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PubMed2004

Proteasome inhibitor, bortezomib, potently inhibits the growth of adult T-cell leukemia cells both in vivo and in vitro.

Adult T-cell leukemia (ATL) is a fatal neoplasm derived from CD4-positive T-lymphocytes, and regardless of intensive chemotherapy, its mean survival time is less than 1 year. Nuclear factor-kappaB (NF-kappaB) activation was reported in HTLV-I associated cells, and has been implicated in oncogenesis and resistance to anticancer agents and apoptosis. We studied the effect of a proteasome inhibitor, bortezomib (formerly known as PS-341), on ATL cells in vitro and in vivo. Bortezomib could inhibit the degradation of IkappaBalpha in ATL cells, resulting in suppression of NF-kappaB and induction of cell death in ATL cells in vitro. Susceptibilities to bortezomib were well correlated with NF-kappaB activation, suggesting that suppression of the NF-kappaB pathway was implicated in the cell death induced by bortezomib. Although the majority of the cell death was apoptosis, necrotic cell death was observed in the presence of a caspase inhibitor, z-VAD-fmk. When bortezomib was administered into SCID mice bearing tumors, it suppressed tumor growth in vivo, showing that bortezomib was effective against ATL cells in vivo. These studies revealed that bortezomib is highly effective against ATL cells in vitro and in vivo by induction of apoptosis, and its clinical application might improve the prognosis of patients with this fatal disease.

Animals↗

PubMed2006

Induction of cell death in adult T-cell leukemia cells by a novel IkappaB kinase inhibitor.

NF-kappaB is constitutively activated in adult T-cell leukemia (ATL) and is considered responsible for cell growth and prevention of cell death. In this study, we demonstrate that NF-kappaB is constitutively activated in various HTLV-1-infected T-cell lines and ATL-derived cell lines irrespectively of Tax expression as evidenced by the phosphorylation of IkappaBalpha and p65 subunit of NF-kappaB, activation of NF-kappaB DNA binding, and upregulation of various target genes including bcl-xL, bcl-2, XIAP, c-IAP1, survivin, cyclinD1, ICAM-1 and VCAM-1. The effects of a novel IkappaB kinase (IKK) inhibitor, 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-4-yl nicotinonitrile (ACHP), were examined on cell growth of these cell lines and fresh ATL leukemic cells. We found that ACHP could inhibit the phosphorylation of IkappaBalpha and p65, as well as NF-kappaB DNA-binding, associated with downregulation of the NF-kappaB target genes and induce cell growth arrest and apoptosis in these cells. When Tax-active and Tax-inactive cell lines were compared, ACHP could preferentially inhibit cell growth of Tax-active cells. Moreover, ACHP exhibited strong apoptosis-inducing activity in fresh ATL cells. These findings indicate that ACHP and its derivatives are effective in inducing ATL cell death and thus feasible candidates for the treatment of ATL.

Apoptosis↗

PubMed2006

Aspirin-triggered Lipoxin A4 inhibition of VEGF-induced endothelial cell migration involves actin polymerization and focal adhesion assembly.

Angiogenesis, the growth of new capillaries from pre-existing ones, occurs through dynamic functions of the endothelial cells (EC), including migration, which is essential to achieve an organized formation of the vessel sprout. We demonstrated previously that an aspirin-triggered lipoxin analog, 15-epi-16-(para-fluoro)-phenoxy-lipoxin A4 (ATL-1), inhibits vascular endothelial growth factor (VEGF)-induced EC migration. In the present study, we investigated the effects of ATL-1 in the actin cytoskeleton reorganization of EC stimulated with VEGF. Pretreatment of EC with ATL-1 caused a reduction in VEGF-induced stress fibers and therefore reduced the intracellular content of filamentous actin. A concomitant impairment in stress-activated protein kinase (SAPK2/p38) phosphorylation suggests that ATL inhibition of VEGF-stimulated actin polymerization involves the SAPK2/p38 pathway. Moreover, ATL-1 treatment inhibited focal adhesion clustering due to inhibition of focal adhesion kinase (FAK) phosphorylation and the subsequent association of FAK with the actin cytoskeleton. This final event, which ultimately allows cell migration, was reverted by an LX receptor antagonist, but not by a cys-LT1R antagonist, indicating an effect via the G-protein-linked LXA4 receptor. Together our results provide evidence that ATL-1 inhibits EC migration via the concerted inhibition of actin polymerization and proper assembly of focal adhesions, supporting a role for these novel lipid mediators as angiogenesis modulators.

Actins↗

PubMed2006

A genomic analysis of adult T-cell leukemia.

Adult T-cell leukemia (ATL) is an intractable malignancy of CD4+ T cells that is etiologically associated with infection by human T-cell leukemia virus-type I. Most individuals in the chronic stage of ATL eventually undergo progression to a highly aggressive acute stage. To clarify the mechanism responsible for this stage progression, we isolated CD4+ cells from individuals in the chronic (n=19) or acute (n=22) stages of ATL and subjected them to profiling of gene expression with DNA microarrays containing >44,000 probe sets. Changes in chromosome copy number were also examined for 24 cell specimens with the use of microarrays harboring approximately 50,000 probe sets. Stage-dependent changes in gene expression profile and chromosome copy number were apparent. Furthermore, expression of the gene for MET, a receptor tyrosine kinase for hepatocyte growth factor (HGF), was shown to be specific to the acute stage of ATL, and the plasma concentration of HGF was increased in individuals in either the acute or chronic stage. HGF induced proliferation of a MET-positive ATL cell line, and this effect was blocked by antibodies to HGF. The HGF-MET signaling pathway is thus a potential therapeutic target for ATL.

Cell Line, Tumor↗

PubMed1997

Expression of CD8beta and alteration of cell surface phenotype in adult T-cell leukaemia cells.

Typical adult T-cell leukaemia (ATL) cells have a CD4+ CD8- cell surface phenotype, but atypical phenotypes such as CD4+ CD8+ and CD4- CD8+ have also been reported. The CD8 molecule is composed of alpha and beta chains and commonly used monoclonal antibodies against CD8 molecule detect only CD8alpha. Since it has been reported that CD8alpha can be induced in mature CD4+ T cells by cell activation, but not CD8beta, we studied whether ATL cells which express CD8alpha may also express CD8beta. We found some cases of CD8alpha+ ATL were also positive for CD8beta. Furthermore, we experienced a case whose ATL cell surface phenotype changed from CD4+ CD8alpha+ CD8beta+ to CD4- CD8alpha+ CD8beta+ and finally to CD4+ CD8alpha- CD8beta-. Southern blot analysis revealed that the monoclonal integration of human T lymphotropic virus type I (HTLV-I) was identical throughout the course of the study, indicating that a single clone had demonstrated the alterations. These data suggest that peripheral CD4+ CD8+ ATL cells can express not only CD8alpha, but also CD8beta and that a single ATL cell clone has the potential to change its surface phenotype in vivo as well as in vitro.

Adult↗

PubMed1997

Quantitative characterization and potential function of membrane Fas/APO-1 (CD95) receptors on leukaemic cells from chronic B and T lymphoid leukaemias.

The expression and function of the Fas-receptor (Fas-R) were examined in chronic lymphocytic leukaemia (CLL), hairy cell leukaemia-variant (HCL-v) and adult T-cell leukaemia (ATL). The expression of Fas-R in freshly isolated leukaemic cells was qualitatively and quantitatively different between each disease; faint in B-CLL, moderate in HCL-v and strong in ATL. Both full-length and alternatively spliced truncated forms of Fas mRNA were detected even in CLL B cells with faint to negative Fas-R, and Fas mRNA was also shown to be capable of increasing in vitro expression, i.e. the message was functional. In contrast, Fas-R expression on ATL cells was heterogenous and usually intense with a mean density approximately 3-fold higher than that of normal T cells. Fas-R was confirmed to have the potential function for anti-Fas monoclonal antibody-mediated cell death in vitro in Fas-R+ ATL cells. The expression level of Fas-R on the cells was higher in chronic than acute ATL (10,360 v 6260 antibody-binding capacity per cell, mFasABC; P<0.05) and was inversely correlated with serum LDH activity, suggesting that the strong Fas-R accounts for the slow progression of chronic ATL and the negative Fas-R protects from Fas-mediated cell death. These results show that Fas-R expression on leukaemic cells is valuable in their characterization and perhaps their function, and may contribute to the progression and immune evasion of malignant clones.

Apoptosis↗

PubMed2001

Aberrant expression of caspase cascade regulatory genes in adult T-cell leukaemia: survivin is an important determinant for prognosis.

Derangement of either apoptosis or cell division is known to play an important role in tumorigenesis. Fas-mediated apoptosis on normal and leukaemic T cells is finely tuned by inhibitory proteins, such as FAP-1, FLIP and survivin, and defective caspase isoform which can attenuate the function of its intact caspase as a decoy molecule. However, complex involvement of such inhibitors in tumour biology relating to apoptotic pathology remains unclear in the neoplasms. We report the aberrant expression of FAP-1, FLIP and survivin mRNAs on leukaemic T cells from adult T-cell leukaemia (ATL) patients. Among these inhibitors, only survivin was aberrantly expressed in all ATL cases, but not in any normal peripheral blood mononuclear cells (PBMCs). Furthermore, survivin mRNA expression level was characteristic in each subtype of ATL and represented an important determinant for ATL prognosis. However, the apoptotic effector of casp-8, which is essential in Fas-mediated signal transduction, was dominant in defective casp-8 rather than intact casp-8 in ATL cells, suggesting a favourable biological situation for escape from apoptosis. Taken together, ATL cells probably possess many different regulatory mechanisms in order to attenuate Fas-mediated signalling and subsequently expand their populations under escape from apoptosis. Among these inhibitors, survivin is a useful bio-marker to assess tumour biology and may be a potential new target for apoptosis-based selective therapy in neoplasms as the expression is a general feature of neoplasia, but not normal tissues.

Apoptosis↗

PubMed2002

Autocrine and/or paracrine growth of adult T-cell leukaemia tumour cells by interleukin 15.

We previously demonstrated that interleukin 2 (IL-2) autocrine/paracrine growth in adult T-cell leukaemia (ATL) cells was closely correlated with clinical aggressiveness. In the present study, we compared the significance of IL-15 and IL-2 in growth of ATL cells and clinical aggressiveness. Thirty-seven patients with ATL were examined: 19 acute and 18 chronic. Autonomous growth and IL-2- or IL-15-responsive growth activities of ATL cells were measured by [3H]-thymidine incorporation after 24 h cultures in vitro. All of the autonomous, IL-15- and IL-2-responsive growth activities of acute-type cells were higher than those of chronic type (P = 0.04, P = 0.03 and P = 0.02 respectively). IL-15- and IL-2-responsive growth activities were highly correlated (P = 0.0001, R2 = 0.837). Enzyme-linked immunosorbent assay (ELISA) showed detectable serum levels of IL-15 and IL-2 in 18 out of 19 and 14 out of 17 patients respectively. Reverse transcription polymerase chain reaction (RT-PCR) revealed IL-15 and IL-2 mRNA expression in 8 out of 11 patients' cells. Anti-IL-2 antibody partially inhibited autonomous growth of ATL cells; anti-IL-15 antibody was less effective. In situ immunochemistry detected IL-15 in cells of three patients and was consistent with the results of RT-PCR. These results suggest that ATL cells grow in an IL-15 autocrine/paracrine manner and that this growth is related to disease aggressiveness in a manner similar to IL-2.

Adult↗

PubMed1997

Evidence for autolysin-mediated primary attachment of Staphylococcus epidermidis to a polystyrene surface.

Biofilm formation on a polymer surface which involves initial attachment and accumulation in multilayered cell clusters (intercellular adhesion) is proposed to be the major pathogenicity factor in Staphylococcus epidermidis foreign-body-associated infections. We have characterized two distinct classes of biofilm-negative Tn917 mutants in S. epidermidis affected in initial attachment (class A) or intercellular adhesion (class B). mut1 (class A mutant) lacks five surface-associated proteins with molecular masses of 120, 60, 52, 45 and 38 kDa and could be complemented by transformation with a 16.4 kb wild-type DNA fragment. The complemented mutant was able to attach to a polystyrene surface, to form a biofilm, and produced all of the proteins missing from mut1. Subcloning experiments revealed that the 60 kDa protein is sufficient for initial attachment. Immunofluorescence microscopy using an antiserum raised against the 60 kDa protein showed that this protein is located at the cell surface. DNA-sequence analysis of the complementing region revealed a single open reading frame which consists of 4005 nucleotides and encodes a deduced protein of 1335 amino acids with a predicted molecular mass of 148kDa. The amino acid sequence exhibits a high similarity (61% identical amino acids) to the atl gene product of Staphylococcus aureus, which represents the major autolysin; therefore the open reading frame was designated atlE. By analogy with the S. aureus autolysin, AtlE is composed of two bacteriolytically active domains, a 60 kDa amidase and a 52 kDa glucosaminidase domain, generated by proteolytic processing. The 120 kDa protein missing from mut1 presumably represents the unprocessed amidase and glucosaminidase domain after proteolytic cleavage of the signal- and propeptide. The 45 and 38kDa proteins are probably the degradation products of the 60 and 52 kDa proteins, respectively. Additionally, AtlE was found to exhibit vitronectin-binding activity, indicating that AtlE plays a role in binding of the cells not only to a naked polystyrene surface during early stages of adherence, but also to plasma protein-coated polymer surfaces during later stages of adherence. Our findings provide evidence for a new function of an autolysin (AtlE) in mediating the attachment of bacterial cells to a polymer surface, representing the prerequisite for biofilm formation.

Adhesins, Bacterial↗

PubMed2000

Bronchiolitis obliterans organizing pneumonia (BOOP) in a case of smouldering adult T-cell leukaemia.

Although various respiratory diseases have been reported in human T lymphotropic virus type-1 (HTLV-1) carriers or patients with adult T-cell leukaemia (ATL), there appears to be no report of the development of bronchiolitis obliterans organizing pneumonia (BOOP) in ATL or HTLV-1-related disorders. We describe a 51-year-old male with smouldering ATL who developed BOOP during a long-term follow up. Bronchoalveolar lavage (BAL) and transbronchial lung biopsy (TBLB) were performed in the right lower lobe B6 with infiltrative shadows. As a result of flow cytometric analysis of peripheral lymphocytes and BAL lymphocytes, histological examination of the biopsied lung specimen, and the clinical course, we excluded the pulmonary infiltration of ATL cells and bacterial infection. Thus, he was diagnosed as having BOOP and successfully treated with corticosteroid therapy. This is probably the first report of BOOP developing in ATL. Bronchiolitis obliterans organizing pneumonia should be considered in the differential diagnosis of pulmonary complications in HTLV-1 carriers or ATL patients since BOOP can be successfully treated by corticosteroids.

Cryptogenic Organizing Pneumonia↗

PubMed2001

Material-specific memory changes after anterior temporal lobectomy as predicted by the intracarotid amobarbital test.

PURPOSE: The intracarotid amobarbital test (IAT) has been shown to predict verbal memory changes after anterior temporal lobectomy (ATL). Seeking to extend these findings, we examined two questions: (a) What is the relationship between material-specific aspects of IAT memory and material-specific memory changes after ATL? and (b) Which IAT memory score(s) optimally predict memory changes after surgery, the memory score after injection ipsilateral to the seizure focus, the memory score after injection contralateral to the seizure focus, or the IAT asymmetry score, comprising the ipsilateral minus contralateral injection scores? METHODS: Seventy left hemisphere language-dominant patients undergoing ATL for treatment of medically refractory seizures were administered a verbal and visuospatial recognition memory test before surgery and 3 weeks after surgery. IAT memory recognition scores for words and designs were used to predict verbal and visuospatial memory changes after surgery. RESULTS: After surgery, left ATL patients declined in verbal memory, whereas right ATL patients declined in visuospatial memory. IAT total recognition memory scores (collapsed across all types of materials) and IAT word memory scores were associated with postoperative verbal memory decline. This relationship was significant for the IAT ipsilateral injection memory scores and the IAT hemispheric asymmetry scores. IAT memory performances were not related to visuospatial memory changes. CONCLUSIONS: Results indicate IAT memory measures to be related to postoperative verbal, but not visuospatial, memory change. A specific relationship was found between postoperative verbal memory change and IAT verbal memory after injection ipsilateral to the seizure focus, when relying primarily on the contralateral hemisphere. This finding is consistent with the functional reserve model of memory change in ATL.

Adult↗

PubMed2001

Memory outcome after left anterior temporal lobectomy in patients with expected and reversed Wada memory asymmetry scores.

PURPOSE: The ideal candidate for anterior temporal lobectomy surgery shows a Wada memory asymmetry (WMA) score characterized by better memory performance in the hemisphere contralateral to the seizure focus relative to the ipsilateral (surgical) hemisphere. However, some surgical candidates show a reversed WMA or better Wada memory performance in the hemisphere of surgical interest relative to the hemisphere contralateral to the seizure focus. To date, no data are available contrasting memory and seizure outcome for these two Wada groups. The present study compared memory and seizure outcome after left anterior temporal lobectomy (L-ATL) in patients showing expected and reversed WMA scores, and also examined the relationship of the individual hemisphere Wada memory scores for predicting verbal memory outcome after L-ATL. METHODS: We compared 6-month postoperative verbal memory change scores and seizure outcome in L-ATL patients with either an expected (n=12) or reversed WMA (n=9) pattern on Wada memory testing. RESULTS: L-ATL patients showing a reversed WMA score had a poorer verbal memory outcome and poorer seizure control after surgery compared with patients showing a WMA score in the expected direction. CONCLUSIONS: L-ATL patients with a reversed WMA score have a greater risk for memory morbidity and poorer seizure outcome than do patients with a WMA score in the expected direction. The WMA score was the best predictor of memory outcome after L-ATL. When the WMA score is not considered, both individual Wada hemisphere scores (contralateral and ipsilateral) provided significant and independent contribution to predicting postoperative verbal memory functioning. These findings are discussed in the context of the functional reserve and hippocampal adequacy models of memory change after temporal lobectomy.

Adult↗

PubMed2003

Prognostic implications of seizure recurrence in the first year after anterior temporal lobectomy.

PURPOSE: Seizure recurrence after anterior temporal lobectomy (ATL) incites concerns of whether seizures will eventually be successfully controlled. Our study evaluated the prognostic significance of seizure recurrence in the first year after ATL. METHODS: The postoperative courses of 175 consecutive patients who had undergone ATL and had > or =2 years of follow-up were studied. Recurrence was considered early if the first seizure occurred within 7 days after ATL and late if it occurred >7 days after ATL. Recurrent seizures were considered provoked when precipitating factors were present, such as interruption of antiepileptic drug (AED) intake. Subsequent outcome was determined at terminal follow-up. RESULTS: Percentage of excellent outcome was comparable between patients whose initial recurrent seizures were auras or simple partial seizures and patients without seizure recurrence in the first year (86.7 vs. 93.1%; p > or = 0.05). However, percentage of excellent outcome was less when the initial recurrent seizure was complex partial, either with or without secondary generalization (44.8%; p < or = 0.01). Outcome was not different between early and late seizure recurrence (excellent in 41.7 vs. 55.7%; p > or = 0.05). Nonetheless, patients with either early or late seizure recurrence were less likely to have excellent outcome than were patients with no seizure recurrence in the first year (p < or = 0.001). Percentage of excellent outcome was best when patients were seizure free in the first year (93.1%), intermediate when initial recurrent seizure was provoked (72.0%), and worst when unprovoked (27.8%) (p < or = 0.001). CONCLUSIONS: In the first postoperative year, the type of initial recurrent seizure, whether aura or complex partial and whether provoked or unprovoked, is associated with long-term prognosis in seizure control after ATL. The timing of the initial seizure recurrence is not as important.

Adolescent↗

PubMed1999

Functional MRI and the Wada test provide complementary information for predicting post-operative seizure control.

Prediction of post-surgical seizure relief and potential cognitive deficits secondary to anterior temporal lobectomy (ATL) are important to pre-surgical planning. Although the intracarotid amobarbital test (IAT) is predictive of post-ATL seizure outcome, development of non-invasive and more precise means for determining post-ATL seizure relief are needed. We previously reported on a technique utilizing functional MRI (fMRI) to evaluate the relative functional adequacy of mesial temporal lobe structures in preparation for ATL. In the present study, we report follow-up outcome data on eight temporal lobe epilepsy (TLE) patients 1-year post-ATL who were evaluated pre-surgically using IAT and fMRI. Functional memory lateralization using fMRI predicted post-ATL seizure outcome as effectively as the IAT. In general, asymmetry of functional mTL activation favouring the non-epileptic hemisphere was associated with seizure-free status at 1-year follow-up. Moreover, when combined, fMRI and IAT provided complementary data that resulted in improved prediction of post-operative seizure control compared with either procedure alone.

Adolescent↗

PubMed2002

Adenosine A2A receptor activation decreases reperfusion injury associated with high-flow reperfusion.

INTRODUCTION: High pulmonary artery flow rates can result in severe reperfusion injury after lung transplantation. Our hypothesis was that selective activation of the adenosine A(2A) receptor with a highly specific analog (ATL-146e) would inhibit leukocyte activation and decrease reperfusion injury after high-flow reperfusion. METHODS: Using our isolated, ventilated, blood-perfused rabbit lung model, all groups (n = 8 per group) underwent lung harvest, 4 hours of cold storage, and blood reperfusion for 30 minutes. Measurements of pulmonary artery pressure (in millimeters of mercury), arterial oxygenation (in millimeters of mercury), myeloperoxidase, peak inspiratory pressure, and wet/dry weight ratio were obtained. Groups 1 (high flow) and 2 (high flow ATL-146e) underwent reperfusion at 120 mL/min for 30 minutes. Groups 3 (controlled high flow) and 4 (controlled high flow ATL-146e) underwent controlled reperfusion with an initial reperfusion of 60 mL/min for the first 5 minutes, followed by a rate of 120 mL/min for 25 minutes. During reperfusion, groups 2 and 4 received ATL-146e at 4 microg. kg(-1). min(-1). RESULTS: ATL-146e significantly improved lung physiologic measurements under both high-flow (group 1 vs group 2) and controlled high-flow (group 3 vs group 4) conditions after 30 minutes. CONCLUSIONS: The adenosine A(2A) receptor analogue ATL-146e significantly decreases the severity of reperfusion injury in the setting of both high-flow and controlled high-flow reperfusion.

Animals↗

PubMed2004

Aspirin triggers antiinflammatory 15-epi-lipoxin A4 and inhibits thromboxane in a randomized human trial.

There is increasing evidence that aspirin initiates biosynthesis of novel antiinflammatory mediators by means of interactions between endothelial cells and leukocytes. These mediators are classified as aspirin-triggered 15-epi-lipoxins. Such compounds may account at least in part for aspirin's clinical benefits, which are distinct from the well appreciated action of aspirin as a platelet inhibitor. Here, we addressed whether aspirin-triggered 15-epilipoxinA4 (ATL) formation is aspirin-dependent in humans and its relationship to aspirin's antiplatelet activity. We conducted a randomized clinical trial among 128 healthy subjects allocated to placebo or to 81-, 325-, or 650-mg daily doses of aspirin for 8 weeks. Plasma thromboxane (TX)B2, an indicator of platelet reactivity, and ATL were assessed from blood collected at baseline and at 8 weeks. Plasma ATL levels significantly increased in the 81-mg aspirin group (0.25 +/- 0.63 ng/ml, P = 0.04), with borderline increases in the 325-mg group (0.16 +/- 0.71 ng/ml) and no apparent significant changes in the 650-mg group (0.01 +/- 0.75 ng/ml, P = 0.96). When ATL and TXB2 were compared, levels changed in a statistically significant and opposite direction (P < 0.01) for all three aspirin doses. These results demonstrated that low-dose aspirin (81 mg daily) initiates production of antiinflammatory ATL opposite to the inhibition of TX. Monitoring ATL may represent a simple clinical parameter to verify an individual's vascular leukocyte antiinflammatory response with low-dose aspirin treatment. These results also emphasize the importance of cell-cell interactions in the modulation of hemostatic, thrombotic, and inflammatory processes.

Adult↗

PubMed2006

HTLV-I basic leucine zipper factor gene mRNA supports proliferation of adult T cell leukemia cells.

Human T cell leukemia virus type I (HTLV-I) causes adult T cell leukemia (ATL) in 2-5% of carriers after a long latent period. An HTLV-I encoded protein, Tax, induces proliferation and inhibits apoptosis, resulting in clonal proliferation of infected cells. However, tax gene expression in ATL cells is disrupted by several mechanisms, including genetic changes in the tax gene and DNA methylation/deletion of the 5' long terminal repeat (LTR). Because Tax is the major target of cytotoxic T-lymphocytes in vivo, loss of Tax expression should enable ATL cells to escape the host immune system. The 5' LTR of HTLV-I is frequently hypermethylated or deleted in ATL cells, whereas the 3' LTR remains unmethylated and intact, suggesting the involvement of the 3' LTR in leukemogenesis. Here we show that a gene encoded by the minus strand of the HTLV-I proviral genome, HTLV-I basic leucine zipper factor (HBZ), is transcribed from 3'-LTR in all ATL cells. Suppression of HBZ gene transcription by short interfering RNA inhibits proliferation of ATL cells. In addition, HBZ gene expression promotes proliferation of a human T cell line. Analyses of T cell lines transfected with mutated HBZ genes showed that HBZ promotes T cell proliferation in its RNA form, whereas HBZ protein suppresses Tax-mediated viral transcription through the 5' LTR. Thus, the single HBZ gene has bimodal functions in two different molecular forms. The growth-promoting activity of HBZ RNA likely plays an important role in oncogenesis by HTLV-I.

Amino Acid Sequence↗

PubMed2003

Interaction of a selective cyclooxygenase-2 inhibitor with aspirin and NO-releasing aspirin in the human gastric mucosa.

In addition to inhibiting cyclooxygenase (COX)-1-derived prostanoid biosynthesis, aspirin acetylates COX-2, enabling the conversion of arachidonic acid to 15(R)-epi lipoxin A4, or aspirin-triggered lipoxin (ATL). Selective COX-2 inhibitors block ATL formation and exacerbate mucosal injury in rats treated with aspirin. In the present study, we have examined whether inhibition of COX-2 activity in healthy volunteers taking aspirin exacerbates gastric mucosal injury and if such an effect would be prevented by NCX-4016, a NO-releasing derivative of aspirin. Thirty-two volunteers were randomized to receive 2 wk of treatment with NCX-4016 (800 mg twice a day) or aspirin (100 mg once a day) alone or in combination with 200 mg of celecoxib twice a day. Mucosal damage was assessed by endoscopy. The mean mucosal injury score was 5.8 +/- 1.8 in subjects treated with aspirin and 2.4 +/- 0.7 (P < 0.01 vs. aspirin) in subjects treated with NCX-4016. Administration of celecoxib increased the injury score in volunteers treated with aspirin (9.9 +/- 1.9) but not in subjects taking NCX-4016 (1.5 +/- 0.8). Aspirin and NCX-4016 caused a comparable suppression of serum thromboxane B2 levels and increased urinary excretion of ATL. Celecoxib inhibited endotoxin-induced prostaglandin E2 generation in whole blood by approximately 80% and abolished ATL formation. These findings suggests that (i) aspirin and NCX-4016 trigger ATL formation in humans, (ii) celecoxib inhibits ATL formation and exacerbates the mucosal injury caused by low doses of aspirin, and (iii) the NO-donating moiety of NCX-4016 protects the gastric mucosa even in the presence of suppression of COX-1 and COX-2.

Adult↗