Proteomic analysis of β-catenin activation in mouse liver by DIGE analysis identifies glucose metabolism as a new target of the Wnt pathway
Proteomic analysis of β-catenin activation in mouse liver by DIGE analysis identifies glucose metabolism as a new target of the Wnt pathway
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DOI：
10.1002/pmic.200800609
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发表时间：
2009-08-01
期刊：
影响因子：
3.4
通讯作者：
Perret, Christine
中科院分区：
文献类型：
--
作者：
Chafey, Philippe;Finzi, Laetitia;Perret, Christine
Wnt/β-连环蛋白信号通路越来越多地参与肝脏发育和生理学。该通路的异常激活是在人类HCC发展过程中观察到的主要遗传事件之一。为了深入了解β-连环蛋白在肝脏中作用的机制，我们使用2-D DIGE结合MS在肝脏特异性缺失Apc导致β-连环蛋白信号传导急性激活的小鼠（Apc（KOliv）小鼠）中进行了定量差异蛋白质组学分析。我们鉴定了94个蛋白质点，这些蛋白质点在突变型Apc（KOliv）和对照小鼠之间显示差异表达，对应于56个单独的蛋白质。大多数鉴定的蛋白质与代谢途径相关，如氨和葡萄糖代谢。我们的分析表明，乳酸脱氢酶活性的增加，以及两个线粒体ATP酶亚基（ATP 5a 1和ATP 5 b）的下调。这些观察结果表明，β-连环蛋白信号传导可以诱导葡萄糖代谢从氧化磷酸化转变为糖酵解，称为“瓦尔堡效应”。F-18-fluoro-2-deoxy-D-glucose-positron emission tomography成像表明，肝脏中β-catenin诱导的特异性代谢重编程并不意味着糖酵解的第一步。这一观察结果可以解释为什么一些HCC难以通过氟-2-脱氧-D-葡萄糖-正电子发射断层扫描成像进行评估。
The Wnt/beta-catenin signaling pathway has been increasingly implicated in liver development and physiology. Aberrant activation of this pathway is one of the major genetic events observed during the process of human HCC development. To gain insight into the mechanism underlying beta-catenin action in the liver, we conducted a quantitative differential proteomic analysis using 2-D DIGE combined with MS, in mice with liver-specific deletion of Apc resulting in acute activation of beta-catenin signaling (Apc(KOliv) mice). We identified 94 protein spots showing differential expression between mutant Apc(KOliv) and control mice, corresponding to 56 individual proteins. Most of the proteins identified were associated with metabolic pathways, such as ammonia and glucose metabolism. Our analysis showed an increase in lactate dehydrogenase activity together with a downregulation of two mitochondrial ATPase subunits (ATP5a1 and ATP5b). These observations indicate that beta-catenin signaling may induce a shift in the glucose metabolism from oxidative phosphorylation to glycolysis, known as the "Warburg effect". Imaging with F-18-fluoro-2-deoxy-D-glucose-positron emission tomography suggests that the specific metabolic reprogramming induced by beta-catenin in the liver does not imply the first step of glycolysis. This observation may explain why some HCCs are difficult to assess by fluoro-2-deoxy-D-glucose-positron emission tomography imaging.