title: Tax protein-induced expression of antiapoptotic Bfl-1 protein contributes to survival of human T-cell leukemia virus type 1 (HTLV-1)-infected T-cells.
abstract: Human T lymphotropic virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia/lymphoma (ATLL). ATLL is a severe malignancy with no effective treatment. HTLV-1 regulatory proteins Tax and HTLV-1 basic leucine zipper factor (HBZ) play a major role in ATLL development, by interfering with cellular functions such as CD4(+) T-cell survival. In this study, we observed that the expression of Bfl-1, an antiapoptotic protein of the Bcl-2 family, is restricted to HTLV-1-infected T-cell lines and to T-cells expressing both Tax and HBZ proteins. We showed that Tax-induced bfl-1 transcription through the canonical NF-κB pathway. Moreover, we demonstrated that Tax cooperated with c-Jun or JunD, but not JunB, transcription factors of the AP-1 family to stimulate bfl-1 gene activation. By contrast, HBZ inhibited c-Jun-induced bfl-1 gene activation, whereas it increased JunD-induced bfl-1 gene activation. We identified one NF-κB, targeted by RelA, c-Rel, RelB, p105/p50, and p100/p52, and two AP-1, targeted by both c-Jun and JunD, binding sites in the bfl-1 promoter of T-cells expressing both Tax and HBZ. Analyzing the potential role of antiapoptotic Bcl-2 proteins in HTLV-1-infected T-cell survival, we demonstrated that these cells are differentially sensitive to silencing of Bfl-1, Bcl-x(L), and Bcl-2. Indeed, both Bfl-1 and Bcl-x(L) knockdowns decreased the survival of HTLV-1-infected T-cell lines, although no cell death was observed after Bcl-2 knockdown. Furthermore, we demonstrated that Bfl-1 knockdown sensitizes HTLV-1-infected T-cells to ABT-737 or etoposide treatment. Our results directly implicate Bfl-1 and Bcl-x(L) in HTLV-1-infected T-cell survival and suggest that both Bfl-1 and Bcl-x(L) represent potential therapeutic targets for ATLL treatment.
authors.affiliation: Université de Lyon, Lyon, France.
authors.forename: Héloïse
authors.initials: H
authors.lastname: Macaire
authors.forename: Aurélien
authors.initials: A
authors.lastname: Riquet
authors.forename: Vincent
authors.initials: V
authors.lastname: Moncollin
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Biémont-Trescol
authors.forename: Madeleine
authors.initials: M
authors.lastname: Duc Dodon
authors.forename: Olivier
authors.initials: O
authors.lastname: Hermine
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Debaud
authors.forename: Renaud
authors.initials: R
authors.lastname: Mahieux
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Mesnard
authors.forename: Marlène
authors.initials: M
authors.lastname: Pierre
authors.forename: Louis
authors.initials: L
authors.lastname: Gazzolo
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bonnefoy
authors.forename: Hélène
authors.initials: H
authors.lastname: Valentin
mesh_terms: D000328:Adult; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D001713:Biphenyl Compounds / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D055785:Gene Knockdown Techniques; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism*; D016758:Genes, jun / Q000235:genetics; D006367:HeLa Cells; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000178:diet therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008025:Ligases / Q000235:genetics / Q000378:metabolism; D008297:Male; D015778:Minor Histocompatibility Antigens; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism; D009596:Nitrophenols / Q000494:pharmacology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D020569:Proto-Oncogene Proteins c-rel; D012191:Retroviridae Proteins; D013449:Sulfonamides / Q000494:pharmacology; D051841:Transcription Factor RelB / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C501332:ABT-737; D000972:Antineoplastic Agents, Phytogenic; C096816:BCL2-related protein A1; C494811:BCL2L1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D001713:Biphenyl Compounds; D004268:DNA-Binding Proteins; D016356:Gene Products, tax; C479751:HBZ protein, human T-cell leukemia virus type I; C559371:JunD protein, human; D015778:Minor Histocompatibility Antigens; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D009596:Nitrophenols; D009687:Nuclear Proteins; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D016755:Proto-Oncogene Proteins c-jun; D020569:Proto-Oncogene Proteins c-rel; C068059:REL protein, human; C497593:RELB protein, human; D012191:Retroviridae Proteins; D013449:Sulfonamides; D014764:Viral Proteins; D051020:bcl-X Protein; C514970:tax protein, Human T-lymphotrophic virus 1; D051841:Transcription Factor RelB; D005047:Etoposide; D008025:Ligases; C028812:guanosine 3',5'-polyphosphate synthetases