed]
252. Yan P, Qu Z, Ishikawa C, Mori N, Xiao G. Human T-cell leukemia virus type I-mediated repression of PDZ-LIM domain-containing protein 2 involves DNA methylation but independent of the viral oncoprotein tax. Neoplasia. 2009;11:1036–1041. [PMC free article] [PubMed]
253. Qu Z, Fu J, Yan P, Hu J, Cheng SY, Xiao G. Epigenetic repression of PDZ-LIM domain-containing protein 2: implications for the biology and treatment of breast cancer. J. Biol. Chem. 2010;285:11786–11792. [PubMed]
254. Qu Z, Yan P, Fu J, Jiang J, Grusby MJ, Smithgall TE, Xiao G. DNA methylation-dependent repression of PDZ-LIM domain-containing protein 2 in colon cancer and its role as a potential therapeutic target. Cancer Res. 2010;70:1766–1772. [PMC free article] [PubMed]
255. Qing G, Yan P, Qu Z, Liu H, Xiao G. Hsp90 regulates processing of NF-kappa B2 p100 involving protection of NF-kappa B-inducing kinase (NIK) from autophagy-mediated degradation. Cell Res. 2007;17:520–530. [PubMed]
256. Qing G, Yan P, Xiao G. Hsp90 inhibition results in autophagy-mediated proteasome-independent degradation of IkappaB kinase (IKK) Cell Res. 2006;16:895–901. [PubMed]
257. Xiao G. Autophagy and NF-kappaB: fight for fate. Cytokine Growth Factor Rev. 2007;18:233–243. [PMC free article] [PubMed]
258. Rivera-Walsh I, Waterfiled M, Xiao G, Fong A, Sun SC. NF-kappaB signaling pathway governs TRAIL gene expression and human T-cell leukemia virus-I Tax-induced T-cell death. J. Biol. Chem. 2001;276:40385–40388. [PubMed]
259. Swaims AY, Khani F, Zhang Y, Roberts AI, Devadas S, Shi Y, Rabson AB. Immune activation induces immortalization of HTLV-1 LTR-Tax transgenic CD4+ T cells. Blood. 2010;116:2994–3003. [PubMed]
260. Franchini G, Mulloy JC, Koralnik IJ, Lo Monico A, Sparkowski JJ, Andresson T, Goldstein DJ, Schlegel R. The human T-cell leukemia/lymphotropic virus type I p12I protein cooperates with the E5 oncoprotein of bovine papillomavirus in cell transformation and binds the 16-kilodalton subunit of the vacuolar H+ ATPase. J. Virol. 1993;67:7701–7704. [PMC free article] [PubMed]
261. Derse D, Mikovits J, Ruscetti F. X-I and X-II open reading frames of HTLV-I are not required for virus replication or for immortalization of primary T-cells in vitro. Virology. 1997;237:123–128. [PubMed]
262. Robek MD, Wong FH, Ratner L. 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. 1998;72:4458–4462. [PMC free article] [PubMed]
263. Ye J, Silverman L, Lairmore MD, Green PL. HTLV-1 Rex is required for viral spread and persistence in vivo but is dispensable for cellular immortalization in vitro. Blood. 2003;102:3963–3969. [PMC free article] [PubMed]
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