DOCSLIB.ORG

Transcription Profile of Cells Infected with Human T-Cell Leukemia Virus Type I Compared with Activated Lymphocytes1

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read 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. Using the Hu6800 GeneChip, we identified ϳ763 genes that response to many stimuli for a variety of biological systems. Harhaj et had differentially regulated expression in at least three of five HTLV-I cell al. (21) and de La Fuente et al. (22) used Atlas human cDNA arrays lines. Classification of these genes into functional groups including cellular to analyze gene expression patterns in HTLV-I-infected PBMCs com- receptors, kinases, phosphatases, cytokines, signal proteins, and transcrip- pared with uninfected PBMCs or HTLV-I-transformed C8166 cells tion factors provides insight into genes and pathways that are differen- compared with nonvirally transformed CEM cells, respectively. Ng et tially regulated during HTLV-I transformation. al. (23) have used NIH OncoChip cDNA arrays to analyze gene expression patterns of ϳ2000 human genes in Tax-expressing Jurkat INTRODUCTION T lymphocytes. These studies have looked at small numbers of sam- ples and identified a few candidate genes important for HTLV-I- HTLV-I3 is the etiologic agent of an aggressive and fatal disease induced pathogenesis. We have chosen GeneChip microarrays (Af- termed ATL and of the neurodegenerative disease tropical spastic fymetrix, Inc.), containing oligonucleotide hybridization probes paraparesis/HTLV-I-associated myelopathy (1–4). HTLV-I has also representative of Ͼ7000 genes, to perform a more comprehensive been less closely associated with uveitis, arthritis, infectious derma- examination of the expression profiles for HTLV-I-immortalized and titis, and immunosuppression (5–7). The principle target for HTLV-I -transformed cell lines and compared these with the expression profile infection in the lymphoid system are mature CD4ϩ CD45ROϩ T of normal activated PBLs. The results presented here extend earlier lymphocytes, although other cell types of lymphoid origin have been studies by identifying a significant number of new genes that have infected by HTLV-I in vitro, including CD8ϩ T cells, B cells, and altered expression in HTLV-I-transformed cells compared with acti- macrophages (8–11). vated PBLs. We have identified several new response pathways The mechanism of oncogenic transformation of host T lymphocytes involving G2/M checkpoint control factors, DNA replication and in ATL remains unclear, and to date there is no effective treatment for licensing factors, transcriptional regulators, and kinase/phosphatase this disease. However, as with other cancers, altered gene expression signaling molecules that are deregulated in HTLV-I-infected cells. of networks of genes are linked to ATL initiation and progression. Moreover, we found that by analyzing several HTLV-I cell lines, gene Several studies (8–11) have established that the viral transcriptional expression changes attributable to individual cell types were de- activator protein Tax plays a critical role in cellular transformation. creased. Tax not only activates expression of viral genes via the viral LTR, but has also been reported to affect the expression or activity of several cellular genes. Several of these genes encode proteins involved in cell MATERIALS AND METHODS growth and cell death including proto-oncogenes, growth factors and their receptors, CDKs, and CDK inhibitors (8–11). Cell Cultures. We isolated PBMCs from healthy, HTLV-I-negative donors using Ficoll density gradient centrifugation. After removal of macrophages, In more recent studies, a role for the HTLV-I accessory proteins, cells were stimulated for 18 h with PHA (2 ␮g/ml) and then grown in RPMI p12, p30, and p13 in gene activation and cell signaling have been 1640 medium supplemented with 10% fetal bovine serum, 100 units/ml demonstrated. All three proteins have been shown to play a role in penicillin-streptomycin, 2 mM glutamine, and 50 units/ml IL-2. Activated cells were expanded for 2 weeks and then total RNA was isolated. Resting cells Received 11/15/01; accepted 4/15/02. were expanded for 2 weeks, washed twice in culture medium not containing The costs of publication of this article were defrayed in part by the payment of page PHA and IL-2, and total RNA was isolated 3 days later. HTLV-I-immortalized charges. This article must therefore be hereby marked advertisement in accordance with cells, Champ (ATL), Bes (ATL), and ACH.WT, were grown in complete 18 U.S.C. Section 1734 solely to indicate this fact. 1 Supplementary data for this article is available at Cancer Research Online (http:// medium supplemented with 50 units/ml IL-2. HTLV-I-transformed cells, C81 cancerres.aacrjournals.org). and Hut102, were grown in complete medium. 2 To whom requests for reprints should be addressed, at Basic Research Laboratory, RNA Isolation and Probe Preparation. mRNA was isolated from total Virus Tumor Biology Section, National Cancer Institute, 9000 Rockville Pike, Bethesda, RNA by the RNeasy and Oligotex mRNA isolation procedures as outlined by MD 20892. Phone: (301) 496-0986; Fax: (301) 496-4951; E-mail: [email protected]. 3 The abbreviations used are: HTLV-I, human T-cell lymphotropic virus type-I; ATL, the manufacturer (Qiagen). Experimental procedures for GeneChip were per- adult T-cell leukemia; LTR, long terminal repeat; CDK, cyclin-dependent kinase; PBMC, formed according to the Affymetrix GeneChip Expression Analysis Technical peripheral blood mononuclear cell; PBL, peripheral blood lymphocyte; PHA, phytohem- Manual (Affymetrix). Briefly, double-stranded cDNA was synthesized from ␣ ␣ agglutinin; IL, interleukin; RT-PCR, reverse transcription-PCR; IL-2R , IL-2 receptor ; mRNA with the SuperScript Choice system (Life Technologies, Inc.) and a TNF, tumor necrosis factor; CK1⑀, casein kinase 1 ⑀; MLK, mixed-lineage kinase; DUS, dual-specificity phosphatase; INPP1, inositol phosphate-1-phosphatase; CREB, cAMP- T7-(dT) 24 (GENSET) primer. In vitro transcription was performed on the cDNA responsive element binding protein; ATF, activating transcription factor. to produce biotin-labeled cRNA with an Enzo Transcription Kit (Enzo) as de- 3562 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2002 American Association for Cancer Research. GENE EXPRESSION PROFILES OF HTLV-I-INFECTED CELLS scribed by the manufacturer. The cRNA was linearly amplified with T7 polym- obtained through PBL culture of an ATL patient, fell into a separate erase, the biotinylated cRNA was cleaned with an RNeasy Mini Kit (Qiagen), cluster distinct from the HTLV-I-transformed cells (C81 and Hut102) fragmented to 50–200 nucleotides, and then hybridized to Affymetrix Hu6800 and the HTLV-I-immortalized cells (Bes and ACH.WT). The shading arrays. The arrays were then processed on the Affymetrix fluidics station and across each sample/bar is an indication of the gene-expression levels scanned on an HP GeneArray scanner. The intensity for each probe set of the array for each of the 7300 genes. For each cell sample, a unique expression was captured with Affymetrix GeneChip Software, according to standard Af- pattern emerges (Fig. 1). A section of the tree has been expanded to fymetrix procedures. To determine the quantitative RNA level, the average dif- ferences representing the perfectly matched minus the mismatched for each gene- show an example of how individual genes performed. As shown, the specific probe set was calculated. The GeneSpring Software (SiliconGenetics) was genes GATA-2, PON2, and PLAGL2 are all overexpressed in the also used to examine the differential gene expression. HTLV-I-infected cells as compared with the PBL samples. This form RT-PCR. Total cellular RNA was isolated with Rnazol B (Tel-Test) as of clustering allows one to identify groups of genes that are expressed described by the manufacturer. RNA (5 ␮g) was converted to cDNA with either similarly or opposite to the control sample. RETROscript (Ambion) as described by the manufacturer. Samples were then From the expression data, we compiled a list of genes deregulated PCR amplified with SuperTaq Plus polymerase (Ambion) to quantitate indi- an average of 2-fold or greater in at least three of five HTLV-I- vidual genes. The PCR primers for Tax were as follows: 5Ј-TGTTTG- infected cell lines, as compared with activated PBLs (Table 1 and Ј Ј Ј GAGACTGTGTACAAGGCG-3 and 5 -CAGGCTGTCAGCGTGACGG-3 . on-line data supplement1). A 2-fold cutoff was chosen based on The primers for IL-2R␣ were as follows: 5Ј-GGTCCCAGGCAGAGAAT- statistical information provided by Affymetrix.
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]
  • 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.
    [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]