Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 295, Issue 27, Pages 9069-9075Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA120.012821
Keywords
ubiquitin; proteolysis; leukemia; oncogene; chromosome translocation; BCR activator of RhoGEF and GTPase; ABL proto-oncogene non-receptor tyrosine kinase; SMAD-specific E3 ubiquitin protein ligase 1 (Smurf1); protein chimera; Philadelphia chromosome; protein degradation; ABL kinase; chromosome rearrangement
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Funding
- Cancer Prevention Institute of Texas [RP170686, RP180769]
- Mays Cancer Center
- William & Ella Owens Medical Research Foundation
- National Natural Science Foundation of China [31671476]
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Chromosome translocation can lead to chimeric proteins that may become oncogenic drivers. A classic example is the fusion of the BCR activator of RhoGEF and GTPase and the ABL proto-oncogene nonreceptor tyrosine kinase, a result of a chromosome abnormality (Philadelphia chromosome) that causes leukemia. To unravel the mechanism underlying BCR-ABL?mediated tumorigenesis, here we compared the stability of ABL and the BCR-ABL fusion. Using protein degradation, cell proliferation, 5-ethynyl-2-deoxyuridine, and apoptosis assays, along with xenograft tumor analysis, we found that the N-terminal segment of ABL, which is lost in the BCR-ABL fusion, confers degradation capacity that is promoted by SMAD-specific E3 ubiquitin protein ligase 1. We further demonstrate that the N-terminal deletion renders ABL more stable and stimulates cell growth and tumorigenesis. The findings of our study suggest that altered protein stability may contribute to chromosome translocation-induced cancer development.
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