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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. © 2020 Yan et al.


Zhengwei Yan, Karthigayan Shanmugasundaram, Dongwen Ma, Jiayu Luo, Shiwen Luo, Hai Rao. The N-terminal domain of the non-receptor tyrosine kinase ABL confers protein instability and suppresses tumorigenesis. The Journal of biological chemistry. 2020 Jul 03;295(27):9069-9075

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PMID: 32439806

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