{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T22:12:59Z","timestamp":1791238379254,"version":"4.1.0"},"reference-count":48,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2014,8,30]],"date-time":"2014-08-30T00:00:00Z","timestamp":1409356800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"funder":[{"name":"JSPS KAKENHI","award":["23590537"],"award-info":[{"award-number":["23590537"]}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2014,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Human T\u2010cell leukemia virus type 1 (HTLV\u20101), an etiological agent of adult T\u2010cell leukemia, immortalizes and transforms primary human T cells in vitro in both an interleukin (IL)\u20102\u2010dependent and IL\u20102\u2010independent manner. Expression of the HTLV\u20101 oncoprotein Tax transforms the growth of the mouse T\u2010cell line CTLL\u20102 from being IL\u20102\u2010dependent to IL\u20102\u2010independent. Withdrawal of IL\u20102 from normal activated T cells induces apoptosis, which is mediated through the inducible expression of several proapoptotic proteins, including Bim. In this study, we found that Tax protects IL\u20102\u2010depleted T cells against Bim\u2010induced apoptosis. Withdrawal of IL\u20102 from CTLL\u20102 cells induced a prominent increase in the level of Bim protein in CTLL\u20102 cells, but not in Tax\u2010transformed CTLL\u20102 cells. This inhibition of Bim in Tax\u2010transformed CTLL\u20102 cells was mediated by two mechanisms: downregulation of <jats:italic>Bim <\/jats:italic><jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content> and posttranscriptional reduction of Bim protein. Transient expression of Tax in CTLL\u20102 cells also inhibited IL\u20102 depletion\u2013induced expression of Bim, however, this decrease in Bim protein expression was not due to downregulation of <jats:italic>Bim <\/jats:italic><jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content>, thus indicating that <jats:italic>Bim <\/jats:italic><jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content> downregulation in Tax\u2010transformed CTLL\u20102 occurs only after long\u2010term expression of Tax. Transient expression of Tax in CTLL\u20102 cells also induced Erk activation, however, this was not involved in the reduction of Bim protein. Knockdown of Bim expression in CTLL\u20102 cells augmented Tax\u2010induced IL\u20102\u2010independent transformation. HTLV\u20101 infection of human T cells also reduced their levels of Bim protein, and restoring Bim expression in HTLV\u20101\u2010infected cells reduced their proliferation by inducing apoptosis. Taken together, these results indicate that Tax\u2010induced downregulation of Bim in HTLV\u20101\u2010infected T cells promotes their IL\u20102\u2010independent growth, thereby supporting the persistence of HTLV\u20101 infection in vivo.<\/jats:p>","DOI":"10.1002\/cam4.329","type":"journal-article","created":{"date-parts":[[2014,8,30]],"date-time":"2014-08-30T07:39:00Z","timestamp":1409384340000},"page":"1605-1614","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Downregulation of proapoptotic Bim augments <scp>IL<\/scp>\u20102\u2010independent T\u2010cell transformation by human T\u2010cell leukemia virus type\u20101 Tax"],"prefix":"10.1002","volume":"3","author":[{"given":"Masaya","family":"Higuchi","sequence":"first","affiliation":[{"name":"Division of Virology Niigata University Graduate School of Medical and Dental Sciences Niigata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiko","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Division of Virology Niigata University Graduate School of Medical and Dental Sciences Niigata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuetsu","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Immunology Graduate School and Faculty of Medicine University of the Ryukyus Okinawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Fujii","sequence":"additional","affiliation":[{"name":"Division of Virology Niigata University Graduate School of Medical and Dental Sciences Niigata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,8,30]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2010.537"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12185-011-0937-1"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2012.00322"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/rmv.1745"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/v3081374"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-08-241117"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.73.6.4856-4865.1999"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.66.7.4570-4575.1992"},{"key":"e_1_2_7_10_1","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1128\/jvi.67.3.1211-1217.1993","article-title":"Proliferative response of Tax1\u2010transduced primary human T cells to anti\u2010CD3 antibody stimulation by an interleukin\u20102\u2010independent pathway","volume":"67","author":"Akagi T.","year":"1993","journal-title":"J. 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