Defective DNA double-strand break repair underlies enhanced tumorigenesis and chromosomal instability in p27-deficient mice with growth factor-induced oligodendrogliomas.
Defective DNA double-strand break repair underlies enhanced tumorigenesis and chromosomal instability in p27-deficient mice with growth factor-induced oligodendrogliomas.
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DOI：
10.1038/onc.2009.465
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发表时间：
2010-03-25
期刊：
影响因子：
8
通讯作者：
Koff, A.
中科院分区：
文献类型：
--
作者：
See, W. L.;Miller, J. P.;Squatrito, M.;Holland, E.;Resh, M. D.;Koff, A.
cdk 抑制剂 Kip 家族的肿瘤抑制活性通常超出其调节细胞周期的作用。在这里，我们证明 p27 在双链 DNA 断裂修复过程中增强 Rad51 的积累。在缺乏 p27kip1 细胞周期蛋白-cdk 结合活性的小鼠中，PDGF 诱导的少突胶质细胞瘤的进展加速。细胞系是通过 RCAS-PDGF 感染培养物中的 nestin-tv-a 脑祖细胞而开发的。 p27缺陷不影响早期传代细胞系的细胞增殖；然而，p27 的缺失会影响染色体稳定性。在 p27 缺陷细胞中，与野生型细胞相比，Atm 和 Chk2 的激活以及 γH2AX 的积累未受影响，并且磷酸组蛋白 H3 染色有丝分裂细胞的数量减少，这与强大的 G2/M 检查点激活一致。然而，在 p27 缺陷细胞的裂解物中，Rad51 灶阳性细胞的百分比下降，并且靶向 BRCA2 C 末端（调节 BRCA2/Rad51 相互作用）的激酶活性增加。还观察到适应检查点的 p27 缺陷细胞中染色单体断裂数量增加。这些发现表明，p27 缺陷细胞中依赖于 Rad51 的双链断裂修复受到阻碍，导致染色体不稳定，这是预后不良的癌症的一个标志。
The tumor suppressive activities of the Kip-family of cdk inhibitors often go beyond their role in regulating the cell cycle. Here, we demonstrate that p27 enhances Rad51 accumulation during repair of double-strand DNA breaks. Progression of PDGF-induced oligodendrogliomas was accelerated in mice lacking the cyclin-cdk binding activities of p27kip1. Cell lines were developed from RCAS-PDGF infection of nestin-tv-a brain progenitor cells in culture. p27 deficiency did not affect cell proliferation in early passage cell lines; however, the absence of p27 affected chromosomal stability. In p27 deficient cells, the activation of Atm and Chk2, and the accumulation of γH2AX was unaffected compared to wild type cells, and the number of phospho-histone H3 staining mitotic cells was decreased, consistent with a robust G2/M checkpoint activation. However, the percentage of Rad51 foci positive cells was decreased, and the kinase activity that targets the C-terminus of BRCA2, regulating BRCA2/Rad51 interactions, was increased in lysates derived from p27 deficient cells. Increased numbers of chromatid breaks in p27 deficient cells that adapted to the checkpoint were also observed. These findings suggest that Rad51-dependent repair of double stranded breaks was hindered in p27 deficient cells, leading to chromosomal instability, a hallmark of cancers with poor prognosis.
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影响因子：
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