Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Genes, pX”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 253 records · Page 14Linked to original sources
PubMed2002

Thioredoxin-mediated redox control of human T cell lymphotropic virus type I (HTLV-I) gene expression.

Thioredoxin (TRX) is a small ubiquitous protein with multiple biological functions, including the thiol-mediated redox-regulation of gene expression. We have previously demonstrated that human TRX is overexpressed as a major protein oxidoreductase in human T cell lymphotropic virus type I (HTLV-I)-infected cells. In the present study, we investigated the relationship between TRX and viral gene expression in HTLV-I infection. To study the mechanism that causes overexpression of TRX in HTLV-I-infected cells, we first examined the effect of the HTLV-I transactivator, Tax, on TRX expression. Induction of HTLV-I Tax protein increased the expression of TRX protein in a Tax-transfected Jurkat cell line, JPX-9. Moreover, chloramphenicol acetyltransferase (CAT) analysis with a reporter gene containing the TRX promoter revealed that Tax activates the transcription of TRX gene. To study the role of overexpressed TRX in HTLV-I infection, we next examined the effect of TRX on HTLV-I long terminal repeat (LTR)-mediated transcription using CAT analysis. In an HTLV-I-infected human T cell line MT-2, the HTLV-I LTR transactivation was suppressed by the overexpression of wild-type TRX, but activated by the introduction of inactive mutant TRX. Moreover, in HTLV-I negative Jurkat T cells, the HTLV-I LTR transactivation induced by Tax was also repressed by overexpression of wild-type TRX. Because cellular redox changes were shown to affect the HTLV-I gene expression, it is likely that TRX modulates the HTLV-I gene expression by regulating cellular redox state. Taken together, these findings suggest that overexpressed TRX, which is induced by HTLV-I Tax, may play an important role in HTLV-I infection through the negative regulation of viral gene expression.

Gene Expression Regulation, Viral↗
PubMed2001

Expression and functional properties of proteins encoded in the x-II ORF of HTLV-I.

With the aim of identifying viral proteins that contribute to the distinctive properties of HTLV-I biology and pathogenicity, several laboratories have investigated the coding potential of the X region of the genome, which includes five partially overlapping open reading frames (ORFs). We and others have shown that, in addition to the essential regulatory proteins Rex and Tax, a number of accessory proteins encoded in the X region can be produced by alternative splicing and multicistronic translation. One X region ORF, termed X-II, produces two protein isoforms named Tof/p30II and p13II, which are expressed from a doubly- and singly-spliced mRNA, respectively. Initial functional analyses demonstrated that Tof/p30II is a nucleolar/nuclear protein that possesses a region capable of binding to RNA, and p13II is a mitochondrial protein that alters the morphology and function of this organelle. Together with data from other laboratories demonstrating the production of antibodies and CTL against x-II ORF products in HTLV-I infected subjects and the requirement of this ORF for efficient viral replication in vivo, these findings suggest that further characterization of Tof/p30II and p13II will yield insight into remaining undefined aspects of HTLV-I pathogenicity and replication.

Amino Acid Sequence↗
PubMed1997

Up-regulation of iNOS mRNA expression and increased production of NO in human monoblast cell line, U937 transfected by HTLV-I tax gene.

We investigated the mRNA expression of inducible nitric oxide synthase (iNOS) and the production of nitric oxide (NO) in human T cell lymphotropic virus type I (HTLV-I) p40tax-transfected U937 cells, a human monoblast cell line. Transfection of HTLV-I p40tax U937 cells induced up-regulation of iNOS mRNA expression and subsequent NO production. Furthermore, interferon gamma (IFN-gamma) stimulation of HTLV-I p40tax-transfected U937 cells enhanced iNOS mRNA expression and NO production. The kinetics of iNOS mRNA expression and NO production indicated maximal effect at 24 and 48 hours, respectively, after culture with or without IFN-gamma. These findings suggest that HTLV-I p40tax can act as a transactivator of NO production in cells of Mo/M phi lineage. To what extent this mechanism may be involved in the pathogenesis of HTLV-I-associated diseases warrants further investigation.

Enzyme Induction↗
PubMed1999

NF-kappaB involvement in the activation of primary adult T-cell leukemia cells and its clinical implications.

The HTLV-I provirus-encoded Tax protein induces NF-kappaB in Tax-transfected Jurkat T cells or HTLVL-I- infected T cells in vitro. Tax induction of NF-kappaB is presumed to be involved in proliferation and activation of primary leukemia cells in vivo. Recent studies have demonstrated that NF-kappaB activities in human T cells are mediated by at least four c-Rel-related DNA binding proteins - p50, p55, p75 and p85. We examined the significance of NF-kappaB induction in primary adult T cell leukemia cells and the induction kinetics of each of the four NF-kappaB species. Marked NF-kappaB activity was detected using an electrophoretic mobility shift assay (EMSA) in the primary cells of patients with acute disease, but little activity was noted in the cells of chronic patients. NF-kappaB activity was enhanced in a time-dependent manner in acute type cells cultured with mitogen-free medium; there was no induction of activity in chronic type cells. UV crosslinking demonstrated all four species of NFkappaB complex - high levels of p50 and lower levels of p55 and p75, in acute type cells; chronic type cells showed only the p50. As a control, normal resting T cells similarly showed only p50; control cells showed little change in activity when cultured without mitogenic stimulation, analogous to chronic type ATL. Northern blotting revealed enhancement of c-rel (encoding p85) and KBFI (encoding p50 and p55) expression in acute type cells during culture, while there was no significant enhancement of mRNAs in chronic type ATL cells or unstimulated normal T cells. Northern blotting also revealed that Tax is upregulated at the mRNA level in acute- but not chronic-type cells during culture. Expression of c-rel and KBF1 mRNAs in acute type cells appeared to be related to Tax mRNA expression. These results suggest that Tax is capable of inducing nuclear expression of all four NF-kappaB species in primary ATL cells of acute type patients, with marked effects on p55, p75, and p85. Tax induction of NF-kappaB species is regulated, at least in part, at a pretranslational level involving increases in c-rel and KBF1 mRNA.

Acute Disease↗
PubMed2000

Why aren't foamy viruses pathogenic?

Foamy viruses are complex retroviruses that lead to either highly cytopathic or persistent infections in vitro, but to non-pathogenic lifelong infections in naturally or accidentally infected hosts. Factors that could contribute to these benign persistent infections include regulated transcription from the two viral promoters, the functions of the Bet accessory protein and the host immune response.

Animals↗
PubMed2006

Thymus-derived leukemia-lymphoma in mice transgenic for the Tax gene of human T-lymphotropic virus type I.

Adult T-cell leukemia-lymphoma (ATLL) is a group of T-cell malignancies caused by infection with human T-lymphotropic virus type I (HTLV-I). Although the pathogenesis of ATLL remains incompletely understood, the viral regulatory protein Tax is centrally involved in cellular transformation. Here we describe the generation of HTLV-I Tax transgenic mice using the Lck proximal promoter to restrict transgene expression to developing thymocytes. After prolonged latency periods, transgenic mice developed diffuse large-cell lymphomas and leukemia with clinical, pathological and immunological features characteristic of acute ATLL. Transgenic mice were functionally immunocompromised and they developed opportunistic infections. Fulminant disease also developed rapidly in SCID mice after engraftment of lymphomatous cells from transgenic mice. Flow cytometry showed that the cells were CD4(-) and CD8(-), but CD44(+), CD25(+) and cytoplasmic CD3(+). This phenotype is indicative of a thymus-derived pre-T-cell phenotype, and disease development was associated with the constitutive activation of NF-kappaB. Our model accurately reproduces human disease and will provide a tool for analysis of the molecular events in transformation and for the development of new therapeutics.

Animals↗
PubMed2004

HTLV-1-encoded p30II is a post-transcriptional negative regulator of viral replication.

Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) persists despite a vigorous virus-specific host immune response, and causes adult T-cell leukemia and lymphoma in approximately 2% of infected individuals. Here we report that HTLV-1 has evolved a genetic function to restrict its own replication by a novel post-transcriptional mechanism. The HTLV-1-encoded p30(II) is a nuclear-resident protein that binds to, and retains in the nucleus, the doubly spliced mRNA encoding the Tax and Rex proteins. Because Tex and Rex are positive regulators of viral gene expression, their inhibition by p30(II) reduces virion production. p30(II) inhibits virus expression by reducing Tax and Rex protein expression.

Cell Line↗
PubMed2005

Dichotomy of all-trans retinoic acid inducing signals for adult T-cell leukemia.

We previously reported that all-trans retinoic acid (ATRA) inhibits growth in human T-cell leukemia virus type 1 (HTLV-1)-positive T-cell lines and fresh cells from patients with adult T-cell leukemia. However, the mechanism of this inhibition is not clear. In the present study, we observed that NF-kappaB transcriptional activity as well as cell growth decreased significantly in HTLV-1-positive T-cell lines in the presence of ATRA. Furthermore, we observed that ATRA reduced HTLV-1 proviral DNA, HTLV-1 genes (gag, tax, or pol mRNA) using the real-time quantitative polymerase chain reaction. SIL-2R was reduced by ATRA in both protein level (culture supernantant) and mRNA level in HTLV-1-positive T-cell lines. Interestingly, ATRA significantly inhibited RT activity similar to azidothimidine (AZT) in HTLV-1-positive T-cell lines. Moreover, AZT inhibited proviral DNA but not NF-kappaB transcriptional activity, and sIL-2R on HTLV-1; however, ATRA inhibited of NF-kappaB, proviral DNA and sIL-2R on HTLV-1. These results suggested that the decrease in sIL-2R induced by ATRA may be caused by the actions of a NF-kappaB inhibitor acting on the NF-kappaB/sIL-2R signal pathway. These results suggested that ATRA could have two roles, as a NF-kappaB inhibitor and as an RT inhibitor.

Adult↗
PubMed1997

Characterization of peripheral blood T-lymphocytes transduced with HTLV-I Tax mutants with different trans-activating phenotypes.

Tax1, a transcriptional trans-activator of the Human T-cell leukemia virus type I (HTLV-I), induces the expression of many cellular genes through interaction with at least three distinct cellular transcription factors; CREB/ATF, NF-kappaB, and SRF. This Tax1-induced activation of cellular genes is considered to be a critical event in T-cell transformation by HTLV-I. To elucidate the role of each Tax1-inducible transcriptional pathway in T-cell transformation, we introduced Tax1 mutants with different trans-activating phenotypes into peripheral blood lymphocytes (PBL) by retroviral vectors. Analysis of these PBLs revealed that activation of the NF-kappaB pathway is sufficient to promote the growth response to IL-2. However, for the clonal expansion of CD4+ T-cells, which is a characteristic result of HTLV-I infection, activation of the CREB/ATF and SRF pathways is also required.

CD4-Positive T-Lymphocytes↗
PubMed1999

Binding of the human T-cell leukemia virus Tax protein to the coactivator CBP interferes with CBP-mediated transcriptional control.

The HTLV-I oncoprotein Tax is required for high level viral transcription and is strongly linked to HTLV-I-associated malignant transformation. Tax stimulates HTLV-I transcription through high affinity binding to the KIX domain of CBP, a pleiotropic coactivator. Several cellular proteins, including c-jun, also bind to KIX and utilize CBP as a coactivator. To test whether Tax binding to KIX may disable cellular CBP function, we examined the potential interplay between Tax and c-jun for binding to KIX. We show that Tax represses the transcription function of c-jun in vivo and demonstrate that both transcription factors bind to an overlapping minimal region of KIX in vitro. c-jun binding to KIX is displaced by Tax, indicating that their binding is mutually exclusive and providing a molecular basis for the observed repression. The competition between Tax and cellular transcription factors for CBP represents a novel pathway for HTLV-I dependent deregulation of gene expression, and may have significant implications for cellular homeostasis and transformation in the HTLV-I infected T-cell.

Binding Sites↗
PubMed1999

Tax protein of HTLV-1 inhibits CBP/p300-mediated transcription by interfering with recruitment of CBP/p300 onto DNA element of E-box or p53 binding site.

Tax protein of human T-cell leukemia virus type 1 (HTLV-1) is a potent transcriptional regulator which can activate or repress specific cellular genes and has been proposed to contribute to leukemogenic processes in adult T-cell leukemia. The molecular mechanism of Tax-mediated trans-activation has been well investigated. However, trans-repression by Tax remains to be studied in detail, although it is known to require a specific DNA element such as E-box or p53 binding site. Examining possible mechanisms of trans-repression, we found that co-expression of E47 and p300 activated E-box dependent transcription and this activation was efficiently repressed by Tax. In this system, Tax bound to p300 and decreased the level of p300 complexed on the E-box element. Similarly, Tax inhibited transcription directed by p53 and CBP, reducing the level of CBP on the p53 binding site. These results indicate that Tax interferes with recruitment of CBP/p300 into protein complexes on E-box and p53 binding site through its binding to CBP/p300. In contrast to these findings, we observed that Tax increased the level of CBP on the viral 21-bp enhancer which is trans-activated by Tax. From these observations, we propose a universal mechanism for Tax-mediated trans-repression and trans-activation of transcription in which Tax binds to CBP/p300 and determines the accessibility of CBP/p300 to protein complexes on specific DNA element.

Binding Sites↗
PubMed1999

Mitochondrial targeting of the p13II protein coded by the x-II ORF of human T-cell leukemia/lymphotropic virus type I (HTLV-I).

The X region of the HTLV-I genome contains four major open reading frames (ORFs), two of which, termed x-I and x-II, are of still undefined biological significance. By indirect immunofluorescence and dual labeling with marker proteins, we demonstrate that p13II, an 87-amino acid protein coded by the x-II ORF, is selectively targeted to mitochondria. Mutational analysis revealed that mitochondrial targeting of p13II is directed by an atypical 10-amino acid signal sequence that is not cleaved upon import and is able to target the Green Fluorescent Protein to mitochondria. Expression of p13II results in specific alterations of mitochondrial morphology and distribution from a typical string-like, dispersed network to round-shaped clusters, suggesting that p13II might interfere with processes relying on an intact mitochondrial architecture. Functional studies of mitochondria with the cationic fluorochrome tetramethylrhodamine revealed that a subpopulation of the cells with p13II-positive mitochondria show a disruption in the mitochondrial inner membrane potential (Apsi), an early event observed in cells committed to apoptosis. Taken together, these results suggest novel virus-cell interactions that might be important in HTLV-I replication and/or pathogenicity.

Alternative Splicing↗
PubMed2000

Functional impairment of p73 and p51, the p53-related proteins, by the human T-cell leukemia virus type 1 Tax oncoprotein.

We have previously demonstrated that the human T-cell leukemia virus type 1 (HTLV-1) Tax oncoprotein represses the trans-activation function of p53 tumor suppressor protein. Recently, several proteins with sequence homology to p53 have been identified. In this study, we demonstrated that Tax represses the trans-activation functions of p73alpha, p73beta, and p51A, the p53-related proteins, as well as p53. Moreover, a mutant Tax of coactivator CBP-binding site (K88A), which activated NF-kappaB but not CREB pathway, could not repress the p73 nor p51 trans-activation functions, indicating that CBP-binding domain of Tax is essential for the suppression of their functions. Using proteins of Gal4-fused N-terminal region of p73 and p51, we showed that Tax-mediated inactivation of p73 or p51 requires for their N-terminal trans-activation domains. Furthermore, only the putative N-terminal trans-activation domains of them did not have enough transcriptional activities and their adjacent regions are essential for their full trans-activation, suggesting the existence of their second trans-activation subdomains. Thus, HTLV-1 Tax inactivated the p53-related proteins through their N-terminal trans-activation domains.

DNA-Binding Proteins↗
PubMed2001

Genome-wide expression changes induced by HTLV-1 Tax: evidence for MLK-3 mixed lineage kinase involvement in Tax-mediated NF-kappaB activation.

The Tax protein of human T-lymphotropic virus type 1 (HTLV-1), an oncoprotein that transactivates viral and cellular genes, plays a key role in HTLV-1 replication and pathogenesis. We used cDNA microarrays to examine Tax-mediated transcriptional changes in the human Jurkat T-cell lines JPX-9 and JPX-M which express Tax and Tax-mutant protein, respectively, under the control of an inducible promoter. Approximately 300 of the over 2000 genes examined were differentially expressed in the presence of Tax. These genes were grouped according to their function and are discussed in the context of existing findings in the literature. There was strong agreement between our results and genes previously reported as being Tax-responsive. Genes that were differentially expressed in the presence of Tax included those related to apoptosis, the cell cycle and DNA repair, signaling factors, immune modulators, cytokines and growth factors, and adhesion molecules. Functionally, we provide evidence that one of these genes, the mixed-lineage kinase MLK-3, is involved in Tax-mediated NF-kappa-B signaling. Our current results provide additional insights into Tax-mediated signaling.

Apoptosis↗
PubMed2005

Natural history of adult T-cell leukemia/lymphoma and approaches to therapy.

After cell-to-cell transmission, HTLV-I increases its viral genome by de novo infection and proliferation of infected cells. Proliferation of infected cells is clonal and persistent in vivo. During the carrier state, infected cells are selected in vivo by the host's immune system, the genetic and epigenetic environment of proviral integration sites, and other factors. In leukemic cells, tax gene expression is frequently impaired by genetic and epigenetic mechanisms. Such loss of Tax expression enables ATL cells to escape the host immune system. On the other hand, ATL cells acquire the ability to proliferate without Tax by intracellular genetic and epigenetic changes. Despite advances in support and the development of novel treatment agents, the prognosis for ATLL remains poor. A number of therapies, however, do appear to improve prognosis compared to CHOP (VEPA). These include interferon-alpha plus zidovudine (probably after 1-2 cycles of CHOP), intensive chemotherapy as in LSG-15 with G-CSF support and Allo-SCT (which includes the potential for cure). Emerging novel approaches include HDAC inhibitors, monoclonal antibodies, and proteasome inhibitors. Comparison between different therapeutic approaches is complicated by the range of natural history of ATLL, different recruitments of naïve-to-therapy, refractory or relapsed patients, and variations in the reporting of outcome that frequently excludes difficult-to-evaluate patients. Moreover, results from relatively small proof-of-principle studies have not been extended with randomized, controlled trials. As a result, currently, there is no clear evidence to support the value of any particular treatment approach over others. To avoid further unnecessary patient suffering and to identify optimal therapy as rapidly as possible, large randomized, controlled trials encompassing multicenter, international collaborations will be necessary.

Adult↗
PubMed2006

Spindle checkpoint protein Bub1 corrects mitotic aberrancy induced by human T-cell leukemia virus type I Tax.

Bub1 is a component of the mitotic spindle checkpoint apparatus. Abnormality of this apparatus is known to cause multinuclei formation, a hallmark of chromosomal instability (CIN). A549, aneuploid cell line, aberrantly passed through the mitotic phase and became multinuclei morphology in the presence of nocodazole. Time-lapse videomicroscopy showed unreported bizarre morphology, which we named 'mitotic lobulation' in A549 cells just before the exit from mitosis and multinuclei formation. External expression of wild-type Bub1-EGFP clearly suppressed the multinuclei formation by retaining A549 cells at the mitotic phase during 48 h of time-lapse observation. This suppressive effect on mitotic aberrancy should not be mere restoration of normal Bub1 function, because A549 cells express proper amount of Bub1, which distributed cytoplasm during interphase and concentrated at kinetochore in metaphase. Furthermore, external expression of wild-type Bub1-EGFP suppressed multinuclei formation induced by Tax both in A549 and HeLa cells. Tax is known to induce mitotic abnormality by binding and inactivating Mad1. These observations, therefore, suggest functional redundancy between Bub1 and other mitotic checkpoint protein(s) and a possibility of correction of mitotic aberrancy by external Bub1 expression.

Cell Cycle Proteins↗
PubMed1993

Comparison of the levels of inositol metabolites in transformed haemopoietic cells and their normal counterparts.

We have compared the levels of inositol metabolites in three pairs of normal and transformed cells which have been matched with respect to their cell lineage, differentiation and proliferation status: (i) normal human myeloid blast cells and the human promyelocytic leukaemic cell line, HL60; (ii) human umbilical-cord T-helper cells and C8166 cells, a HTLV-1-transformed T-helper cell line; and (iii) an interleukin 3-dependent long-term culture of murine pro-B-cells (BAF3) and BAF3 cells transformed by transfection with the bcr-abl oncogene. Complex patterns of inositol metabolites were present in each of the cell populations. Although there were a number of differences in the levels of certain inositol metabolites between individual cell populations in the paired groups, we did not observe any consistent difference in the levels of inositol metabolites between the proliferating normal and transformed cells. In particular, our data do not support the reported correlation between elevated glycerophosphoinositol (GroPIns) levels and transformation of cells by membrane and cytoplasmic oncogenes which has been reported by other workers. All the cells contained high concentrations of Ins(1,3,4,5,6)P5 (between 12 and 55 microM) and InsP6 (between 37 and 105 microM). The HTLV1-transformed T-helper cells had particularly high levels of total inositol phosphates (predominantly GroPIns, an unidentified inositol bisphosphate and InsP6). The observations are discussed with reference to cell transformation and to the differentiation status of the paired populations.

Animals↗