Mechanisms of Bcr-Abl-mediated NF-kappaB/Rel activation

Exp Hematol. 2003 Jun;31(6):504-11. doi: 10.1016/s0301-472x(03)00069-9.

Abstract

Bcr-Abl constitutes a deregulated tyrosine kinase involved in the pathogenesis of chronic myeloid leukemia (CML) and a subset of acute lymphoblastic leukemia (ALL). Although activation of the transcription factor NF-kappaB/Rel has been demonstrated, mechanisms of NF-kappaB/Rel activation by Bcr-Abl remain obscure. In this paper we demonstrate activation of NF-kappaB/Rel by Bcr-Abl and for the first time by v-Abl. Furthermore, we investigated mechanisms of NF-kappaB/Rel induction by Bcr-Abl and v-Abl. Both Bcr-Abl and v-Abl induced NF-kappaB/Rel DNA binding in Ba/F3 cells. DNA binding was a result of nuclear translocation of p65/RelA, whereas p65/RelA expression was unaffected. Nuclear translocation of p65/RelA is at least partially due to increased IkappaBalpha degradation, which is independent of IkappaB kinase (IKK) activity. IKK activity is not deregulated by Bcr-Abl and v-Abl. NF-kappaB/Rel transactivation was dependent on abl kinase activity but independent of Grb2 and Grb10 binding tobcr sequences. In addition, NF-kappaB/Rel activation was dependent on Ras activity. Primary CML blasts showed constitutive p65/RelA NF-kappaB/Rel DNA binding activity. Thus NF-kappaB/Rel represents a potential target for molecular therapies in CML.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Cell Line
  • DNA / metabolism
  • Fusion Proteins, bcr-abl / physiology*
  • Humans
  • I-kappa B Kinase
  • I-kappa B Proteins / metabolism
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • Mice
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • Oncogene Proteins v-abl / physiology
  • Oncogene Proteins v-rel / metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism
  • Transcriptional Activation
  • ras Proteins

Substances

  • I-kappa B Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • Oncogene Proteins v-abl
  • Oncogene Proteins v-rel
  • NF-KappaB Inhibitor alpha
  • DNA
  • Fusion Proteins, bcr-abl
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • Chuk protein, mouse
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • Ikbkb protein, mouse
  • Ikbke protein, mouse
  • ras Proteins