6月29日，《神經(jīng)科學(xué)期刊》（The Journal of Neuroscience）發(fā)表了中科院生物物理研究所腦與認(rèn)知國(guó)家重點(diǎn)實(shí)驗(yàn)室袁增強(qiáng)研究組有關(guān)c-Abl-MST1信號(hào)通路介導(dǎo)的氧化壓力條件下神經(jīng)細(xì)胞凋亡的最新研究成果,。該項(xiàng)工作由博士研究生肖磊等在袁增強(qiáng)研究員的指導(dǎo)下完成,。
氧化壓力影響細(xì)胞的生存和穩(wěn)態(tài)，參與了包括神經(jīng)退行性疾病的病理過程等在內(nèi)的各種生物學(xué)進(jìn)程,，而氧化壓力是如何影響這些生命進(jìn)程的分子機(jī)制仍有待闡明,。袁增強(qiáng)研究員在哈佛大學(xué)的一系列研究工作已經(jīng)闡明，蛋白激酶MST1通過直接激活轉(zhuǎn)錄因子FOXO介導(dǎo)了氧化壓力條件下神經(jīng)細(xì)胞的凋亡,，然而MST1的上游調(diào)控機(jī)制尚不清楚,。
以此為出發(fā)點(diǎn)，肖磊等發(fā)現(xiàn)了在氧化壓力條件下,，酪氨酸激酶c-Abl作為上游激酶,，可以引起MST1在酪氨酸433位點(diǎn)的磷酸化 (如圖)，而這一磷酸化穩(wěn)定并激活了MST1,。一方面,，泛素連接酶CHIP介導(dǎo)了MST1泛素化降解過程，c-Abl通過磷酸化MST1抑制了其泛素化降解途徑從而穩(wěn)定了MST1,；另一方面,，氧化壓力引起的MST1酪氨酸433位點(diǎn)的磷酸化加強(qiáng)了MST1與FOXO3之間的相互作用進(jìn)而激活FOXO3的促凋亡轉(zhuǎn)錄功能。
進(jìn)一步的研究表明,，c-Abl介導(dǎo)的MST1酪氨酸433位點(diǎn)的磷酸化對(duì)于氧化壓力引起的體外原代培養(yǎng)和在體的海馬神經(jīng)元的細(xì)胞凋亡至關(guān)重要,。該研究闡明了c-Abl-MST1信號(hào)通路可能參與了神經(jīng)退行性疾病的病理過程，對(duì)于治療以神經(jīng)細(xì)胞凋亡為特征的老年癡呆癥和帕金森氏病等神經(jīng)退行性疾病提供了理論基礎(chǔ)和潛在的藥物設(shè)計(jì)靶標(biāo),，具有一定的應(yīng)用前景,。
該工作得到了國(guó)家自然科學(xué)基金，科技部等項(xiàng)目的支持,。（生物谷Bioon.com）
生物谷推薦原文出處：
The Journal of Neuroscience doi: 10.1523/?JNEUROSCI.0035-11.2011
The c-Abl-MST1 Signaling Pathway Mediates Oxidative Stress-Induced Neuronal Cell Death
Lei Xiao, Dongmei Chen, Peng Hu, Junbing Wu, Weizhe Liu, Yanhong Zhao, Mou Cao, Yuan Fang, Wenzhi Bi, Zheng Zheng, Jian Ren, Guangju Ji, Yan Wang, and Zengqiang Yuan
Oxidative stress influences cell survival and homeostasis, but the mechanisms underlying the biological effects of oxidative stress remain to be elucidated. The protein kinase MST1 (mammalian Ste20-like kinase 1) plays a major role in oxidative stress-induced cell death in primary mammalian neurons. However, the mechanisms that regulate MST1 in oxidative stress responses remain largely unknown. In the present study, we demonstrate that the protein kinase c-Abl phosphorylates MST1 at Y433, which triggers the stabilization and activation of MST1. Inhibition of c-Abl promotes the degradation of MST1 through C terminus of Hsc70-interacting protein (CHIP)-mediated ubiquitination, and thereby attenuates cell death. Oxidative stress induces the c-Abl-dependent tyrosine phosphorylation of MST1 and increases the interaction between MST1 and FOXO3 (Forkhead box O3), thereby activating the MST1-FOXO signaling pathway, leading to cell death in both primary culture neurons and rat hippocampal neurons. The identification of the c-Abl tyrosine kinase as a novel upstream activator of MST1 suggests that the c-Abl-MST1 signaling cascade plays an important role in cellular responses to oxidative stress.
