Overexpression of NBS1 contributes to transformation through the activation of phosphatidylinositol 3-kinase/Akt
Overexpression of NBS1 contributes to transformation through the activation of phosphatidylinositol 3-kinase/Akt
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DOI：
10.1074/jbc.m501449200
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发表时间：
2005-09-16
影响因子：
4.8
通讯作者：
Wu, KJ
中科院分区：
文献类型：
--
作者：
Chen, YC;Su, YN;Wu, KJ
奈megen断裂综合征（NBS）是一种染色体不稳定综合征，与癌症易感性、放射敏感性、小头畸形和生长迟缓有关。NBS基因产物NBS1 （p95）或nibrin是hMre11复合体的一部分，是与双链断裂修复相关的核心参与者。我们之前证明了c-Myc直接激活NBS1的表达。本研究表明，NBS1在Rat1a和HeLa细胞中的组成性表达诱导/增强了它们的转化。使用短干扰RNA抑制内源性NBS1水平可降低两种肿瘤细胞系的转化活性。40-52%的非小细胞肺癌、肝癌和食管癌样本中NBS1表达升高。NBS1过表达刺激磷脂酰肌醇（PI） 3激酶活性，导致Akt及其下游靶点如糖原合成酶激酶3 β和哺乳动物雷帕霉素靶点在不同细胞系和肿瘤样品中的磷酸化水平升高。一种pi3激酶抑制剂（LY294002）可以抑制NBS1过表达诱导的转化。通过短干扰RNA抑制内源性Akt表达降低了过表达NBS1的Rat1a细胞的转化活性。这些结果表明，NBS1的过表达是一个致癌事件，通过激活pi3激酶/Akt促进转化。
Nijmegen breakage syndrome (NBS) is a chromosomal instability syndrome associated with cancer predisposition, radiosensitivity, microcephaly, and growth retardation. The NBS gene product, NBS1 (p95) or nibrin, is a part of the hMre11 complex, a central player associated with double strand break repair. We previously demonstrated that c-Myc directly activates NBS1 expression. Here we have shown that constitutive expression of NBS1 in Rat1a and HeLa cells induces/enhances their transformation. Repression of endogenous NBS1 levels using short interference RNA reduces the transformation activity of two tumor cell lines. Increased NBS1 expression is observed in 40-52% of non-small cell lung carcinoma, hepatoma, and esophageal cancer samples. NBS1 overexpression stimulates phosphatidylinositol ( PI) 3-kinase activity, leading to increased phosphorylation levels of Akt and its downstream targets such as glycogen synthase kinase 3 beta and mammalian target of rapamycin in different cell lines and tumor samples. Transformation induced by NBS1 overexpression can be inhibited by a PI3-kinase inhibitor (LY294002). Repression of endogenous Akt expression by short interference RNA decreases the transformation activity of Rat1a cells overexpressing NBS1. These results indicate that overexpression of NBS1 is an oncogenic event that contributes to transformation through the activation of PI3-kinase/Akt.