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PubMed2002

PTCL: lessons from adult T-cell leukemia.

Peripheral T-cell lymphoma (PTCL) is a neoplastc disease of peripheral T-lymphocytes/NK cells, including PTCL unspecified, anaplastic large T-cell lymphoma (ALCL), IBL-like T-cell lymphoma (AILD), intestinal T-cell lymphoma (ITCL) and adult T-cell leukemia/lymphoma (ATL). The incidence of PTCL is relatively uncommon although its incidence shows significant variations in the geographical regions and racial populations. In Asia, its incidence is high due to HTLV-I infection in Japan. Molecular mechanisms of oncogenesis of PTCLs remain unknown. Therefore, analyses of ATL will give us a clue to clarify the molecular mechanism.

Female↗
PubMed2003

Stationary phase-like properties of the bacteriophage lambda Rex exclusion phenotype.

The rex genes of bacteriophage lambda were found to protect lysogenic Escherichia coliK host cells against killing by phage T4 rII, when compared in parallel to isogenic Rex(-) lysogens and nonlysogens. This protective effect was abrogated upon mutation of the host stationary-phase sigma factor RpoS. Rex(+) lysogens infected by T4 rII contracted, formed aggregates and shed flagella, thus resembling cells entering stationary phase. These phenotypes were accentuated in nonlysogenic cells carrying multicopy plasmids expressing rexA-rexB: cells were about two-fold contracted in length, expressed membrane-bound and detached flagella, were insensitive to infection by a variety of phages and clumped extensively; in addition, cultures of these cells were odorous. Our observations support the hypothesis that the Rex system can cause a stationary-phase-like response that protects the host against infection by T4 rII.

Bacterial Proteins↗
PubMed2006

Tax & rex: overlapping genes of the Deltaretrovirus group.

Bovine leukemia virus and human T-cell leukemia viruses I and II, members of the Deltaretrovirus group, have two regulatory genes, tax and rex, that are coded in overlapping reading frames. We found that sequence variations in the rex gene of each virus result in amino acid differences significantly more often than variations in the tax gene. For all three viruses the highest ratio of non-synonymous to synonymous changes was found in the rex gene. In the overlapping regions of tax and rex, the second codon position of Rex corresponds to the third codon position of Tax. Nucleotide C was present in all genes of the three viruses at the highest frequency and this bias was most pronounced in the rex gene. More specifically we found that the C bias and nucleotide variation is greatest at the second codon position of Rex and the third codon position of Tax in the area of tax/rex overlap. Changes in the second codon position of Rex always resulted in amino acid change whereas changes in the third codon position of Tax resulted in amino acid changes less than a third of the time. Analysis of the amino acid frequencies in both proteins shows that there is a disproportionately large percentage of the amino acids alanine, proline, serine and threonine (the four amino acids whose second codon position is C) in Rex. These findings led us to hypothesize that the Rex protein can withstand more amino acid changes than can the Tax protein suggesting that the Tax protein experiences higher evolutionary constraints and is the more conserved of the two proteins.

Amino Acid Sequence↗
PubMed1995

HTLV tax-rex DNA and antibodies in idiopathic amyotrophic lateral sclerosis.

In an attempt to verify the possible role of retrovirus in idiopathic amyotrophic lateral sclerosis (ALS), the sera of 21 ALS patients admitted to the Neurological Unit of the Don Gnocchi Foundation in Milan, Italy, and of 9 ALS patients from Ulm University in Germany have been evaluated for the presence of antibodies to the human T-lymphotropic viruses (HTLV-I and HTLV-II). The sera of 30 healthy individuals and 20 HIV-infected but HTLV-negative subjects have been also studied as control. Moreover, the HTLV tax-rex and pol DNA sequence have been searched in the peripheral blood mononuclear cells (PBMCs) of 15 ALS patients and 15 HIV-positive HTLV-negative subjects using a nested PCR currently employed in our laboratory for the study of HTLV infections. Antibodies to one or more HTLV proteins have been found by using a Western blot (WB) kit in the sera of 10 Italian and 7 German ALS cases, while all the healthy controls were negative and only one HIV-positive subject had antibodies to HTLV gp21. HTLV tax-rex sequences have been found in the PBMCs of 6 ALS patients while all the controls were negative. All 15 ALS cases and controls were negative for HTLV pol DNA indicating that only the most conserved region of the HTLV genome could be detected. On the whole our data indicate that some ALS patients have antibodies to HTLV proteins and that the tax-rex region of the HTLV genome can be found in their PBMCs.

Adult↗
PubMed1991

Regulation of HTLV-II gene expression by Rex involves positive and negative cis-acting elements in the 5'long terminal repeat.

Regulation of human T-cell leukemia virus type II (HTLV-II) gene expression by the trans-acting viral protein, Rex, is mediated through specific cis-acting sequences in the HTLV-II long terminal repeat (LTR). Augmentation of 5' LTR-linked gene expression by Rex requires two distinct cis-acting elements: one termed the "Rex-responsive element" (RxRE), which allows Rex to overcome the inhibitory effect of a second, termed the "cis-acting repressive sequences" (CRS). The HTLV-II RxRE is located between nt +91 and +317 relative to the cap site in the R/U5 region of the 5'LTR, and the HTLV-II CRS is contained within the RxRE from nt +208 to +317, which is downstream of the splice donor site, in the R/U5 region of the 5' LTR. Deletion of the CRS results in significantly increased cytoplasmic levels of LTR-linked mRNA independent of the presence of Rex. Our results show that Rex acts post-transcriptionally and induces a shift from nucleus to cytoplasm of gag/pol mRNA, the only HTLV-II mRNA that contains both the RxRE and the CRS in the 5' LTR-derived leader sequence.

Base Sequence↗
PubMed1993

The rex genes of lambda prophage modify ultraviolet light and N-methyl-N-nitrosourea-induced responses to DNA damage in Escherichia coli.

Inactivation and mutagenesis of Escherichia coli by ultraviolet light and N-methyl-N-nitrosourea (MNU) were examined in isogenic strains that were (i) free of lambda phage, (ii) lysogenic for lambda or (iii) contained the lambda rexAB operon on a plasmid (prex20). Inactivation was enhanced when rex genes were present and this enhancement was greater for MNU than for UV. Mutagenesis was not greatly affected by the presence of the rex genes with one exception; UV-induced glnU degrees suppressor mutations were reduced in the strain harboring prex20. Control experiments using a strain containing only plasmid pACYC184 showed no effect on inactivation. A small depression in UV-induced mutagenesis was observed, however. These data suggest that the lambda RexAB proteins interfere with processes necessary for recovery from DNA damage and for fixation of one example of UV-induced mutation. This and other recent observations of effects by rex genes are discussed.

Bacteriophage lambda↗
PubMed1991

Murine retroviral vectors expressing the tax1 gene of human T-cell leukemia virus type 1.

Murine retroviral vectors which express the tax1 gene of human T-cell leukemia virus type 1 (HTLV-1) have been constructed. A significant increase in virus titer was achieved by inserting a portion of the gag region of Moloney murine leukemia virus. Using these vectors, tax1 was stably introduced into primary human T-cells derived from peripheral blood lymphocytes. Expression of the functional tax1 in infected cells was confirmed by trans-activation of HTLV-1 long terminal repeat-directed transcription. These vectors provide a useful means of investigating the function of tax1 in natural target cells for HTLV-1.

Animals↗
PubMed1993

HTLV-1 Tax: regulation of gene expression and disease.

The human T cell leukemia virus type 1 (HTLV-1) is a retrovirus that causes adult T cell leukemia and the neurological disorder tropical spastic paraparesis. Pathology apparently results from the activities of the Tax protein, which trans-activates the expression of viral and cellular genes by binding to various enhancer-binding proteins needed for transcription. This ultimately results in cell transformation, immortalization and disease.

Base Sequence↗
PubMed2005

Activation of a cryptic splice site in the tax gene of HTLV-I by a single nucleotide change.

We identified a T-to-C mutation 2 nucleotides (nt) upstream from the AG in a GT-AG intron between exons 2 and 3 in the human T-cell leukemia virus type I (HTLV-I) tax mRNA. This mutation resulted in the preferential usage of an alternative splice site, causing a 75-nt elongation of tax mRNA and reduced production of viral antigens. When the clone containing this T-to-C mutation was reverted to the wild-type (T) DNA sequence, normal splicing of tax mRNA ensued and viral production was restored. These results suggest that the nucleotide at the position 2nt upstream from the AG in a GT-AG intron is important for the proper splicing of the HTLV-I tax gene, although it is not considered important for splicing in eukaryotes.

Alternative Splicing↗
PubMed2005

Capture of antigen-specific T lymphocytes from human blood by selective immortalization to establish long-term T-cell lines maintaining primary cell characteristics.

To establish long-term, antigen-specific T-cell lines and clones, we selectively immortalized antigen-responsive T cells from human peripheral blood mononuclear cells (PBMCs). PBMCs were stimulated with either alloantigen or soluble antigen, then infected with a murine leukemia virus-based retroviral vector carrying an immortalizing gene, either the Tax gene from human T-cell leukemia virus type 1, or the human telomerase-reverse transcriptase gene. Since such vectors can only integrate in dividing cells, only antigen-activated T cells are efficiently transduced. This approach generated immortalized antigen-specific CD4+ and CD8+ T-cell lines that maintained strictly IL-2-dependent growth and HLA-restricted, antigen-specific responsiveness, some of which have been in continuous culture for longer than 1 year, far in excess of the survival of parallel control non-immortalized cultures. Clones derived from these lines showed antigen-specific proliferation with induced cytokine and chemokine production, and, in the case of a CD8+ T-cell clone, antigen-specific cytolytic activity. This approach provides a convenient, reproducible means for generating a stable, continuously renewable source of antigen-specific T lymphocytes for a variety of studies of T cell biology.

Amino Acid Sequence↗
PubMed2005

Curcumin suppresses constitutive activation of AP-1 by downregulation of JunD protein in HTLV-1-infected T-cell lines.

Activation of the activator protein 1 (AP-1) plays a critical role in oncogenesis by human T-cell leukemia virus type 1 (HTLV-1), the etiologic agent of adult T-cell leukemia (ATL), and is required for maintenance of the malignant phenotype. Curcumin (diferuloylmethane), the major pigment of the spice turmeric, has anti-tumor activity; however, the effect of curcumin against ATL has not been elucidated. In this study, we examined the effects of curcumin on AP-1 activity in HTLV-1-infected T-cell lines. Curcumin suppressed the constitutive AP-1 DNA-binding and transcriptional activity in HTLV-1-infected T-cell line. Curcumin also inhibited HTLV-1 Tax-induced AP-1 transcriptional activity. JunD was detectable as a major component of the AP-1-DNA complex in HTLV-1-infected T-cell lines using the supershift assay. The expression of JunD was suppressed by curcumin treatment. Curcumin inhibited the growth of HTLV-1-infected T-cell lines by inducing cell cycle arrest followed by apoptosis. Our results suggest that suppression of the constitutively active AP-1 by curcumin is due to, at least in-part, reducing the expression of JunD by curcumin. Inhibition of AP-1 activity by curcumin may be one of the mechanisms responsible for the anti-ATL effect of curcumin. We propose that curcumin is a potentially promising compound for the treatment of ATL.

Apoptosis↗
PubMed2004

Ex vivo survival of peripheral blood mononuclear cells in sheep induced by bovine leukemia virus (BLV) mainly occurs in CD5- B cells that express BLV.

Bovine leukemia virus (BLV) is the etiologic agent of enzootic bovine leukosis (EBL). In a previous report, we found that in a sheep model, only CD5(-) B cells proliferated clonally, while CD5(+) B cells rapidly decreased when the disease progressed to the lymphoma stage. We demonstrate here that, although both CD5(+) and CD5(-) B cells, but not CD4(+) T, CD8(+) T and gammadeltaTCR(+)T cells, are protected from spontaneous ex vivo apoptosis in sheep infected with wild-type and a mutant BLV that encodes a mutant Tax D247G protein with elevated trans-activation activity, only CD5(-) B cells become the main target for ex vivo survival when the disease proceeds to the persistent lymphocytotic stage, which showed an increased expansion of the CD5(-) B cells. In addition, we identified, by four-color flow cytometric analysis, that in CD5(-) B cells, the apoptotic rates of cells that expressed wild-type and mutant BLV were greatly decreased compared with those of BLV-negative cells. There was only a slight reduction in the apoptotic rates in BLV-positive cells from CD5(+) B cells. In addition, supernatants from peripheral blood mononuclear cell (PBMC) cultures from wild-type- and mutant BLV-infected sheep mainly protected CD5(-) B cells from spontaneous apoptosis. Our results suggest that, although BLV can protect both CD5(+) and CD5(-) B cells from ex vivo apoptosis, the mechanisms accounting for the ex vivo survival between these two B-cell subsets differ. Therefore, it appears that the phenotypic changes in cells that express CD5 at the lymphoma stage could result from a difference in susceptibility to apoptosis in CD5(+) and CD5(-) B cells in BLV-infected sheep.

Animals↗
PubMed2006

CCAAT/enhancer-binding proteins modulate human T cell leukemia virus type 1 long terminal repeat activation.

CCAAT/enhancer-binding protein (C/EBP) basic region/leucine zipper (bZIP) transcription factors have been shown to form heterodimers with cAMP-responsive element binding protein 2 (CREB-2), a transcription factor involved in regulating basal and Tax-mediated transactivation of the human T cell leukemia virus type 1 (HTLV-1) long terminal repeat (LTR). In cells of the monocyte-macrophage lineage (proposed to play a role in HTLV-1 pathogenesis as an accessory target cell), several members of the C/EBP family are expressed at high levels and may have functional impact on both basal and Tax-mediated transactivation of the HTLV-1 LTR. Basal activation of the HTLV-1 LTR was enhanced by overexpression of C/EBPbeta, C/EBPdelta, or C/EBPepsilon, whereas transactivation of the LTR by Tax was inhibited by overexpression of C/EBPalpha and C/EBPbeta. Inhibition of Tax-mediated transactivation of the HTLV-1 LTR was co-activator-independent, did not require C/EBP binding to the Tax-responsive elements, and may involve heterodimerization with CREB factors.

Base Sequence↗
PubMed1991

The nucleolar localisation signal of the HTLV-I protein p27rex is important for stabilisation of IL-2 receptor alpha subunit mRNA by p27rex.

In this study we investigated the mechanism of stabilisation of IL-2 receptor alpha subunit mRNA by the HTLV-I protein p27rex. We tested the role of the nucleolar targetting signal in rex by introducing mutations. Three deletion mutants could not express rex protein in the nucleolus and although protein was still expressed in the nucleoplasm none of the mutants could stabilise IL-2R alpha mRNA. A substitution mutant could be expressed in the nucleolus and could also stabilise IL-2R alpha mRNA. The data show that the nucleolar targetting signal is crucial for stabilisation of IL-2R alpha mRNA by rex and raise the possibility that transport of mRNA from nucleus to cytoplasm can involve the nucleolus.

Animals↗
PubMed1998

Characterization of the internal promoter of human T-cell leukemia virus type I.

The HTLV-I provirus contains two different promoters: the classical retroviral promoter in the 5' long terminal repeat (LTR) and our previously identified second promoter in the pol gene just upstream of the ATG codon of the tax gene. Here, we demonstrated that the internal promoter expresses the gene for Tax but not Rex. As the deletion of upstream of the transcriptional initiation site (nt 5130) caused down-regulation of the promoter activity, we termed the region HTLV-I internal regulatory element (HIRE). We found a cellular sequence-specific DNA binding protein which binds to HIRE. Furthermore, we demonstrated that the 3' LTR regulates Tax expression from the internal promoter. These findings may shed light on a novel mechanism for gene expression in complex retroviruses of the HTLV family.

Amino Acid Sequence↗
PubMed1998

Evidence that protein kinase A activity is required for the basal and tax-stimulated transcriptional activity of human T-cell leukemia virus type-I long terminal repeat.

The present study was undertaken to investigate the role of protein kinase A (PKA) in the control of human T-cell leukemia virus type-I (HTLV-I) long terminal repeat (LTR) expression, since this issue is still controversial. For this purpose we employed two human T-cell lines; the Jurkat cells in which long exposure to diBu-cAMP severely down-regulated the catalytic subunit of PKA (PKA-C), and H-9 cells in which such exposure markedly increased PKA-C level. Transient transfection assays revealed that addition of diBu-cAMP 1 h before or after transfection profoundly increased HTLV-I LTR directed CAT expression and synergistically enhanced its stimulation by the viral transactivator tax gene product in both cell lines. However longer exposure to diBu-cAMP before transfection reduced LTR-CAT expression to below its basal level and completely abolished its stimulation by tax in Jurkat cells, and this diBu-cAMP inhibitory effect could be abrogated by co-transfection of a PKA-C expressing vector. By contrast, in H-9 cells, this long exposure to diBu-cAMP continued enhancing LTR-CAT expression and its tax-mediated transactivation, and this stimulatory effect of diBu-cAMP could be diminished by the PKA-specific inhibitor N-12-(p-bromocinnamylamine)ethyll-5-isoquinolinsulfonamid e (H-89). Notably, in the absence of diBu-cAMP treatment H-89 reduced LTR-CAT expression to below its basal level and prevented its stimulation by tax in both cell lines. Together these findings indicate not only that cAMP-activated PKA stimulates HTLV-I LTR expression and its transactivation by tax, but even in the absence of PKA activating signals the basal HTLV-I LTR expression as well as its stimulation by tax are both dependent on a basal PKA activity.

Bucladesine↗
PubMed1997

Lack of evidence for HTLV tax-rex DNA in motor neurone disease.

It has recently been claimed (Ferrante et al., 1995. HTLV tax-rex DNA and antibodies in idiopathic amyotrophic lateral sclerosis. J. Neurol. Sci. 129 (Suppl.) 140-144) that human T-lymphotropic virus (HTLV) tax-rex sequences are detectable in the peripheral blood mononuclear cells (PBMCs) of 40% of patients with motor neurone disease (MND). In an attempt to confirm this we employed a highly sensitive 'nested' polymerase chain reaction (PCR) assay, capable of detecting single molecules of HTLV proviral DNA, to look for tax-rex sequences in the PBMCs of 43 patients with MND. We were unable to detect the presence of HTLV tax-rex in any of 43 MND patients tested, using three different PCR primer sets under both high and low stringency conditions. Using the same DNA samples we were able to detect the presence of the single-copy pyruvate dehydrogenase gene, thus demonstrating that the extracted DNA was indeed amplifiable by PCR. To further exclude the possibility that the extracted DNA samples contained unrecognised inhibitory factors we conducted spiking experiments with trace amounts (approximately 10 copies) of HTLV proviral DNA. Spiked samples yielded PCR products of the expected size. We are therefore unable to confirm the presence of HTLV tax-rex sequences in this disease.

Adult↗
PubMed1997

Arthritis syndromes associated with human T cell lymphotropic virus type I infection.

Arthritis syndromes occur associated with HTLV-I infection both in the presence and in the absence of clinical ATL, and polyarthritis may be the presenting manifestation of HTLV-I-associated ATL. In both clinical settings, HTLV-I-infected T cells home to affected joints, and tax-transgenic mouse studies have suggested a pathogenic role for the HTLV-I tax gene in inducing synovial cell proliferation in HAA. Understanding the pathogenesis of rheumatoid arthritis-like arthritis syndromes that occur in the setting of HTLV-I infection should also provide insights into understanding of cellular and molecular mechanisms of synovial cell proliferation in HTLV-I-negative rheumatoid arthritis.

Animals↗