HTLV-1 Tax-induced NF-κB activation is synergistically enhanced by 12-O-tetradecanoylphorbol-13-acetate: mechanism and implications for Tax oncogenicity
| Autor: | Mary Bakhanashvili, Inbal Azran-Shaish, Mahmoud Huleihel, Mordechai Aboud, Yulia Tabakin-Fix |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Cytoplasm
Leukemia T-Cell Molecular Sequence Data Response element Biology Transfection 12-O-Tetradecanoylphorbol-13-acetate Jurkat cells Cell Line Jurkat Cells chemistry.chemical_compound Drug Discovery Humans Genetics (clinical) Protein kinase C Human T-lymphotropic virus 1 Base Sequence T-plasminogen activator Binding protein NF-kappa B Promoter NF-κB Gene Products tax CREB-Binding Protein Cell biology chemistry Biochemistry Mutation Carcinogens Tetradecanoylphorbol Acetate Molecular Medicine |
| Zdroj: | Journal of Molecular Medicine. 86:799-814 |
| ISSN: | 1432-1440 0946-2716 |
| DOI: | 10.1007/s00109-008-0335-1 |
| Popis: | Nuclear factor kappa B (NF-kappaB) factors regulate a wide range of physiological and oncogenic processes. Normally, these factors are transiently activated by specific external signals which induce their dissociation from inhibitors of kappaB (IkappaB) and subsequent translocation to the nucleus where p65 links to the cyclic adenosine monophosphate response element binding protein (CBP)-p300 and P/CAF coactivators that are essential for its transcriptional activity. The pathogenic potential of human T-cell leukemia virus type 1 (HTLV-1) Tax protein is partly ascribed to its capacity to constitutively activate NF-kappaB factors because constitutive activity of these factors play an important role in the pathophysiology of adult T-cell leukemia (ATL) and tropical spastic paraparesis-HTLV-1 associated myelopathy (TSP-HAM). In assessing the possibility of modulating Tax pathogenic potential by external factors, we focused here on 12-O -tetradecanoylphorbol-13-acetate (TPA) which is a potent protein kinase C (PKC) activator. There are conflicting reports regarding the effect of TPA and PKC on NF-kappaB. Therefore, we reassessed this issue and also investigated their influence on Tax-mediated activation of these factors. We found that TPA promoted NF-kappaB nuclear translocation and the DNA binding of p65 dimers through PKC activation. However, both TPA and ectopically expressed PKC had only a marginal effect on the transcriptional competence of these dimers, indicating that the DNA binding of such dimers is insufficient by itself for gene activation. Notably, however, both TPA and the ectopic PKC displayed strong synergistic enhancement of the Tax-induced activation of the NF-kappaB transcriptional function. In contrast, TPA and the ectopic PKC only slightly elevated the low activation of the NF-kappaB transcriptional capacity by cytoplasmic Tax mutants, indicating that the nuclear translocation of Tax was essential for this synergism. Subsequent experiments suggested that TPA contributed to this synergism by increasing the pool of free p65 which Tax could link to CBP and elevate, thereby, the amount of a p65-Tax-CBP ternary complex that could bind to NF-kappaB-responsive promoters and stimulate their expression. Finally, we demonstrated that this synergism operated also in HTLV-1-infected human T-cells. Earlier reports have shown a close linkage of pathological PKC-activating conditions (e.g., infectious and inflammatory diseases) to certain malignancies. On this ground, the present study suggests that such conditions may enhance the risk for ATL and TSP-HAM in HTLV-1 carriers by increasing the Tax-induced NF-kappaB activation. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink