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)
Department of Preventive Medicine and AIDS Research, Nagasaki University, Japan. n-mori@net.nagasaki-u.ac.jp
N
N
Mori
M
M
Morishita
T
T
Tsukazaki
C Z
CZ
Giam
A
A
Kumatori
Y
Y
Tanaka
N
N
Yamamoto
D030201:Activin Receptors, Type I; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000502:physiology*; D016356:Gene Products, tax / Q000502:physiology*; D016355:Genes, pX; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology; D008168:Lung; D046911:Macromolecular Substances; D008907:Mink; D009414:Nerve Growth Factors; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012045:Regulatory Sequences, Nucleic Acid; D015398:Signal Transduction / Q000187:drug effects*; D051785:Smad Proteins; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D015533:Transcriptional Activation; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D029867:Xenopus Proteins; D014982:Xenopus laevis
D004268:DNA-Binding Proteins; D016356:Gene Products, tax; D046911:Macromolecular Substances; D009414:Nerve Growth Factors; D009687:Nuclear Proteins; D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; D051785:Smad Proteins; D051899:Smad2 Protein; C497785:Smad2 protein, Xenopus; D051900:Smad3 Protein; D051901:Smad4 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D029867:Xenopus Proteins; C490808:smad4.1 protein, Xenopus; C117263:smad4.2 protein, Xenopus; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I