Abstract
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.
Highlights
More than 500 chromosome translocation events have been tied to cancers, accounting for ;20% of malignant tumors [1, 2]
Significant proportions of chronic myeloid leukemia and acute lymphocytic leukemia cases are tied to the Philadelphia chromosome translocation [3], a reciprocal exchange of DNA between chromosome 22 and chromosome 9, producing a chimeric protein, BCR-ABL, with tyrosine kinase activity [4,5,6]
ABL is rapidly degraded by the proteasome, which is promoted by the SMAD-specific E3 ubiquitin protein ligase 1 (Smurf1) ubiquitin ligase and is dependent on the first 45 amino acids of ABL, which are missing in the BCR-ABL fusion
Summary
ABL turnover is faster than that of BCR-ABL and is mediated by the ubiquitin-proteasome system. Ubiquitylated ABL species were detected in cells expressing FLAGABL (Fig. 1I) and were enriched upon the addition of MG132 (Fig. 1I) These results suggest that ABL degradation is mediated by the ubiquitin-proteasome system. Given the distinct degradation rates of BCR-ABL and ABL (Fig. 1), we wondered whether the N-terminal segment is key to ABL turnover To evaluate this conjecture, we assessed the stability of the ABL445 deletion mutant, lacking the first 45 amino acids. We examined whether ABL445 expression could inhibit GM-CSF deprivation-induced apoptosis Both ABL445 and BCR-ABL markedly reduced apoptosis (Fig. 4E), suggesting that ABL445 promotes cell growth and survival. The effect of ABL derivatives on tumor growth was evaluated by monitoring the tumor volume for mice bearing BCRABL, ABL445, ABL, or vector control (Fig. 5B). The results indicate that ABL445 expression promotes tumorigenesis in vivo
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