TY - JOUR
T1 - HTLV-1 Tax-induced NF-κB activation is synergistically enhanced by 12-O-tetradecanoylphorbol-13-acetate
T2 - Mechanism and implications for Tax oncogenicity
AU - Azran-Shaish, Inbal
AU - Tabakin-Fix, Yulia
AU - Huleihel, Mahmoud
AU - Bakhanashvili, Mary
AU - Aboud, Mordechai
N1 - Funding Information:
Acknowledgements This study was supported by grants from the Israel Science Foundation and from the Joint Cancer Research Program of the Israeli Ministry of Sciences and Technology and the German Cancer Research Center.
PY - 2008/7/1
Y1 - 2008/7/1
N2 - Nuclear factor kappa B (NF-κB) 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 κB (IκB) 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-κB 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-κB. Therefore, we reassessed this issue and also investigated their influence on Tax-mediated activation of these factors. We found that TPA promoted NF-κB 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-κB transcriptional function. In contrast, TPA and the ectopic PKC only slightly elevated the low activation of the NF-κB 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-κB-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-κB activation.
AB - Nuclear factor kappa B (NF-κB) 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 κB (IκB) 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-κB 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-κB. Therefore, we reassessed this issue and also investigated their influence on Tax-mediated activation of these factors. We found that TPA promoted NF-κB 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-κB transcriptional function. In contrast, TPA and the ectopic PKC only slightly elevated the low activation of the NF-κB 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-κB-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-κB activation.
KW - CBP
KW - HTLV-1 Tax
KW - NF-κB
KW - PKC
KW - TPA
KW - p65
UR - http://www.scopus.com/inward/record.url?scp=46149093204&partnerID=8YFLogxK
U2 - 10.1007/s00109-008-0335-1
DO - 10.1007/s00109-008-0335-1
M3 - Article
C2 - 18425496
AN - SCOPUS:46149093204
SN - 0946-2716
VL - 86
SP - 799
EP - 814
JO - Journal of Molecular Medicine
JF - Journal of Molecular Medicine
IS - 7
ER -