{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T04:37:03Z","timestamp":1760243823740,"version":"build-2065373602"},"reference-count":59,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2011,8,18]],"date-time":"2011-08-18T00:00:00Z","timestamp":1313625600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Adult T-cell leukemia (ATL) is one of the primary diseases caused by Human T-cell Leukemia Virus type 1 (HTLV-1) infection. The virally-encoded Tax protein is believed to initiate early events in the development of this disease, as it is able to promote immortalization of T-cells and transformation of other cell types. These processes may be aided by the ability of the viral protein to directly deregulate expression of specific cellular genes through interactions with numerous transcriptional regulators. To identify gene promoters where Tax is localized, we isolated Tax-DNA complexes from an HTLV-1-infected T-cell line through a chromatin immunoprecipitation (ChIP) assay and used the DNA to probe a CpG island microarray. A site within the RNASET2 gene was found to be occupied by Tax. Real-time PCR analysis confirmed this result, and transient expression of Tax in uninfected cells led to the recruitment of the viral protein to the promoter. This event correlated with a decrease in the level of RNase T2 mRNA and protein, suggesting that Tax represses expression of this gene. Loss of RNase T2 expression occurs in certain hematological malignancies and other forms of cancer, and RNase T2 was recently reported to function as a tumor suppressor. Consequently, a reduction in the level of RNase T2 by Tax may play a role in ATL development.<\/jats:p>","DOI":"10.3390\/v3081485","type":"journal-article","created":{"date-parts":[[2011,8,18]],"date-time":"2011-08-18T11:29:37Z","timestamp":1313666977000},"page":"1485-1500","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Direct Inhibition of RNAse T2 Expression by the HTLV-1 Viral Protein Tax"],"prefix":"10.3390","volume":"3","author":[{"given":"Nicholas","family":"Polakowski","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, 600 Moye Boulevard, Greenville, NC 27834, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongjin","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, 600 Moye Boulevard, Greenville, NC 27834, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabelle","family":"Lemasson","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, 600 Moye Boulevard, Greenville, NC 27834, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2011,8,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1007\/s11899-007-0035-x","article-title":"Adult T-cell leukemia\/lymphoma and HTLV-1","volume":"2","author":"Mahieux","year":"2007","journal-title":"Curr. Hematol. Malig. Rep."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/1742-4690-1-20","article-title":"Role of Tax protein in human T-cell leukemia virus type-I leukemogenicity","volume":"1","author":"Azran","year":"2004","journal-title":"Retrovirology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1038\/nm1389","article-title":"Thymus-derived leukemia-lymphoma in mice transgenic for the Tax gene of human T-lymphotropic virus type I","volume":"12","author":"Hasegawa","year":"2006","journal-title":"Nat. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"5986","DOI":"10.1038\/sj.onc.1208976","article-title":"Impact of HTLV-I Tax on cell cycle progression and the cellular DNA damage repair response","volume":"24","author":"Marriott","year":"2005","journal-title":"Oncogene"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Lever, A.M.L., Jeang, K.T., and Berkhout, B. (2010). Recent Advances in Human Retroviruses: Principles of Replication and Pathogenesis. Advances in Retroviral Research, World Scientific Publishing Co.","DOI":"10.1142\/9789814295314"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"16299","DOI":"10.1074\/jbc.M706426200","article-title":"Human T-cell leukemia virus type 1 oncoprotein tax represses ZNF268 expression through the cAMP-responsive element-binding protein\/activating transcription factor pathway","volume":"283","author":"Wang","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2161","DOI":"10.1128\/JVI.75.5.2161-2173.2001","article-title":"CREB\/ATF-dependent repression of cyclin a by human T-cell leukemia virus type 1 Tax protein","volume":"75","author":"Kibler","year":"2001","journal-title":"J. Virol."},{"key":"ref_8","first-page":"29","article-title":"Insight into the tumor suppressor function of CBP through the viral oncoprotein Tax","volume":"9","author":"Nyborg","year":"2000","journal-title":"Gene Expr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"10551","DOI":"10.1074\/jbc.275.14.10551","article-title":"The human T cell leukemia\/lymphotropic virus type 1 Tax protein represses MyoD-dependent transcription by inhibiting MyoD-binding to the KIX domain of p300. A potential mechanism for Tax-mediated repression of the transcriptional activity of basic helix-loop-helix factors","volume":"275","author":"Riou","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"9396","DOI":"10.1128\/JVI.72.11.9396-9399.1998","article-title":"The human T-cell leukemia virus type 1 oncoprotein Tax inhibits the transcriptional activity of c-Myb through competition for the CREB binding protein","volume":"72","author":"Colgin","year":"1998","journal-title":"J. Virol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1089\/08892220050193065","article-title":"Tax oncoprotein trans-represses endogenous B-myb promoter activity in human T cells","volume":"16","author":"Nicot","year":"2000","journal-title":"AIDS Res. Hum. Retroviruses"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1186\/1742-4690-5-76","article-title":"The HTLV-1 Tax interactome","volume":"5","author":"Boxus","year":"2008","journal-title":"Retrovirology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/j.cbi.2010.06.005","article-title":"HTLV-1 Tax: Linking transformation, DNA damage and apoptotic T-cell death","volume":"188","author":"Chlichlia","year":"2010","journal-title":"Chem. Biol. Interact."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1038\/sj.emboj.7601054","article-title":"Activation of the anaphase promoting complex by HTLV-1 tax leads to senescence","volume":"25","author":"Kuo","year":"2006","journal-title":"EMBO J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"14069","DOI":"10.1128\/JVI.79.22.14069-14078.2005","article-title":"Induction of cell cycle arrest by human T-cell lymphotropic virus type 1 Tax in hematopoietic progenitor (CD34+) cells: Modulation of p21cip1\/waf1 and p27kip1 expression","volume":"79","author":"Tripp","year":"2005","journal-title":"J. Virol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3001","DOI":"10.1128\/JVI.00086-10","article-title":"Complex cell cycle abnormalities caused by human T-lymphotropic virus type 1 Tax","volume":"85","author":"Yang","year":"2011","journal-title":"J. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1038\/sj.onc.1204178","article-title":"Cloning and characterization of a senescence inducing and class II tumor suppressor gene in ovarian carcinoma at chromosome region 6q27","volume":"20","author":"Acquati","year":"2001","journal-title":"Oncogene"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.tibs.2010.02.002","article-title":"T2 Family ribonucleases: Ancient enzymes with diverse roles","volume":"35","author":"Luhtala","year":"2010","journal-title":"Trends Biochem. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1006\/geno.1997.4679","article-title":"Mammalian Rh\/T2\/S-glycoprotein ribonuclease family genes: Cloning of a human member located in a region of chromosome 6 (6q27) frequently deleted in human malignancies","volume":"42","author":"Trubia","year":"1997","journal-title":"Genomics"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3875","DOI":"10.1182\/blood.V97.12.3875","article-title":"Comparative genomic hybridization analysis in adult T-cell leukemia\/lymphoma: Correlation with clinical course","volume":"97","author":"Tsukasaki","year":"2001","journal-title":"Blood"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1038\/sj.onc.1205067","article-title":"Physical and transcript map of the region between D6S264 and D6S149 on chromosome 6q27, the minimal region of allele loss in sporadic epithelial ovarian cancer","volume":"21","author":"Liu","year":"2002","journal-title":"Oncogene"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/S0304-3835(01)00677-2","article-title":"A novel homozygous deletion at chromosomal band 6q27 in an ovarian cancer cell line delineates the position of a putative tumor suppressor gene","volume":"173","author":"Lin","year":"2001","journal-title":"Cancer Lett."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"69","DOI":"10.3727\/096504008784523658","article-title":"RNASET2 as a tumor antagonizing gene in a melanoma cancer model","volume":"17","author":"Monti","year":"2008","journal-title":"Oncol. Res."},{"key":"ref_24","first-page":"1159","article-title":"Tumor and metastasis suppression by the human RNASET2 gene","volume":"26","author":"Acquati","year":"2005","journal-title":"Int. J. Oncol."},{"key":"ref_25","first-page":"1146","article-title":"Chromosome 6 encoded RNaseT2 protein is a cell growth regulator","volume":"14","author":"Liu","year":"2010","journal-title":"J. Cell Mol. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1073\/pnas.1013746108","article-title":"Microenvironmental control of malignancy exerted by RNASET2, a widely conserved extracellular RNase","volume":"108","author":"Acquati","year":"2010","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2760","DOI":"10.1002\/cncr.22327","article-title":"A recombinant human RNASET2 glycoprotein with antitumorigenic and antiangiogenic characteristics: Expression, purification, and characterization","volume":"107","author":"Smirnoff","year":"2006","journal-title":"Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1186\/1742-4690-7-61","article-title":"Expression of a protein involved in bone resorption, Dkk1, is activated by HTLV-1 bZIP factor through its activation domain","volume":"7","author":"Polakowski","year":"2010","journal-title":"Retrovirology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2933","DOI":"10.1093\/bioinformatics\/bti473","article-title":"MatInspector and beyond: Promoter analysis based on transcription factor binding sites","volume":"21","author":"Cartharius","year":"2005","journal-title":"Bioinformatics"},{"key":"ref_30","first-page":"2360","article-title":"Constitutive activation of NF-kappaB in primary adult T-cell leukemia cells","volume":"93","author":"Mori","year":"1999","journal-title":"Blood"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1593\/neo.03388","article-title":"Tax-independent constitutive IkappaB kinase activation in adult T-cell leukemia cells","volume":"6","author":"Hironaka","year":"2004","journal-title":"Neoplasia"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/S0092-8674(02)00654-2","article-title":"Cooperation between complexes that regulate chromatin structure and transcription","volume":"108","author":"Narlikar","year":"2002","journal-title":"Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1074\/jbc.M310069200","article-title":"Protein profile of tax-associated complexes","volume":"279","author":"Wu","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"7241","DOI":"10.1038\/sj.onc.1205701","article-title":"The interaction of HTLV-1 Tax with HDAC1 negatively regulates the viral gene expression","volume":"21","author":"Ego","year":"2002","journal-title":"Oncogene"},{"key":"ref_35","first-page":"581","article-title":"Histone deacetylase 3 represses HTLV-1 tax transcription","volume":"16","author":"Villanueva","year":"2006","journal-title":"Oncol. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"pe1","DOI":"10.1126\/scisignal.3103pe1","article-title":"New endogenous regulators of class I histone deacetylases","volume":"3","author":"Riccio","year":"2010","journal-title":"Sci. Signal"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"23903","DOI":"10.1074\/jbc.M803116200","article-title":"An interaction between the human T cell leukemia virus type 1 basic leucine zipper factor (HBZ) and the KIX domain of p300\/CBP contributes to the down-regulation of tax-dependent viral transcription by HBZ","volume":"283","author":"Clerc","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"13075","DOI":"10.1074\/jbc.M512193200","article-title":"Tax-dependent displacement of nucleosomes during transcriptional activation of human T-cell leukemia virus type 1","volume":"281","author":"Lemasson","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1038\/381328a0","article-title":"Effects on NF-kappa B1\/p105 processing of the interaction between the HTLV-1 transactivator Tax and the proteasome","volume":"381","author":"Rousset","year":"1996","journal-title":"Nature"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"15720","DOI":"10.1074\/jbc.M100131200","article-title":"Human T-cell leukemia virus type I Tax repression of p73beta is mediated through competition for the C\/H1 domain of CBP","volume":"276","author":"Lemasson","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"49459","DOI":"10.1074\/jbc.M209566200","article-title":"Transcription factor binding and histone modifications on the integrated proviral promoter in HTLV-I-infected T-cells","volume":"277","author":"Lemasson","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/S0076-6879(03)76021-2","article-title":"High-throughput screening of chromatin immunoprecipitates using CpG-island microarrays","volume":"376","author":"Oberley","year":"2004","journal-title":"Methods Enzymol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1038\/ng0394-236","article-title":"Purification of CpG islands using a methylated DNA binding column","volume":"6","author":"Cross","year":"1994","journal-title":"Nat. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/S0076-6879(03)76020-0","article-title":"Use of chromatin immunoprecipitation assays in genome-wide location analysis of mammalian transcription factors","volume":"376","author":"Ren","year":"2004","journal-title":"Methods Enzymol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"13108","DOI":"10.1073\/pnas.96.23.13108","article-title":"Mechanism by which the IFN-beta enhanceosome activates transcription","volume":"96","author":"Yie","year":"1999","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1093\/nar\/11.5.1475","article-title":"Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei","volume":"11","author":"Dignam","year":"1983","journal-title":"Nucleic Acids Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"11445","DOI":"10.1073\/pnas.88.24.11445","article-title":"Interaction of the human T-cell lymphotrophic virus type I (HTLV-I) transcriptional activator Tax with cellular factors that bind specifically to the 21-base-pair repeats in the HTLV-I enhancer","volume":"88","author":"Zhao","year":"1991","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2142","DOI":"10.1038\/onc.2009.498","article-title":"The HTLV-1 tax protein cooperates with phosphorylated CREB, TORC2 and p300 to activate CRE-dependent cyclin D1 transcription","volume":"29","author":"Kim","year":"2010","journal-title":"Oncogene"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2110","DOI":"10.1182\/blood-2006-11-058388","article-title":"Negative regulation of the SH2-homology containing protein-tyrosine phosphatase-1 (SHP-1) P2 promoter by the HTLV-1 Tax oncoprotein","volume":"110","author":"Cheng","year":"2007","journal-title":"Blood"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/1742-4690-3-43","article-title":"Involvement of HTLV-I Tax and CREB in aneuploidy: A bioinformatics approach","volume":"3","author":"Gupta","year":"2006","journal-title":"Retrovirology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1126\/science.2309119","article-title":"HTLV-I trans-activator protein, Tax, is a trans-repressor of the human b-polymerase gene","volume":"247","author":"Jeang","year":"1990","journal-title":"Science"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1975","DOI":"10.1128\/jvi.71.3.1975-1983.1997","article-title":"Transrepression of lck gene expression by human T-cell leukemia virus type 1-encoded p40Tax","volume":"71","author":"Lemasson","year":"1997","journal-title":"J. Virol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"28503","DOI":"10.1074\/jbc.270.48.28503","article-title":"Transcriptional repression of p53 by human T-cell leukemia virus type I Tax protein","volume":"270","author":"Uittenbogaard","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1006\/viro.1999.9760","article-title":"Down-regulation of the INK4 family of cyclin-dependent kinase inhibitors by tax protein of HTLV-1 through two distinct mechanisms","volume":"259","author":"Suzuki","year":"1999","journal-title":"Virology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1158\/0008-5472.CAN-06-3053","article-title":"Human T-cell leukemia virus oncoprotein tax represses nuclear receptor-dependent transcription by targeting coactivator TAX1BP1","volume":"67","author":"Chin","year":"2007","journal-title":"Cancer Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"5431","DOI":"10.1128\/JVI.02460-09","article-title":"Induction of reactive oxygen species by human T-cell leukemia virus type 1 tax correlates with DNA damage and expression of cellular senescence marker","volume":"84","author":"Kinjo","year":"2010","journal-title":"J. Virol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3050","DOI":"10.4049\/jimmunol.161.6.3050","article-title":"Human T cell leukemia virus-I (HTLV-I) Tax-mediated apoptosis in activated T cells requires an enhanced intracellular prooxidant state","volume":"161","author":"Los","year":"1998","journal-title":"J. Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1083\/jcb.200811119","article-title":"The RNase Rny1p cleaves tRNAs and promotes cell death during oxidative stress in Saccharomyces cerevisiae","volume":"185","author":"Thompson","year":"2009","journal-title":"J. Cell Biol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/S0165-2478(96)02651-X","article-title":"Transactivation of an inducible anti-oxidative stress protein, human thioredoxin by HTLV-I Tax","volume":"54","author":"Masutani","year":"1996","journal-title":"Immunol. Lett."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/3\/8\/1485\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:57:07Z","timestamp":1760219827000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/3\/8\/1485"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,8,18]]},"references-count":59,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2011,8]]}},"alternative-id":["v3081485"],"URL":"https:\/\/doi.org\/10.3390\/v3081485","relation":{},"ISSN":["1999-4915"],"issn-type":[{"type":"electronic","value":"1999-4915"}],"subject":[],"published":{"date-parts":[[2011,8,18]]}}}