Effect of Bcr sequences on the cellular function of the Bcr-Abl oncoprotein.
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.
McWhirter
J R
JR
Department of Biology and Center for Molecular Genetics, University of California at San Diego, La Jolla 92093-0322, USA.
Wang
J Y
JY
D000199:Actins / Q000648:ultrastructure; D000818:Animals; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000648:ultrastructure; D004273:DNA, Neoplasm / Q000235:genetics; D004789:Enzyme Activation; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D016350:Leucine Zippers; D011485:Protein Binding; D017433:Protein Structure, Secondary; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D018909:src Homology Domains
D000199:Actins; D004273:DNA, Neoplasm; D016044:Fusion Proteins, bcr-abl; D016315:Proto-Oncogene Proteins c-abl