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HTLV-1 Tax has been shown to have a prosurvival role in infected T cells by enhancing expression of the Bcl-2 family of antiapoptotic proteins. In this study, we show that the expression of proapoptotic BH3-only proteins Bim (Bcl-2-interacting mediator of cell death) and Bid (BH3-interacting domain death agonist) is diminished in HTLV-1-infected leukemic cells. Using a Tax-inducible system and a transient overexpression approach, we demonstrate that Tax downregulates Bid and Bim expression at the transcriptional level. We show that reinforced expression of Bim and Bid in HTLV-1-infected T-cell lines sensitizes CD95\/TRAIL- and anticancer drug-induced apoptosis. Furthermore, we show that Tax suppresses Bid and Bim expression by enhancing hypoxia-inducible factor-1<jats:italic>\u03b1<\/jats:italic> (HIF-1<jats:italic>\u03b1<\/jats:italic>) protein expression. siRNA knockdown of HIF-1<jats:italic>\u03b1<\/jats:italic> or chemical inhibition of the transactivation activity of HIF-1<jats:italic>\u03b1<\/jats:italic> resulted in an increase in Bid and Bim expression and, consequently, in an increase in CD95\/TRAIL- and anticancer drug-induced apoptosis in HTLV-1-infected leukemic T-cell lines. Our study provides evidence that besides upregulation of prosurvival Bcl-2 proteins, Tax may also confer apoptosis resistance to HTLV-1-infected T cells by suppressing the expression of the proapoptotic BH3-only proteins Bim and Bid.<\/jats:p>","DOI":"10.1038\/cddis.2014.536","type":"journal-article","created":{"date-parts":[[2014,12,18]],"date-time":"2014-12-18T14:00:05Z","timestamp":1418911205000},"page":"e1575-e1575","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Tax contributes apoptosis resistance to HTLV-1-infected T cells via suppression of Bid and Bim expression"],"prefix":"10.1038","volume":"5","author":[{"given":"A","family":"M\u00fchleisen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Giaisi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R","family":"K\u00f6hler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P H","family":"Krammer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Li-Weber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2014,12,18]]},"reference":[{"key":"BFcddis2014536_CR1","doi-asserted-by":"publisher","first-page":"5931","DOI":"10.1038\/sj.onc.1208981","volume":"24","author":"M Yoshida","year":"2005","unstructured":"Yoshida M . 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