Activation of HIV-1 long terminal repeat transcription and virus replication via NF-kappa B-dependent and -independent pathways by potent phosphotyrosine phosphatase inhibitors, the peroxovanadium compounds

被引:76
作者
Barbeau, B
Bernier, R
Dumais, N
Briand, G
Olivier, M
Faure, R
Posner, BI
Tremblay, M
机构
[1] UNIV LAVAL,CTR RECH INFECTIOL,FAC MED,CTR HOSP UNIV QUEBEC,ST FOY,PQ G1V 4G2,CANADA
[2] UNIV LAVAL,DEPT MICROBIOL,FAC MED,CTR HOSP UNIV QUEBEC,UNITE RECH PEDIAT,ST FOY,PQ G1V 4G2,CANADA
[3] UNIV LAVAL,DEPT MED,FAC MED,CTR HOSP UNIV QUEBEC,ST FOY,PQ G1V 4G2,CANADA
[4] MCGILL UNIV,DEPT MED,MONTREAL,PQ H3A 1A1,CANADA
关键词
D O I
10.1074/jbc.272.20.12968
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Replication of human immunodeficiency virus type 1 (HIV-1) is increased by different cytokines and T cell activators, also known to modulate tyrosine phosphorylation levels, A novel class of protein tyrosine phosphatase (PTP) inhibitors, peroxovanadium (pV) compounds, were tested for a putative effect on HIV-1 long terminal repeat (LTR) activity, We found that these PTP inhibitors markedly enhanced HIV-1 LTR activity in 1G5 cells, a stably transfected cell line that harbors an HIV-1 LTR-driven luciferase construct, A direct correlation between the extent of tyrosine phosphorylation and the level of HIV-1 LTR inducibility was seen after treatment with three different pV compounds, Transient transfection experiments were carried out in several T cell lines, and after addition of pV, a marked increase in HIV-1 LTR activity was measured, Monocytoid cells were tested using U937-derived cell lines and were also found to be sensitive to the pV-mediated potentiating effect on HIV-1 LTR activity, A significant reduction of the pV-mediated increase in HIV-1 LTR activity was seen in cells transiently transfected with an HIV-1 LTR-driven luciferase construct bearing a mutation in both NF-kappa B binding sites although detectable levels of induction remained, Electrophoretic mobility shift assays allowed the identification of the nuclear translocation of the NF-kappa B p50.p65 heterodimer complex induced by pV compounds, A dominant negative version of the repressor I kappa B alpha mutated on serines 32 and 36 impeded pV-induced NF-kappa B-dependent luciferase activity, Western blot analysis showed a clear diminution in the protein level of I kappa B alpha starting 30 min after pV treatment of Jurkat E6.1 cells which is indicative of its degradation, On the other hand, no increase in tyrosine phosphorylation was ob sewed on I kappa B alpha itself, Finally, we tested the PTP inhibitors on four cell lines latently infected with HIV-1 and showed a consistent pV-mediated increase in virion production, Thus, our studies suggest that pV-mediated activation of HIV-1 LTR activity is controlled by the nuclear translocation of the NF-kappa B transcription factor, which is mediated by I kappa B alpha serine phosphorylation and degradation, but also by a still undefined NF-kappa B-independent pathway.
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收藏
页码:12968 / 12977
页数:10
相关论文
共 57 条
[1]   A SENSITIVE REPORTER CELL-LINE FOR HIV-1 TAT ACTIVITY, HIV-1 INHIBITORS, AND T-CELL ACTIVATION EFFECTS [J].
AGUILARCORDOVA, E ;
CHINEN, J ;
DONEHOWER, L ;
LEWIS, DE ;
BELMONT, JW .
AIDS RESEARCH AND HUMAN RETROVIRUSES, 1994, 10 (03) :295-301
[2]   A RAPID MICROPREPARATION TECHNIQUE FOR EXTRACTION OF DNA-BINDING PROTEINS FROM LIMITING NUMBERS OF MAMMALIAN-CELLS [J].
ANDREWS, NC ;
FALLER, DV .
NUCLEIC ACIDS RESEARCH, 1991, 19 (09) :2499-2499
[3]   REGULATION OF HUMAN-IMMUNODEFICIENCY-VIRUS INFECTION - IMPLICATIONS FOR PATHOGENESIS [J].
ANTONI, BA ;
STEIN, SB ;
RABSON, AB .
ADVANCES IN VIRUS RESEARCH, VOL 43, 1994, 43 :53-145
[4]   ACTIVATION OF DNA-BINDING ACTIVITY IN AN APPARENTLY CYTOPLASMIC PRECURSOR OF THE NF-KAPPA-B TRANSCRIPTION FACTOR [J].
BAEUERLE, PA ;
BALTIMORE, D .
CELL, 1988, 53 (02) :211-217
[5]  
BAEUERLE PA, 1994, ANNU REV IMMUNOL, V12, P141, DOI 10.1146/annurev.immunol.12.1.141
[6]   A 65-KD SUBUNIT OF ACTIVE NF-KAPPA-B IS REQUIRED FOR INHIBITION OF NF-KAPPA-B BY I-KAPPA-B [J].
BAEUERLE, PA ;
BALTIMORE, D .
GENES & DEVELOPMENT, 1989, 3 (11) :1689-1698
[7]   I-KAPPA-B - A SPECIFIC INHIBITOR OF THE NF-KAPPA-B TRANSCRIPTION FACTOR [J].
BAEUERLE, PA ;
BALTIMORE, D .
SCIENCE, 1988, 242 (4878) :540-546
[8]   The NF-kappa B and I kappa B proteins: New discoveries and insights [J].
Baldwin, AS .
ANNUAL REVIEW OF IMMUNOLOGY, 1996, 14 :649-683
[9]  
BAUR A, 1994, J IMMUNOL, V152, P976
[10]   HOMOLOGOUS INTERFERENCE RESULTING FROM THE PRESENCE OF DEFECTIVE PARTICLES OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 [J].
BERNIER, R ;
TREMBLAY, M .
JOURNAL OF VIROLOGY, 1995, 69 (01) :291-300