Human T-cell leukemia virus type I oncoprotein Tax represses Smad-dependent transforming growth factor beta signaling through interaction with CREB-binding protein/p300.
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)
Mesh Terms:
Activin Receptors, Type I, Animals, Binding Sites, COS Cells, Carcinoma, Hepatocellular, Cell Transformation, Neoplastic, Cercopithecus aethiops, DNA-Binding Proteins, Gene Products, tax, Genes, pX, Humans, Liver Neoplasms, Lung, Macromolecular Substances, Mink, Nuclear Proteins, Protein Binding, Protein-Serine-Threonine Kinases, Receptors, Transforming Growth Factor beta, Recombinant Fusion Proteins, Regulatory Sequences, Nucleic Acid, Signal Transduction, Smad2 Protein, Smad3 Protein, Smad4 Protein, Trans-Activators, Transcriptional Activation, Transfection, Transforming Growth Factor beta, Tumor Cells, Cultured, Xenopus Proteins, Xenopus laevis
Activin Receptors, Type I, Animals, Binding Sites, COS Cells, Carcinoma, Hepatocellular, Cell Transformation, Neoplastic, Cercopithecus aethiops, DNA-Binding Proteins, Gene Products, tax, Genes, pX, Humans, Liver Neoplasms, Lung, Macromolecular Substances, Mink, Nuclear Proteins, Protein Binding, Protein-Serine-Threonine Kinases, Receptors, Transforming Growth Factor beta, Recombinant Fusion Proteins, Regulatory Sequences, Nucleic Acid, Signal Transduction, Smad2 Protein, Smad3 Protein, Smad4 Protein, Trans-Activators, Transcriptional Activation, Transfection, Transforming Growth Factor beta, Tumor Cells, Cultured, Xenopus Proteins, Xenopus laevis
Blood
Date: Apr. 01, 2001
PubMed ID: 11264182
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