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.

中文翻译：

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非受体酪氨酸激酶 ABL 的 N 端结构域赋予蛋白质稳定性并抑制肿瘤发生。

染色体易位可导致嵌合蛋白的产生，从而可能成为致癌驱动因素。一个典型的例子是 RhoGEF 和 GTPase 的 BCR 激活剂与 ABL 原癌基因非受体酪氨酸激酶的融合，这是导致白血病的染色体异常（费城染色体）的结果。为了揭示 BCR-ABL 介导的肿瘤发生的机制，我们在这里比较了 ABL 和 BCR-ABL 融合的稳定性。通过蛋白质降解、细胞增殖、5-乙炔基-2-脱氧尿苷和细胞凋亡测定以及异种移植肿瘤分析，我们发现 BCR-ABL 融合中丢失的 ABL N 末端片段赋予了降解能力，由 SMAD 特异性 E3 泛素蛋白连接酶 1 促进。我们进一步证明，N 端缺失使 ABL 更加稳定，并刺激细胞生长和肿瘤发生。我们的研究结果表明，蛋白质稳定性的改变可能有助于染色体易位诱导的癌症发展。