title: Tax contributes apoptosis resistance to HTLV-1-infected T cells via suppression of Bid and Bim expression.
abstract: The human T-lymphotropic virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia (ATL). 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-1α (HIF-1α) protein expression. siRNA knockdown of HIF-1α or chemical inhibition of the transactivation activity of HIF-1α 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.
authors.affiliation: Tumor Immunology Program D030, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Mühleisen
authors.affiliation: Tumor Immunology Program D030, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Giaisi
authors.affiliation: Tumor Immunology Program D030, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Köhler
authors.affiliation: Tumor Immunology Program D030, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
authors.forename: P H
authors.initials: PH
authors.lastname: Krammer
authors.affiliation: Tumor Immunology Program D030, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Li-Weber
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics* / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D002460:Cell Line; D015536:Down-Regulation; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology* / Q000821:virology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D000072224:Bcl-2-Like Protein 11; D016356:Gene Products, tax; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; C514970:tax protein, Human T-lymphotrophic virus 1