Zhengwei Yan, Karthigayan Shanmugasundaram, Dongwen Ma, Jiayu Luo, Shiwen Luo, Hai Rao
The Journal of biological chemistry 2020 Jul 03Chromosome 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
PMID: 32439806
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