Abstract
Human T-cell leukemia virus type I (HTLV-I) Tax is a potent transcriptional regulator that can activate or repress specific cellular genes and that has been proposed to contribute to leukemogenesis in adult T-cell leukemia. Previously, HTLV-I- infected T-cell clones were found to be resistant to growth inhibition by transforming growth factor (TGF)-beta. Here it is shown that Tax can perturb Smad-dependent TGF-beta signaling even though no direct interaction of Tax and Smad proteins could be detected. Importantly, a mutant Tax of CREB-binding protein (CBP)/p300 binding site, could not repress the Smad transactivation function, suggesting that the CBP/p300 binding domain of Tax is essential for the suppression of Smad function. Because both Tax and Smad are known to interact with CBP/p300 for the potentiation of their transcriptional activities, the effect of CBP/p300 on suppression of Smad-mediated transactivation by Tax was examined. Overexpression of CBP/p300 reversed Tax-mediated inhibition of Smad transactivation. Furthermore, Smad could repress Tax transcriptional activation, indicating reciprocal repression between Tax and Smad. These results suggest that Tax interferes with the recruitment of CBP/p300 into transcription initiation complexes on TGF-beta-responsive elements through its binding to CBP/p300. The novel function of Tax as a repressor of TGF-beta signaling may contribute to HTLV-I leukemogenesis. (Blood. 2001;97:2137-2144)
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Activin Receptors, Type I*
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Animals
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Binding Sites
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COS Cells
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Carcinoma, Hepatocellular / pathology
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Cell Transformation, Neoplastic / genetics
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Chlorocebus aethiops
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DNA-Binding Proteins / physiology*
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Gene Products, tax / physiology*
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Genes, pX
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Humans
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Liver Neoplasms / pathology
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Lung
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Macromolecular Substances
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Mink
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Nerve Growth Factors
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Protein Binding
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / physiology
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Receptor, Transforming Growth Factor-beta Type I
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Receptors, Transforming Growth Factor beta / genetics
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Receptors, Transforming Growth Factor beta / physiology
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Recombinant Fusion Proteins / physiology
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Regulatory Sequences, Nucleic Acid
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Signal Transduction / drug effects*
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Smad Proteins
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Smad2 Protein
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Smad3 Protein
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Smad4 Protein
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Trans-Activators / physiology*
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Transcriptional Activation
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Transfection
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Transforming Growth Factor beta / antagonists & inhibitors*
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Tumor Cells, Cultured
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Xenopus Proteins*
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Xenopus laevis
Substances
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DNA-Binding Proteins
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Gene Products, tax
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Macromolecular Substances
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Nerve Growth Factors
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Nuclear Proteins
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Receptors, Transforming Growth Factor beta
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Recombinant Fusion Proteins
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SMAD2 protein, human
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SMAD3 protein, human
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SMAD4 protein, human
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Smad Proteins
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Smad2 Protein
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Smad2 protein, Xenopus
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Smad3 Protein
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Smad4 Protein
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Trans-Activators
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Transforming Growth Factor beta
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Xenopus Proteins
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smad4.1 protein, Xenopus
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smad4.2 protein, Xenopus
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Protein Serine-Threonine Kinases
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Activin Receptors, Type I
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Receptor, Transforming Growth Factor-beta Type I