Effect of Bcr sequences on the cellular function of the Bcr-Abl oncoprotein

Oncogene. 1997 Oct 2;15(14):1625-34. doi: 10.1038/sj.onc.1201342.


In Philadelphia chromosome (Ph1)-positive human leukemia, the c-Abl tyrosine kinase is activated by fusion to sequences encoded by the breakpoint cluster region (bcr) gene. Two major types of Bcr-Abl fusion proteins have been found in human leukemia. Fusion of the N-terminal 426 amino acids of Bcr generates p190(Bcr-Abl) which is mostly found in acute lymphocytic leukemia (ALL), whereas fusion of the N-terminal 902 or 927 amino acids of Bcr generates p210(Bcr-Abl) mostly found with chronic myelogenous leukemia (CML). Previous studies have demonstrated that both the Bcr and the Abl functional domains contribute to the oncogenic activity of Bcr-Abl proteins. Present in both p190 and p210 is the N-terminal coiled-coil of Bcr (aa 1-63), which is shown here to be functionally replaceable with the leucine zipper of the yeast transcription factor GCN4. The ZIP-Bcr-Abl protein transforms Rat-1/myc cells, is autophosphorylated on tyrosine and localized predominantly to actin filaments. Thus, formation of homo-oligomers through either Bcr or GCN4 coiled-coil can activate the tyrosine kinase and F-actin binding functions of Abl. We also found that a Bcr-Abl fusion containing only Bcr amino acids (1-191) can efficiently transform Rat-1/myc cells. Fusion of additional Bcr sequences (aa 192-923) did not affect the transformation of Rat-1/myc cells but progressively reduced the disruptive effect on the actin cytoskeleton. In particular, the Dbl homology domain present in p210(Bcr-Abl) but not in p190(Bcr-Abl) contributes to the stabilization of actin fibers. The modulatory effect of Bcr sequences on actin structure may underlie the apparent pathogenic variations between the different Bcr-Abl fusion proteins.

Publication types

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

MeSH terms

  • Actins / ultrastructure
  • Animals
  • Cell Transformation, Neoplastic
  • Cells, Cultured
  • Cytoskeleton / ultrastructure
  • DNA, Neoplasm / genetics
  • Enzyme Activation
  • Fusion Proteins, bcr-abl / chemistry
  • Fusion Proteins, bcr-abl / physiology*
  • Humans
  • Leucine Zippers
  • Protein Binding
  • Protein Structure, Secondary
  • Proto-Oncogene Proteins c-abl / metabolism
  • Rats
  • Structure-Activity Relationship
  • src Homology Domains


  • Actins
  • DNA, Neoplasm
  • Fusion Proteins, bcr-abl
  • Proto-Oncogene Proteins c-abl