Department of Molecular and Cellular Biochemistry, University of Kentucky, 741 S. Limestone Street, BBSRB, Lexington, KY 40536-0509, United States.
Neurosci Lett. 2012 Dec 7;531(2):125-30. doi: 10.1016/j.neulet.2012.10.036. Epub 2012 Nov 2.
Rit, along with Rin and Drosophila Ric, comprises the Rit subfamily of Ras-related small GTPases. Although the cellular functions of many Ras family GTPases are well established, the physiological significance of Rit remains poorly understood. Loss of Rit sensitizes multiple mammalian cell lines and mouse embryonic fibroblasts (MEFs) derived from Rit(-/-) mice to oxidative stress-mediated apoptosis. However, whether Rit-mediated pro-survival signaling extends to other cell types, particularly neurons, is presently unknown. Here, to examine these issues we generated a transgenic mouse overexpressing constitutively active Rit (Rit(Q79L)) exclusively in neurons, under control of the Synapsin I promoter. Active Rit-expressing hippocampal neurons display a dramatic increase in oxidative stress resistance. Moreover, pharmacological inhibitor studies demonstrate that p38 MAPK, rather than a MEK/ERK signaling cascade, is required for Rit-mediated protection. Together, the present studies identify a critical role for the Rit-p38 MAPK signaling cascade in promoting hippocampal neuron survival following oxidative stress.
Rit 与 Rin 和 Drosophila Ric 一起构成 Ras 相关小分子 GTP 酶的 Rit 亚家族。尽管许多 Ras 家族 GTP 酶的细胞功能已经得到很好的证实，但 Rit 的生理意义仍知之甚少。 Rit 的缺失使多种哺乳动物细胞系和源自 Rit(-/-) 小鼠的小鼠胚胎成纤维细胞 (MEF) 对氧化应激介导的细胞凋亡敏感。然而， Rit 介导的生存信号是否扩展到其他细胞类型，特别是神经元，目前尚不清楚。在这里，为了研究这些问题，我们生成了一种在神经元中特异性过表达组成性激活 Rit (Rit(Q79L)) 的转基因小鼠，受突触素 I 启动子的控制。活性 Rit 表达的海马神经元显示出氧化应激抗性的显著增加。此外，药理学抑制剂研究表明，p38 MAPK 而不是 MEK/ERK 信号级联反应，是 Rit 介导的保护所必需的。总之，本研究确定了 Rit-p38 MAPK 信号级联在促进氧化应激后海马神经元存活中的关键作用。
