Human T-cell leukemia virus type I oncoprotein Tax represses Smad-dependent transforming growth factor beta signaling through interaction with CREB-binding protein/p300

Blood. 2001 Apr 1;97(7):2137-44. doi: 10.1182/blood.v97.7.2137.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type I*
  • Animals
  • Binding Sites
  • COS Cells
  • Carcinoma, Hepatocellular / pathology
  • Cell Transformation, Neoplastic / genetics
  • Chlorocebus aethiops
  • DNA-Binding Proteins / physiology*
  • Gene Products, tax / physiology*
  • Genes, pX
  • Humans
  • Liver Neoplasms / pathology
  • Lung
  • Macromolecular Substances
  • Mink
  • Nerve Growth Factors
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Protein Binding
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / physiology
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / physiology
  • Recombinant Fusion Proteins / physiology
  • Regulatory Sequences, Nucleic Acid
  • Signal Transduction / drug effects*
  • Smad Proteins
  • Smad2 Protein
  • Smad3 Protein
  • Smad4 Protein
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Trans-Activators / physiology*
  • Transcriptional Activation
  • Transfection
  • Transforming Growth Factor beta / antagonists & inhibitors*
  • Tumor Cells, Cultured
  • Xenopus Proteins*
  • Xenopus laevis

Substances

  • DNA-Binding Proteins
  • Gene Products, tax
  • Macromolecular Substances
  • Nerve Growth Factors
  • Nuclear Proteins
  • Receptors, Transforming Growth Factor beta
  • Recombinant Fusion Proteins
  • SMAD2 protein, human
  • SMAD3 protein, human
  • SMAD4 protein, human
  • Smad Proteins
  • Smad2 Protein
  • Smad2 protein, Xenopus
  • Smad3 Protein
  • Smad4 Protein
  • Trans-Activators
  • Transforming Growth Factor beta
  • Xenopus Proteins
  • smad4.1 protein, Xenopus
  • smad4.2 protein, Xenopus
  • Protein Serine-Threonine Kinases
  • Activin Receptors, Type I
  • Receptor, Transforming Growth Factor-beta Type I