Document Detail

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.
MedLine Citation:
PMID:  22553204     Owner:  NLM     Status:  MEDLINE    
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.
Héloïse Macaire; Aurélien Riquet; Vincent Moncollin; Marie-Claude Biémont-Trescol; Madeleine Duc Dodon; Olivier Hermine; Anne-Laure Debaud; Renaud Mahieux; Jean-Michel Mesnard; Marlène Pierre; Louis Gazzolo; Nathalie Bonnefoy; Hélène Valentin
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-05-02
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-06-18     Completed Date:  2012-08-24     Revised Date:  2013-06-25    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  21357-70     Citation Subset:  IM    
Université de Lyon, Lyon, France.
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MeSH Terms
Antineoplastic Agents, Phytogenic / pharmacology
Basic-Leucine Zipper Transcription Factors / genetics,  metabolism
Biphenyl Compounds / pharmacology
CD4-Positive T-Lymphocytes / metabolism*,  pathology,  virology
Cell Survival
DNA-Binding Proteins / genetics,  metabolism
Etoposide / pharmacology
Gene Knockdown Techniques
Gene Products, tax / genetics,  metabolism*
Genes, jun / genetics
HeLa Cells
Human T-lymphotropic virus 1 / genetics,  metabolism*
Leukemia-Lymphoma, Adult T-Cell / diet therapy,  genetics,  metabolism*,  pathology
Ligases / genetics,  metabolism
NF-kappa B p50 Subunit / genetics,  metabolism
Nitrophenols / pharmacology
Nuclear Proteins / genetics,  metabolism
Piperazines / pharmacology
Proto-Oncogene Proteins c-bcl-2 / genetics,  metabolism*
Proto-Oncogene Proteins c-jun / genetics,  metabolism
Sulfonamides / pharmacology
Transcription Factor RelB / genetics,  metabolism
Transcription, Genetic / drug effects,  genetics
Viral Proteins / genetics,  metabolism
bcl-X Protein / genetics,  metabolism
Reg. No./Substance:
0/ABT-737; 0/Antineoplastic Agents, Phytogenic; 0/BCL2-related protein A1; 0/BCL2L1 protein, human; 0/Basic-Leucine Zipper Transcription Factors; 0/Biphenyl Compounds; 0/DNA-Binding Proteins; 0/Gene Products, tax; 0/HBZ protein, human T-cell leukemia virus type I; 0/HIVEN86A protein, human; 0/JunD protein, human; 0/NF-kappa B p50 Subunit; 0/NFKB1 protein, human; 0/Nitrophenols; 0/Nuclear Proteins; 0/Piperazines; 0/Proto-Oncogene Proteins c-bcl-2; 0/Proto-Oncogene Proteins c-jun; 0/RELB protein, human; 0/Sulfonamides; 0/Viral Proteins; 0/bcl-X Protein; 0/tax protein, Human T-lymphotrophic virus 1; 147337-75-5/Transcription Factor RelB; 33419-42-0/Etoposide; EC 6.-/Ligases; EC 6.-/guanosine 3',5'-polyphosphate synthetases

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