High levels of cytoplasmic HTLV-1 Tax mutant proteins retain a Tax-NF-kappaB-CBP ternary complex in the cytoplasm.
The oncogenic potential of HTLV-1 Tax protein is partially ascribed to its capacity to activate NF-kappaB. The current view is that Tax acts first in the cytoplasm to dissociate NF-kappaB factors from the IkappaB proteins and enable their nuclear translocation, then Tax links p65(RelA), within the nucleus, to CBP/p300 and P/CAF, which are essential for its optimal transcriptional activity. Our present study challenges the paradigm that Tax-p65(RelA)-CBP/p300 assembly occurs in the nucleus. Using Tax mutants defective for nuclear localization we show that at low levels these mutants induce the nuclear translocation of NF-kappaB factors but not their transcriptional activity, whereas at high levels they trap CBP and free p65(RelA) in the cytoplasm and block, thereby, their transcriptional function. In contrast, wild-type (w.t.) Tax strongly stimulated NF-kappaB-dependent gene expression in all tested experimental settings. These data suggest that the Tax-p65(RelA)-CBP ternary complex is established in the cytoplasm rather than in the nucleus. When this complex is formed with w.t. Tax, the entire moiety translocates into the nucleus and exerts high transcriptional activity. However, if the complex is formed with the cytoplasmic Tax mutants, the resulting moiety is retained in the cytoplasm and is, therefore, devoid of transcriptional activity.
Azran
Inbal
I
Department of Microbiology and Immunology, Cancer Research Center, Faculty of Health Sciences, Ben-Gurion University of Negev, Beer Sheva 84105, Israel.
Jeang
Kuan-Teh
KT
Aboud
Mordechai
M
D050882:CREB-Binding Protein; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA
D016356:Gene Products, tax; D020672:I-kappa B Proteins; D046912:Multiprotein Complexes; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009687:Nuclear Proteins; D015534:Trans-Activators; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D017868:Cyclic AMP-Dependent Protein Kinases