DOCSLIB.ORG

The Internal Methionine Codons of Human T-Cellleukemia Virus Type

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Internal Methionine Codons of Human T-Cellleukemia Virus Type JOURNAL OF VIROLOGY, Oct. 1990, p. 4914-4921 Vol. 64, No. 10 0022-538X/90/104914-08$02.00/0 Copyright C) 1990, American Society for Microbiology The Internal Methionine Codons of Human T-Cell Leukemia Virus Type II rex Gene Are Not Required for p24rex Production or Virus Replication and Transformation PATRICK L. GREEN,' YIMING XIE,' AND IRVIN S. Y. CHEN' 2* Division of Hematology-Oncology, Department of Medicine,' and Department of Microbiology and Immunology,2 UCLA School of Medicine and Jonsson Comprehensive Cancer Center, Los Angeles, California 90024-1736 Received 21 May 1990/Accepted 12 July 1990 Human T-cell leukemia virus types I (HTLV-I) and II (HTLV-II) have two nonstructural trans-acting regulatory genes, tax and rex, located in the 3' region of the viral genome. The tax gene product (HTLV-I p4O't and HTLV-II p37) is the transcriptional activator of the viral long terminal repeat. The rex gene encodes two protein products, p27rex/p2lrex and p26`ex/p24rex in HTLV-I and HTLV-II, respectively. Rex acts posttran- scriptionally to facilitate accumulation of full-length gaglpol and singly spliced env mRNA in the cytoplasm of HTLV-infected cells. Previous studies showed that the first ATG of the rex gene is critical for Rex production and function. The importance of the internal ATGs to Rex function is not known. However, in vitro mutagenesis of the HTLV-I rex gene has provided indirect evidence which suggests that p2lrex, and by analogy HTLV-II p24rex, results from initiation at an internal AUG of the taxlrex mRNA. By using an infectious molecular clone of HTLV-II, we investigated the importance of the internal ATGs of the rex gene on Rex protein production and function. Our results indicate that p24rex of HTLV-II is not initiated at an internal AUG and that the internal methionine codons are not crucial to the function of the rex gene and, ultimately, the transforming properties of the virus. Human T-cell leukemia virus types I (HTLV-I) and II for interleukin-2 (26), the interleukin-2 receptor (1, 8, 19), (HTLV-II) have been identified as the causative agents of and granulocyte-macrophage colony-stimulating factor (31, some forms of leukemia and chronic neurological disorders 51). Several studies have implicated Tax in the HTLV in humans. HTLV-I causes adult T-cell leukemia in a small oncogenic process (14, 30, 48). percentage of seropositive individuals (18, 33) and, more The rex reading frame produces two proteins of 27 and 21 recently, has been linked with a progressive demyelinating kilodaltons in HTLV-I (p27rex and p21rex) (23) and 26 and 24 syndrome termed HTLV-I-associated myelopathy (32) or kilodaltons in HTLV-II (p26rex and p24rex) (37, 44). Amino- tropical spastic paraparesis (11). HTLV-II has been associ- terminal deletions of Rex coding sequences and specific ated only with rare forms of T-cell leukemia related to point mutations which abolish Rex protein production indi- hairy-cell leukemia (22, 38, 40), and thus its disease associ- cate that Rex acts posttranscriptionally to increase the ratio ation is less substantiated. However, recent studies revealed of incompletely spliced mRNAs (encoding Gag, Pol, and that a significant percentage of intravenous drug abusers in Env proteins) to completely spliced mRNA (encoding Tax the United States and Europe harbor HTLV-II (25, 36, 49), and Rex), resulting in highly regulated viral gene expression indicating that the virus is more prevalent in the population (16, 17, 20). The individual contribution of the smaller rex than first estimated. gene product, if any, has not been determined. HTLV transforms peripheral blood T lymphocytes in The precise relationship of the two rex gene products is vitro, as defined by their continuous proliferation in the not known, although it has been established that both absence of exogenous interleukin-2 (7, 34, 50), even though share the its genome lacks a classical oncogene and does not insert at proteins same carboxy terminus (28). One study specific sites within the host genome (41, 42). Three mRNA which involved in vitro translation of in vitro-synthesized species have been identified for HTLV. A full-length ge- HTLV-I RNA containing specific site-directed mutations in nomic mRNA (8.2 kilobases [kb]) and a subgenomic mRNA the rex open reading frame demonstrated that deletion of an (4.3 kb), in which one intron is spliced out, encode the internal methionine initiation codon resulted in the loss of characteristic retroviral Gag and Pol proteins and Env p2lrex (29). These results suggested that p2lrex is synthesized protein, respectively. A second subgenomic mRNA (2.1 kb), from an internal methionine initiation codon of the doubly which has an additional intron removed, encodes both the spliced taxlrex mRNA. Studies corroborating these results tax and rex gene products via translation in separate over- have not been performed in infected cells, due to the lack of lapping reading frames. The tax reading frame produces a an infectious clone of HTLV-I; thus, the function of the 40-kilodalton protein in HTLV-I (p40ax) and a 37-kilodalton smaller Rex protein has not been elucidated. protein in HTLV-II (p37ax), which localizes to the nucleus By using an infectious clone of HTLV-II, we investigated of infected cells (12, 21, 29, 46). Tax has been shown to the importance of the internal methionine codons of the rex increase the rate of transcription from the viral long terminal gene on p24rex production, viral replication, and transforma- repeat (LTR) (4, 5, 10, 43), as well as from the cellular genes tion. By using site-directed mutagenesis, the internal ATGs in the rex reading frame were systematically mutated. We report here that p24rex is not initiated at an internal methio- nine codon and that the internal methionine codons are not * Corresponding author. crucial to the function of the rex gene. 4914 VOL. 64, 1990 HTLV-II rex GENE 4915 MATERIALS AND METHODS (determined by the Bio-Rad protein assay), and percentages of ['4C]chloramphenicol acetylation were quantified by scin- Cell lines. 729-6, an Epstein-Barr virus-transformed hu- tillation counting of excised spots. man B-cell line, was maintained in Iscove medium supple- Metabolic labeling and immunoprecipitation. Stable 729 mented with 5% fetal calf serum (FCS) and antibiotics. transfected cell lines were labeled at 106 cells per ml with BJAB, an Epstein-Barr-negative Burkitt's lymphoma cell [35S]methionine-cysteine (Tran35S-label; ICN Biochemicals, line (kindly provided by W. Hall, Cornell University), was Inc. [100 ,uCi/ml]) in methionine-cysteine-free RPMI 1640 maintained in RPMI 1640 medium supplemented with 10% medium supplemented with 10% dialyzed FCS. Cells were FCS and antibiotics. Peripheral blood lymphocytes were labeled overnight at 37°C. Cells were lysed in radioimmuno- isolated by centrifugation over Ficoll-Hypaque of fresh precipitation buffer, and the lysates were ultracentrifuged at blood obtained from normal donors or from leukopacks 100,000 x g for 1 h. The lysates were immunoprecipitated by purchased from the Red Cross. These cells were grown in using either HTLV-II-specific human antisera or antibody RPMI 1640 medium supplemented with 20% FCS and anti- directed against the COOH-terminal tridecapeptide se- biotics. quence encoded by rex (44). Immune complexes were col- Plasmids and mutagenesis. pH6neo, an HTLV-IT infectious lected with protein A-Sepharose (Pharmacia, Inc.), and the proviral clone, LTR-II-CAT, and SV2neo have been de- proteins were separated on sodium dodecyl sulfate-poly- scribed previously (6, 45). Plasmids with the prefix "BC" acrylamide gels. Gels were treated with En3Hance (Dupont, are all derived from the plasmid BC12/CMV/IL-2 (9), which NEN Research Products) for fluorography and exposed to contains a simian virus 40 (SV40) origin of replication and X-Omat R film (Eastman Kodak Co.). the cytomegalovirus immediate early promoter. Proper in- DNA transfer and hybridization. High-molecular-weight sertion of genes downstream of the cytomegalovirus pro- DNA was extracted from stable 729 transfectants or HTLV- moter results in high levels of expression in 729 cells and II-infected BJAB cells and analyzed by the method of peripheral blood lymphocytes. BCHTLV contains the com- Southern (47), as described elsewhere (15). The probe con- plete coding region of HTLV-II (BamHI-BamHI, nucleo- sisted of an HTLV-Il-specific (1,176 bp XhoI-Clal fragment) tides [nt] 361 to 8550) and expresses all viral gene products. 32P-oligo-labeled fragment. BCHTLVCla (Tax- and Rex-), BCHTLVSph (Rex-), and RNA preparation and S1 nuclease analysis. Total cellular BCHTLVrex term (Rex-) contain rex and/or tax mutations RNA was prepared by lysing the cells in 4.7 M urea-1.3% that have been previously described (37). BCHTLV-UT sodium dodecyl sulfate-0.23 M NaCl-6.7 mM Tris (pH contains a deletion in the apparently nontranslated region 8.0)0.67 mM EDTA, followed by three phenol-chloroform between nt 6660 and 6984 (pH6neo-UT contains the identical extractions. RNA was pelleted by ultracentrifugation deletion in the pH6neo vector). BCHTLV-SA contains a through a CsCl pad (30,000 rpm for 16 h), suspended in 10 550-base-pair (bp) deletion in the nontranslated region be- mM Tris, pH 7.6-1 mM EDTA, and the concentration was tween nt 6660 and 7210, which also results in removal of the determined by spectrophotometry. S1 nuclease analysis was splice acceptor signal sequence for taxlrex exon 3, and thus performed with 25 ,ug of total RNA (5 ,ug of sample RNA and is Tax- and Rex- (pH6neo-SA contains the identical dele- 20 ,ug of uninfected cell RNA) and a [-y-32P]dATP-labeled tion in the pH6neo vector).
Load more

Recommended publications
  • Human T-Cell Leukemia Virus Type I Tax Transactivates Human Interleukin 8 Gene Through Acting Concurrently on AP-1 and Nuclear Factor-KB-Like Sites
    [CANCER RESEARCH 58. 3993-4000. September 1. 1998] Human T-Cell Leukemia Virus Type I Tax Transactivates Human Interleukin 8 Gene through Acting Concurrently on AP-1 and Nuclear Factor-KB-like Sites Naoki Mori,1 Naofumi Mukaida, Dean W. Ballard, Kouji Matsushima, and Naoki Vaniamolo Department of Preventive Medicine and AIDS Research. Research Field of Palhogenesis and Clinical Sciences, Institute of Tropical Medicine, Nagasaki University, Nagasaki 852, Japan ¡N.M.. N. YJ; Department of Pharmacology. Cancer Research Institute, Kanazawa University, Kanayiwa 920, Japan ¡N.M.¡:Department of Molecular Preventive Medicine, School of Medicine. University of Tok\o. Tokyo 113, Japan ¡K.M.I: and Howard Hughes Medical Institute. Vanderhilt University School of Medicine. Nashville, Tennessee 37232-0295 [D. W. BJ ABSTRACT unclear but could be one of the common pathological findings among diseases associated with HTLV-I infection. The transactivator protein, Tax, from the human T-cell leukemia virus IL-8 has potent chemotactic activity for T lymphocytes, as well as type I (HTLV-I) transactivates both viral and cellular genes. Previously, neutrophils (1, 2). Interestingly, T lymphocytes are 10-fold more we had shown that interleukin 8 (II.-8) is constitutively expressed in sensitive to IL-8 than neutrophils in chemotaxis (3). Thus, IL-8 is an HTLV-I-infected cells and in cells transiently expressing Tax. We show here that the II -X promoter is Tax responsive in Jurkat T cells. Further important mediator for tissue infiltration of various subsets of leuko more, using several deletion and mutated plasmids of the 5'-flanking cytes (7).
    [Show full text]
  • Interaction of Bovine Leukemia Virus Transactivator Tax with Bzip Proteins
    VIROLOGY 214, 207–214 (1995) Interaction of Bovine Leukemia Virus Transactivator Tax with bZip Proteins IMRE M. BOROS,1 FENG TIE, and CHOU-ZEN GIAM2 Division of Infectious Diseases, Department of Medicine, Case Western Reserve University, Cleveland, Ohio 44106 Received June 7, 1995; accepted October 2, 1995 The bovine leukemia virus transactivator, BLV Tax, augments transcription from three imperfect 21-bp repeats in the viral transcriptional regulatory region. Each BLV 21-bp repeat contains a cAMP response element (CRE) in the center and unique 5* and 3* neighboring sequences which are crucial for the transcriptional activation by BLV Tax. Here we describe the interactions of recombinant BLV Tax with cellular bZip proteins. The recombinant BLV Tax, tagged at the carboxy terminus with a hexahistidine extension, was prepared by solubilization in 6 M guanidine hydrochloride and renaturation on the Ni2/- chelating Sepharose gel matrix. The renatured BLV TaxH6 activates the BLV LTR when introduced into HeLa cells by scrape loading. Furthermore, the purified BLV TaxH6 enhances binding of members of the CREB/ATF family of bZip proteins to CRE motifs by interacting with their bZip domains in vitro. Chemical cross-linking indicates that dimerization of bZip proteins such as CREB becomes greatly facilitated in the presence of BLV Tax. These results suggest that BLV Tax interacts directly with CREB/ATF-like factors to activate viral mRNA transcription. q 1995 Academic Press, Inc. INTRODUCTION flanking the CRE dictate the exclusive inducibility of the 3 BLV or HTLV-I 21-bp repeats by the respective Tax pro- Bovine leukemia virus (BLV) and human T-lympho- teins (Fujisawa et al., 1989; Montagne et al., 1990; Paca tropic virus type I (HTLV-I) belong to a group of oncore- Uccaralertkun et al., 1994).
    [Show full text]
  • S12977-020-00538-W.Pdf
    Millen et al. Retrovirology (2020) 17:30 https://doi.org/10.1186/s12977-020-00538-w Retrovirology RESEARCH Open Access A novel positive feedback-loop between the HTLV-1 oncoprotein Tax and NF-κB activity in T-cells Sebastian Millen, Lina Meretuk, Tim Göttlicher, Sarah Schmitt, Bernhard Fleckenstein and Andrea K. Thoma‑Kress* Abstract Background: Human T‑cell leukemia virus type 1 (HTLV‑1) infects primarily CD4+ T‑lymphocytes and evoques severe diseases, predominantly Adult T‑Cell Leukemia/ Lymphoma (ATL/L) and HTLV‑1‑associated Myelopathy/ Tropical Spastic Paraparesis (HAM/TSP). The viral transactivator of the pX region (Tax) is important for initiating malignant transformation, and deregulation of the major signaling pathway nuclear factor of kappa B (NF‑κB) by Tax represents a hallmark of HTLV‑1 driven cancer. Results: Here we found that Tax mutants which are defective in NF‑κB signaling showed diminished protein expres‑ sion levels compared to Tax wildtype in T‑cells, whereas Tax transcript levels were comparable. Strikingly, constant activation of NF‑κB signaling by the constitutive active mutant of inhibitor of kappa B kinase (IKK2, IKK‑β), IKK2‑EE, rescued protein expression of the NF‑κB defective Tax mutants M22 and K1‑10R and even increased protein levels of Tax wildtype in various T‑cell lines while Tax transcript levels were only slightly afected. Using several Tax expres‑ sion constructs, an increase of Tax protein occurred independent of Tax transcripts and independent of the promoter used. Further, Tax and M22 protein expression were strongly enhanced by 12‑O‑Tetradecanoylphorbol‑13‑Acetate [TPA; Phorbol 12‑myristate 13‑acetate (PMA)]/ ionomycin, inducers of NF‑κB and cytokine signaling, but not by tumor necrosis factor alpha (TNF‑α).
    [Show full text]
  • Chimeric Proteins Composed of Jun and CREB Define Domains
    JOURNAL OF VIROLOGY, Oct. 1995, p. 6209–6218 Vol. 69, No. 10 0022-538X/95/$04.0010 Copyright q 1995, American Society for Microbiology Chimeric Proteins Composed of Jun and CREB Define Domains Required for Interaction with the Human T-Cell Leukemia Virus Type 1 Tax Protein MIN JEAN YIN, EVYIND PAULSSEN, JACOB SEELER,† AND RICHARD B. GAYNOR* Departments of Internal Medicine and Microbiology, Divisions of Molecular Virology and Hematology-Oncology, University of Texas Southwestern Medical Center, Dallas, Texas 75235-8594 Received 5 April 1995/Accepted 26 June 1995 The regulation of human T-cell leukemia virus type 1 (HTLV-1) long terminal repeat gene expression is dependent on three cis-acting elements known as 21-bp repeats and the transactivator protein Tax. Mutagen- esis has demonstrated that sequences in each of the 21-bp repeats can be divided into three domains designated A, B, and C. Tax stimulates the binding of CREB to the B domain, which is essential for Tax activation of HTLV-1 gene expression. In this study, we demonstrate that Tax will stimulate the binding of CREB to the HTLV-1 21-bp repeats but does not stimulate CREB binding to the consensus cyclic AMP response element (CRE) element found in the somatostatin promoter. However, Tax stimulates CREB binding to a consensus CRE in the context of the 21-bp repeats, indicating the importance of these sequences in stimulating CREB binding. To determine the mechanism by which Tax stimulates CREB binding and determine potential interactions between Tax and CREB, we used the mammalian two-hybrid system in conjunction with in vitro binding and gel retardation assays.
    [Show full text]
  • Transcription Profile of Cells Infected with Human T-Cell Leukemia Virus Type I Compared with Activated Lymphocytes1
    [CANCER RESEARCH 62, 3562–3571, June 15, 2002] Transcription Profile of Cells Infected with Human T-cell Leukemia Virus Type I Compared with Activated Lymphocytes1 Cynthia A. Pise-Masison, Michael Radonovich, Renaud Mahieux, Pramita Chatterjee, Craig Whiteford, Janet Duvall, Claire Guillerm, Antoine Gessain, and John N. Brady2 Basic Research Laboratory, Virus Tumor Biology Section, National Cancer Institute, Bethesda, Maryland 20892 [C. A. P-M., M. R., P. C., J. D., C. G., J. N. B.]; Unite d’Epidemiologie et Physiopathologie des Virus Oncogenes, Batiment SIDA-Retrovirus, Institut Pasteur, 75724, Cedex 15, Paris, France [R. M., A. G.]; and Advanced Technology Center, National Institutes of Health, Gaithersburg, Maryland [C. W.] ABSTRACT vivo for viral infectivity and replication (12–16). In addition, the p12 protein has been implicated in the MHC class I-mediated immune Human T-cell leukemia virus type I (HTLV-I) is the etiologic agent for response and T-cell signaling (16–18). The viral protein p13 has also adult T-cell leukemia and the neurological disorder tropical spastic para- recently been reported to regulate cellular signaling pathways (19). -paresis/HTLV-I-associated myelopathy. CD4؉ T lymphocytes, the pri mary hosts for HTLV-I, undergo a series of changes that lead to T-cell Finally, the p30 protein is reported to play a role in transcriptional activation, immortalization, and transformation. To gain insight into the regulation with the use of Gal4-p30 fusion constructs (20). genetic differences between activated and HTLV-I-infected lymphocytes, DNA microarray technology has facilitated the development of a we performed Affymetrix GeneChip analysis of activated and HTLV-I- more complete and inclusive analysis of gene expression profiles in infected cells.
    [Show full text]
  • Both Wild-Type and Strongly Attenuated Bovine Leukemia
    JOURNAL OF VIROLOGY, Jan. 1997, p. 630–639 Vol. 71, No. 1 0022-538X/97/$04.0010 Copyright q 1997, American Society for Microbiology Both Wild-Type and Strongly Attenuated Bovine Leukemia Viruses Protect Peripheral Blood Mononuclear Cells from Apoptosis FRANCK DEQUIEDT,1 EMMANUEL HANON,2 PIERRE KERKHOFS,3 PAUL-PIERRE PASTORET,2 4 1,5 1 1 DANIEL PORTETELLE, ARSE`NE BURNY, RICHARD KETTMANN, AND LUCAS WILLEMS * Department of Molecular Biology and Animal Physiology1 Faculty of Agronomy, B5030 Gembloux, and Department of Microbiology,4 Department of Immunology/Vaccinology, University of Lie´ge, B43 bis, B4000 Lie`ge,2 National Institute of Veterinary Research, B1120 Uccle,3 and Department of Molecular Biology, University of Brussels, B1640 Rhode-St-Gene`se,5 Belgium Received 17 June 1996/Accepted 7 October 1996 Bovine leukemia virus (BLV) and the human T-cell leukemia viruses belong to the same subfamily of oncoviruses. Although much attention has focused on the mechanisms of cell proliferation and transformation by these viruses, experiments on the apoptotic process have yielded conflicting data in in vitro cell culture. Experimental infection of sheep with BLV proviruses offers the opportunity to analyze apoptosis in vivo. Here, we show that BLV-infected peripheral mononuclear cells, cultivated ex vivo, are protected from spontaneous programmed cell death. Moreover, the virus is able to specifically interfere with the apoptotic program of infected B lymphocytes. Strongly attenuated mutant proviruses that harbor deletions in the G4 and/or R3 genes also decrease the global susceptibility to apoptosis at levels similar to those obtained with the wild-type virus.
    [Show full text]
  • Development of Ultra-Super Sensitive Immunohistochemistry and Its Application to the Etiological Study of Adult T-Cell Leukemia/Lymphoma
    Advance Publication Acta Histochem. Cytochem. 45 (2): 83–106, 2012 doi:10.1267/ahc.11034 AHCActa0044-59911347-5800JapanTokyo,AHC1103410.1267/ahc.11034Review Histochemica Society Japan of Histochemistry et Cytochemica and Cytochemistry Review Development of Ultra-Super Sensitive Immunohistochemistry and Its Application to the Etiological Study of Adult T-Cell Leukemia/Lymphoma Kazuhisa Hasui1, Jia Wang1,5, Yuetsu Tanaka2, Shuji Izumo3, Yoshito Eizuru4 and Takami Matsuyama1 1Division of Immunology, Department of Infection and Immunity, Institute Research Center (Health Research Course), Kagoshima University Graduate School of Medical and Dental Sciences, 2Department of Immunology, Graduate School of Medicine, University of the Ryukyus, 3Chronic Viral Diseases Div. of Molecular Pathology, Center for Chronic Viral Diseases (Infection and Immunity), Institute Research Center (Health Research Course), Kagoshima University Graduate School of Medical and Dental Sciences, 4Chronic Viral Diseases Div. of Persistent & Oncogenic Viruses, Center for Chronic Viral Diseases (Infection and Immunity), Institute Research Center (Health Research Course), Kagoshima University Graduate School of Medical and Dental Sciences and 5Present address: INAMORI Frontier Research Center, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819–0395, Japan 00 Received July 15, 2011; accepted February 14, 2012; published online April 21, 2012 © 2012Antigen The Japanretrieval Society (AR) andof Histochemistry ultra-super sensitive and immunohistochemistry (ultra-IHC) have been established for application to archival human pathology specimens. The original ultra-IHC was the ImmunoMax method or the catalyzed signal amplification system (ImmunoMax/CSA method), comprising the streptavidin-biotin complex (sABC) method and catalyzed reporter deposition (CARD) reaction with visualization of its deposition. By introducing procedures to diminish non-specific staining in the original ultra-IHC method, we developed the modified ImmunoMax/CSA method with AR heating sections in an AR solution (heating-AR).
    [Show full text]
  • Gene Regulation Mediated by Interaction Between HTLV-1 Promoter Elements and Transcription Factors Tax and CREB
    Virology 256, 303–312 (1999) Article ID viro.1999.9600, available online at http://www.idealibrary.com on Gene Regulation Mediated by Interaction between HTLV-1 Promoter Elements and Transcription Factors Tax and CREB Itamar Goren, Eynat Tavor, and Alik Honigman1 Department of Virology, The Hebrew University–Hadassah Medical School, Jerusalem, Israel Received October 13, 1998; returned to author for revision November 23, 1998; accepted January 13, 1999 In this work we examine the role of three genetic control components in the regulation of HTLV-1 transcription: cyclic AMP-responsive element (CRE)-binding protein (CREB), the HTLV-1 trans-activator Tax, and the three Tax-responsive elements (TREs). We demonstrate that the in vivo efficiency of the HTLV-1 promoter basal expression in cell culture depends on the spacing between the three TRE elements, located at the HTLV-1 LTR (long terminal repeat), whereas the level of transcription activation mediated by Tax is affected by the number of TREs. In the presence of only one TRE, the enhancement of expression by Tax is affected by the distance between the single TRE and the transcription start site. Following CREB binding to the LTR, additional DNase I hypersensitive sites are generated in the region between the two distal TREs (I and II), while in the presence of Tax, such sites are generated also in the region between TREs II and III. Neither cooperative binding of CREB to the TREs nor preferential binding of CREB to a particular TRE was observed. Tax binding to the CREB/TRE complex does not change the DNase I protection pattern.
    [Show full text]
  • Human T Lymphotropic Virus Type 1 (HTLV-1): Molecular Biology and Oncogenesis
    Viruses 2010, 2, 2037-2077; doi:10.3390/v2092037 OPEN ACCESS viruses ISSN 1999-4915 www.mdpi.com/journal/viruses Review Human T Lymphotropic Virus Type 1 (HTLV-1): Molecular Biology and Oncogenesis Priya Kannian 1,2 and Patrick L. Green 1,2,3,4,* 1 Center for Retrovirus Research, The Ohio State University, Columbus, OH 43210, USA; E-Mail: [email protected] 2 Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA 3 Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA 4 Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +1 614-688-4899; Fax: +1 614-292-6473. Received: 7 July 2010; in revised form: 25 August 2010 / Accepted: 15 September 2010 / Published: 24 September 2010 Abstract: Human T lymphotropic viruses (HTLVs) are complex deltaretroviruses that do not contain a proto-oncogene in their genome, yet are capable of transforming primary T lymphocytes both in vitro and in vivo. There are four known strains of HTLV including HTLV type 1 (HTLV-1), HTLV-2, HTLV-3 and HTLV-4. HTLV-1 is primarily associated with adult T cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-2 is rarely pathogenic and is sporadically associated with neurological disorders. There have been no diseases associated with HTLV-3 or HTLV-4 to date. Due to the difference in the disease manifestation between HTLV-1 and HTLV-2, a clear understanding of their individual pathobiologies and the role of various viral proteins in transformation should provide insights into better prognosis and prevention strategies.
    [Show full text]
  • Role of Human T-Lymphotropic Virus Type 1 P30(Ii) And
    ROLE OF HUMAN T-LYMPHOTROPIC VIRUS TYPE 1 P30(II) AND SURFACE ENVELOPE AS DETERMINANTS OF IN VIVO PATHOGENESIS DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Lee Silverman, DVM, DACVP * * * * * The Ohio State University 2005 Dissertation Committee: Approved by Dr. Michael Lairmore, Advisor Dr. Kathleen Boris-Lawrie Advisor Dr. Natarajan Muthusamy Veterinary Biosciences Graduate Dr. Thomas Rosol Program ABSTRACT Human T-cell leukemia virus type 1 (HTLV-1) is the first identified human retrovirus. It is the causative agent of adult T-cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paresis, and it has been implicated in a variety of other immune-mediated disorders such as dermatitis, polymyositis, and uveitis. HTLV-1 exhibits high genetic stability in vivo. In addition to the canonical retroviral gag, pol, and env genes, HTLV-1 contains four open reading frames (ORF) in its pX region. ORF II encodes two proteins, p30II and p13II, both of which are incompletely characterized. p30II localizes to the nucleus/nucleolus and has distant homology to the transcription factors, Oct-1, Pit-1, and POU-M1. p30II modulates cellular and viral gene expression at the transcriptional and post-transcriptional level. Herein, we determine the in vivo significance of p30II by inoculating rabbits with cell lines expressing either a wild-type clone of HTLV-1 (ACH.1) or a clone containing a mutation in ORF II, which eliminated wild-type p30II expression (ACH.30.1). ACH.1-inoculated rabbits maintained higher HTLV-1- specific antibody titers than ACH.30.1-inoculated rabbits, and all ACH.1- inoculated rabbits were seropositive for HTLV-1, whereas only two of six ACH.30.1-inoculated rabbits were seropositive.
    [Show full text]
  • 263.Full.Pdf
    The HTLV-I Tax Protein Transcriptionally Modulates OX40 Antigen Expression Rüdiger Pankow, Horst Dürkop, Ute Latza, Hans Krause, Ulrich Kunzendorf, Thomas Pohl and Silvia Bulfone-Paus This information is current as of October 2, 2021. J Immunol 2000; 165:263-270; ; doi: 10.4049/jimmunol.165.1.263 http://www.jimmunol.org/content/165/1/263 Downloaded from References This article cites 48 articles, 23 of which you can access for free at: http://www.jimmunol.org/content/165/1/263.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 2, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2000 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The HTLV-I Tax Protein Transcriptionally Modulates OX40 Antigen Expression1 Ru¨diger Pankow,* Horst Du¨rkop,† Ute Latza,†‡ Hans Krause,§ Ulrich Kunzendorf,¶ Thomas Pohl,* and Silvia Bulfone-Paus2* OX40 is a member of the TNF receptor family, expressed on activated T cells.
    [Show full text]
  • Identification of HTLV-1 Tax-1 and HBZ Binding Partners, and Their Role in HTLV-1 Biology and Pathogenesis
    Identification of HTLV-1 Tax-1 and HBZ Binding Partners, and Their Role in HTLV-1 Biology and Pathogenesis DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Jacob Jamal Al-Saleem Graduate Program in Molecular, Cellular and Developmental Biology The Ohio State University 2016 Dissertation Committee: Dr. Patrick L. Green, Ph.D, Advisor Dr. Jesse Kwiek, Ph.D Dr. Li Wu, Ph.D Dr. Stefan Niewiesk, DVM, Ph.D Copyrighted by Jacob Jamal Al-Saleem 2016 Abstract Human T cell Leukemia Virus type 1 (HTLV-1) is estimated to have infected 15-20 million individuals world-wide. A subgroup of infected individuals develop diseases associated with viral infection, which include adult T cell leukemia and HTLV-1 associated myelopathy/tropic spastic paraparesis. A closely related virus, HTLV-2, shares 70% nucleotide similarity with HTLV-1, but is not associated with any disease. Previous research has demonstrated that Tax-1 serves as the primary oncoprotein of HTLV-1, and its deletion or functional disruption completely ablates the transforming capacity of HTLV-1. Tax-2 (HTLV-2) has been demonstrated to have lower transforming capabilities than Tax-1. These differences are attributed to two domains present in Tax-1 yet absent in Tax-2; the four-amino acid PDZ binding motif (PBM) and an eight-amino acid leucine zipper-like region (LZ). These domains have been demonstrated to be required for the ability of Tax-1 to activate the alternative NF-κB pathway. Chapter Two of this dissertation analyzes the role that the alternative NF-κB pathway plays in HTLV-1 mediated T cell transformation.
    [Show full text]