Interplay between Menin and K-Ras in Regulating Lung Adenocarcinoma*
Interplay between Menin and K-Ras in Regulating Lung Adenocarcinoma*
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DOI：
10.1074/jbc.m112.382416
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发表时间：
2012-10
期刊：
影响因子：
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通讯作者：
Yuan Wu;Zijie Feng;Shu-Bin Gao;Smita S Matkar;Bin Xu;H. Duan;Xiao Lin;Shan-Hua Li;X. Hua;G. Jin
中科院分区：
文献类型：
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作者：
Yuan Wu;Zijie Feng;Shu-Bin Gao;Smita S Matkar;Bin Xu;H. Duan;Xiao Lin;Shan-Hua Li;X. Hua;G. Jin
背景：MEN 1基因在肺癌发生发展中的作用尚不清楚。结果如下：K-Ras通过增加DNA甲基化来抑制menin表达，而menin通过抑制Ras的活化来抑制Ras介导的信号传导。结论：K-Ras与menin的相互作用在肺癌的发生发展中起重要的调控作用。意义：这些结果揭示了menin介导的肺癌抑制的新机制。MEN 1编码核蛋白menin，在肺癌中作为肿瘤抑制因子，在人原发性肺腺癌中经常失活。在这里，我们表明MEN 1的失活与K-Ras在MEN 1启动子处的DNA甲基化增加有关。一方面，激活的K-Ras上调DNA甲基转移酶的表达，并增强DNA甲基转移酶1与MEN 1启动子的结合，导致肺癌细胞MEN 1基因的DNA甲基化增加;另一方面，menin至少部分通过阻止GRB 2和SOS 1与Ras结合来降低活性Ras-GTP的水平，而不影响GRB 2和SOS 1的表达。在人肺腺癌样品中，我们进一步证明了menin表达的降低与Ras表达的增强相关（p < 0.05）。最后，Men 1基因的切除显著加速了Men 1f/f; K-RasG 12 D/+;Cre ER小鼠模型中K-RasG 12 D诱导的肿瘤形成。总之，这些发现揭示了活化的K-Ras和menin之间以前未知的联系，这是肺癌发展中肿瘤活化和抑制的重要相互作用。
Background: The role of MEN1 gene in development of lung cancer is poorly understood. Results: K-Ras inhibits menin expression via increasing DNA methylation, whereas menin inhibits Ras-mediated signaling via suppressing activation of Ras. Conclusion: The interplay between K-Ras and menin plays an important role in regulating the development of lung cancer. Significance: These results have unraveled a novel mechanism underlying menin-mediated repression of lung cancer. MEN1, which encodes the nuclear protein menin, acts as a tumor suppressor in lung cancer and is often inactivated in human primary lung adenocarcinoma. Here, we show that the inactivation of MEN1 is associated with increased DNA methylation at the MEN1 promoter by K-Ras. On one hand, the activated K-Ras up-regulates the expression of DNA methyltransferases and enhances the binding of DNA methyltransferase 1 to the MEN1 promoter, leading to increased DNA methylation at the MEN1 gene in lung cancer cells; on the other hand, menin reduces the level of active Ras-GTP at least partly by preventing GRB2 and SOS1 from binding to Ras, without affecting the expression of GRB2 and SOS1. In human lung adenocarcinoma samples, we further demonstrate that reduced menin expression is associated with the enhanced expression of Ras (p < 0.05). Finally, excision of the Men1 gene markedly accelerates the K-RasG12D-induced tumor formation in the Men1f/f;K-RasG12D/+;Cre ER mouse model. Together, these findings uncover a previously unknown link between activated K-Ras and menin, an important interplay governing tumor activation and suppression in the development of lung cancer.