Abstract
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 p190Bcr-Abl which is mostly found in acute lymphocytic leukemia (ALL), whereas fusion of the N-terminal 902 or 927 amino acids of Bcr generates p210Bcr-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 p210Bcr-Abl but not in p190Bcr-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.
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McWhirter, J., Wang, J. Effect of Bcr sequences on the cellular function of the Bcr-Abl oncoprotein. Oncogene 15, 1625–1634 (1997). https://doi.org/10.1038/sj.onc.1201342
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DOI: https://doi.org/10.1038/sj.onc.1201342
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