Human T-cell lymphotropic virus type 1 Tax represses c-Myb-dependent transcription through activation of the NF-kappaB pathway and modulation of coactivator usage.
The proto-oncogene c-myb is essential for a controlled balance between cell growth and differentiation. Aberrant c-Myb activity has been reported for numerous human cancers, and enforced c-Myb transcription can transform cells of lymphoid origin by stimulating cellular proliferation and inhibiting apoptotic pathways. Here we demonstrate that activation of the NF-kappaB pathway by the HTLV-1 Tax protein leads to transcriptional inactivation of c-Myb. This conclusion was supported by the fact that Tax mutants unable to stimulate the NF-kappaB pathway could not inhibit c-Myb transactivating functions. In addition, inhibition of Tax-mediated NF-kappaB activation by coexpression of IkappaBalpha restored c-Myb transcription, and Tax was unable to block c-Myb transcription in a NEMO knockout cell line. Importantly, physiological stimuli, such as signaling with the cellular cytokines tumor necrosis factor alpha, interleukin 1 beta (IL-1beta), and lipopolysaccharide, also inhibited c-Myb transcription. These results uncover a new link between extracellular signaling and c-Myb-dependent transcription. The mechanism underlying NF-kappaB-mediated repression was identified as sequestration of the coactivators CBP/p300 by RelA. Interestingly, an amino-terminal deletion form of p300 lacking the C/H1 and KIX domains and unable to bind RelA retained the ability to stimulate c-Myb transcription and prevented NF-kappaB-mediated repression.
Nicot
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Section of Animal Models and Retroviral Vaccines, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA. cbeden@helix.nih.gov
Mahieux
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Pise-Masison
C
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Brady
J
J
Gessain
A
A
Yamaoka
S
S
Franchini
G
G
D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D050881:E1A-Associated p300 Protein; D004789:Enzyme Activation; D017353:Gene Deletion; D016356:Gene Products, tax / Q000378:metabolism*; D020672:I-kappa B Proteins; D015151:Immunoblotting; D007375:Interleukin-1 / Q000378:metabolism; D008025:Ligases / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D000090063:Proto-Oncogene Mas; D020598:Proto-Oncogene Proteins c-myb / Q000378:metabolism*; D011817:Rabbits; D012156:Reticulocytes / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection
D004268:DNA-Binding Proteins; D016356:Gene Products, tax; D020672:I-kappa B Proteins; D007375:Interleukin-1; C000715470:MAS1 protein, human; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D009687:Nuclear Proteins; D000090063:Proto-Oncogene Mas; D020598:Proto-Oncogene Proteins c-myb; D015534:Trans-Activators; D000072000:NF-KappaB Inhibitor alpha; D008156:Luciferases; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse; D008025:Ligases; C028812:guanosine 3',5'-polyphosphate synthetases