Activation of the PI3K/Akt signal transduction pathway and increased levels of insulin receptor in protein repair-deficient mice
Activation of the PI3K/Akt signal transduction pathway and increased levels of insulin receptor in protein repair-deficient mice
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DOI：
10.1111/j.1474-9728.2004.00136.x
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发表时间：
2005-02-01
期刊：
影响因子：
7.8
通讯作者：
Clarke, S
中科院分区：
文献类型：
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作者：
Farrar, C;Houser, CR;Clarke, S
蛋白质L-异天冬氨酸（D-天冬氨酸）O-甲基转移酶是一种催化蛋白质中异戊酰损伤修复的酶。与野生型小鼠（Pcmt 1 +/+小鼠）相比，缺乏这种酶的小鼠（Pcmt 1-/-小鼠）的大脑大小逐渐增加，这是一种可能与PI 3 K/Akt信号转导途径改变相关的表型。在这里，我们表明，这一途径的组成部分，包括Akt，GSK 3 β和PDK-1，更高度磷酸化的Pcmt 1-/-小鼠的大脑中，特别是在海马细胞，与Pcmt 1 +/+小鼠相比。在海马体中的这一途径的上游元素的检查显示，Pcmt 1-/-小鼠有增加的胰岛素样生长因子-I（IGF-I）受体和/或胰岛素受体的激活。蛋白质印迹分析显示Pcmt 1-/-小鼠海马中胰岛素受体蛋白水平增加约200%，IGF-I受体蛋白水平增加约50%。在成年大脑的其他区域以及青少年和成年Pcmt 1-/-小鼠的大脑、肝脏、心脏和睾丸的全组织提取物中也发现了更高水平的胰岛素受体蛋白。在葡萄糖耐量试验期间，成年Pcmt 1-/-小鼠的血浆胰岛素水平无显著差异。然而，他们确实显示出更高的血糖峰值水平，表明葡萄糖耐量轻度受损。我们提出，Pcmt 1-/-小鼠改变了胰岛素途径的调节，可能是作为一种补偿性反应，改变葡萄糖摄取或代谢或作为一种适应性反应，在大脑和其他组织中的异戊酰蛋白损伤的一般积累。
Protein L-isoaspartate (D-aspartate) O-methyltransferase is an enzyme that catalyses the repair of isoaspartyl damage in proteins. Mice lacking this enzyme (Pcmt1-/- mice) have a progressive increase in brain size compared with wild-type mice (Pcmt1+/+ mice), a phenotype that can be associated with alterations in the PI3K/Akt signal transduction pathway. Here we show that components of this pathway, including Akt, GSK3beta and PDK-1, are more highly phosphorylated in the brains of Pcmt1-/- mice, particularly in cells of the hippocampus, in comparison with Pcmt1+/+ mice. Examination of upstream elements of this pathway in the hippocampus revealed that Pcmt1-/- mice have increased activation of insulin-like growth factor-I (IGF-I) receptor and/or insulin receptor. Western blot analysis revealed an approximate 200% increase in insulin receptor protein levels and an approximate 50% increase in IGF-I receptor protein levels in the hippocampus of Pcmt1-/- mice. Higher levels of the insulin receptor protein were also found in other regions of the adult brain and in whole tissue extracts of brain, liver, heart and testes of both juvenile and adult Pcmt1-/- mice. There were no significant differences in plasma insulin levels for adult Pcmt1-/- mice during glucose tolerance tests. However, they did show higher peak levels of blood glucose, suggesting a mild impairment in glucose tolerance. We propose that Pcmt1-/- mice have altered regulation of the insulin pathway, possibly as a compensatory response to altered glucose uptake or metabolism or as an adaptive response to a general accumulation of isoaspartyl protein damage in the brain and other tissues.