p38 MAPK-mediated activation of NF-kappaB by the RhoGEF domain of Bcr

Oncogene. 2002 Jul 11;21(30):4601-12. doi: 10.1038/sj.onc.1205678.

Abstract

The oncogenic fusion protein p210 Bcr-Abl is causally associated with virtually all cases of chronic myelogenous leukemia. The wild-type Bcr product has several recognizable structural and functional motifs including a domain that contains guanine nucleotide exchange activity for Rho family GTPases (DH/PH domain). Although this domain is retained within p210 Bcr-Abl, it has no known signaling activities in vivo. Here we report that a fragment of Bcr that encodes the isolated DH/PH domain is a potent activator of the NF-kappaB transcription factor. Within the context of full length Bcr, this activity is regulated by proximal flanking sequences that suppress the DH/PH domain encoded guanine nucleotide exchange activity. NF-kappaB activation by Bcr is not mediated by nuclear translocation, but rather by p38 mitogen-activated protein kinase (MAPK)-dependent modification of the RelA/p65 transactivation domain. Although we were able to demonstrate that Bcr can function as an exchange factor for Cdc42 in vivo, NF-kappaB activation appears to occur via a Cdc42-independent mechanism. These studies constitute direct evidence that the Bcr RhoGEF domain can function in vivo, and identify a new signaling activity that may contribute to the transforming potential of p210 Bcr-Abl.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Animals
  • Binding Sites
  • COS Cells
  • Cell Nucleus / metabolism
  • Electrophoretic Mobility Shift Assay
  • Fusion Proteins, bcr-abl / chemistry
  • Fusion Proteins, bcr-abl / metabolism
  • Guanine Nucleotide Exchange Factors / metabolism*
  • MAP Kinase Signaling System
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism*
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / chemistry
  • NF-kappa B / metabolism*
  • Oncogene Proteins / chemistry*
  • Oncogene Proteins / metabolism*
  • Promoter Regions, Genetic / genetics
  • Protein Structure, Tertiary
  • Protein-Tyrosine Kinases*
  • Proto-Oncogene Proteins c-bcr
  • Proto-Oncogene Proteins*
  • Response Elements / genetics
  • Rho Guanine Nucleotide Exchange Factors
  • Transcriptional Activation
  • Transfection
  • Tumor Necrosis Factor-alpha / pharmacology
  • cdc42 GTP-Binding Protein / metabolism
  • p38 Mitogen-Activated Protein Kinases
  • rac1 GTP-Binding Protein / metabolism
  • rhoA GTP-Binding Protein / metabolism

Substances

  • Guanine Nucleotide Exchange Factors
  • NF-kappa B
  • Oncogene Proteins
  • Proto-Oncogene Proteins
  • Rho Guanine Nucleotide Exchange Factors
  • Tumor Necrosis Factor-alpha
  • Protein-Tyrosine Kinases
  • Fusion Proteins, bcr-abl
  • Bcr protein, mouse
  • Proto-Oncogene Proteins c-bcr
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • cdc42 GTP-Binding Protein
  • rac1 GTP-Binding Protein
  • rhoA GTP-Binding Protein