{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T07:19:20Z","timestamp":1773299960814,"version":"3.50.1"},"reference-count":42,"publisher":"American Society for Microbiology","issue":"17","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2015,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Human T-cell leukemia virus type 1 (HTLV-1) is associated with adult T-cell leukemia (ATL) and transforms T cells\n            <jats:italic>in vitro<\/jats:italic>\n            . To our knowledge, the functional role of reactive oxygen species (ROS)-generating NADPH oxidase 5 (Nox5) in HTLV-1 transformation remains undefined. Here, we found that Nox5\u03b1 expression was upregulated in 88% of 17 ATL patient samples but not in normal peripheral blood T cells. Upregulation of the Nox5\u03b1 variant was transcriptionally sustained by the constitutive Janus family tyrosine kinase (Jak)-STAT5 signaling pathway in interleukin-2 (IL-2)-independent HTLV-1-transformed cell lines, including MT1 and MT2, whereas it was transiently induced by the IL-2-triggered Jak-STAT5 axis in uninfected T cells. A Nox inhibitor, diphenylene iodonium, and antioxidants such as N-acetyl cysteine blocked proliferation of MT1 and MT2 cells. Ablation of Nox5\u03b1 by small interfering RNAs abrogated ROS production, inhibited cellular activities, including proliferation, migration, and survival, and suppressed tumorigenicity in immunodeficient NOG mice. The findings suggest that Nox5\u03b1 is a key molecule for redox-signal-mediated maintenance of the HTLV-1 transformation phenotype and could be a potential molecular target for therapeutic intervention in cancer development.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            HTLV-1 is the first human oncogenic retrovirus shown to be associated with ATL. Despite the extensive study over the years, the mechanism underlying HTLV-1-induced cell transformation is not fully understood. In this study, we addressed the expression and function of ROS-generating Nox family genes in HTLV-1-transformed cells. Our report provides the first evidence that the upregulated expression of Nox5\u03b1 is associated with the pathological state of ATL peripheral blood mononuclear cells and that Nox5\u03b1 is an integral component of the Jak-STAT5 signaling pathway in HTLV-1-transformed T cells. Nox5\u03b1-derived ROS are critically involved in the regulation of cellular activities, including proliferation, migration, survival, and tumorigenicity, in HTLV-1-transformed cells. These results indicate that Nox5\u03b1-derived ROS are functionally required for maintenance of the HTLV-1 transformation phenotype. The finding provides new insight into the redox-dependent mechanism of HTLV-1 transformation and raises an intriguing possibility that Nox5\u03b1 serves as a potential molecular target to treat HTLV-1-related leukemia.\n          <\/jats:p>","DOI":"10.1128\/jvi.00983-15","type":"journal-article","created":{"date-parts":[[2015,6,25]],"date-time":"2015-06-25T01:55:41Z","timestamp":1435197341000},"page":"9080-9089","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":17,"title":["Superoxide-Generating Nox5\u03b1 Is Functionally Required for the Human T-Cell Leukemia Virus Type 1-Induced Cell Transformation Phenotype"],"prefix":"10.1128","volume":"89","author":[{"given":"Tomonari","family":"Shigemura","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masaaki","family":"Shiohara","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masayoshi","family":"Kato","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Biochemistry, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuichi","family":"Furuta","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Biochemistry, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuko","family":"Kaneda","sequence":"additional","affiliation":[{"name":"Division of Tumor and Cellular Biochemistry, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuhiro","family":"Morishita","sequence":"additional","affiliation":[{"name":"Division of Tumor and Cellular Biochemistry, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroo","family":"Hasegawa","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masahiro","family":"Fujii","sequence":"additional","affiliation":[{"name":"Division of Virology, Niigata University Graduate School of Medicine and Dental Science, Niigata, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agnes","family":"Gorlach","sequence":"additional","affiliation":[{"name":"Experimental and Molecular Pediatric Cardiology, Department of Pediatric Cardiology and Congenital Heart Disease, German Heart Center Munich at the Technical University, Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenichi","family":"Koike","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tohru","family":"Kamata","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Biochemistry, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.78.10.6476"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.77.12.7415"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/294770a0"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.80.17.5402"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.66.7.4570-4575.1992"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.19.1.475"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1208975"},{"key":"e_1_3_2_9_2","first-page":"2360","article-title":"Constitutive activation of NF-kappaB in primary adult T-cell leukemia cells","volume":"93","author":"Mori N","year":"1999","unstructured":"Mori N, Fujii M, Ikeda S, Yamada Y, Tomonaga M, Ballard DW, Yamamoto N. 1999. 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