Catalytic subunit of DNA-dependent protein kinase: Impact on lymphocyte development and tumorigenesis
Catalytic subunit of DNA-dependent protein kinase: Impact on lymphocyte development and tumorigenesis
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DOI：
10.1073/pnas.96.4.1403
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发表时间：
1999-02-16
影响因子：
11.1
通讯作者：
Li, GC
中科院分区：
文献类型：
--
作者：
Kurimasa, A;Ouyang, H;Li, GC
DNA依赖蛋白激酶(DNA-PK)由一个异源二聚体DNA结合复合体Ku70和Ku80和一个大的催化亚基DNA-PKcs组成。为了研究DNA-PKcs在淋巴细胞发育、辐射敏感性和肿瘤发生中的作用，我们通过同源重组破坏了小鼠DNA-PKcs。DNA-PKcs基因缺失的小鼠既不表现出生长迟缓，也不表现出高发生率的T细胞淋巴瘤，但表现出严重的免疫缺陷和辐射过敏。与Ku70-/-和Ku80-/-表型不同，DNA-PKcs缺失小鼠的V(D)J编码被阻断，但不能形成信号端关节。此外，DNA-PKcs的失活导致肠粘膜的增殖和异常发育，并产生异常的隐窝病灶，提示DNA-PKcs在肿瘤抑制中的新作用。
The DNA-dependent protein kinase (DNA-PK) consists of a heterodimer DNA-binding complex, Ku70 and Ku80, and a large catalytic subunit, DNA-PKcs, To examine the role of DNA-PKcs in lymphocyte development, radiation sensitivity, and tumorigenesis, we disrupted the mouse DNA-PKcs by homologous recombination. DNA-PKcs-null mice exhibit neither growth retardation nor a high frequency of T cell lymphoma development, but show severe immunodeficiency and radiation hypersensitivity. In contrast to the Ku70-/- and Ku80-/- phenotype, DNA-PKcs-null mice are blocked for V(D)J coding but not for signal-end joint formation. Furthermore, inactivation of DNA-PKcs leads to hyperplasia and dysplasia of the intestinal mucosa and production of aberrant crypt foci, suggesting a novel role of DNA-PKcs in tumor suppression.