Dependence of dexamethasone-induced Akt/FOXO1 signaling, upregulation of MAFbx, and protein catabolism upon the glucocorticoid receptor
Dependence of dexamethasone-induced Akt/FOXO1 signaling, upregulation of MAFbx, and protein catabolism upon the glucocorticoid receptor
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DOI：
10.1016/j.bbrc.2008.11.123
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发表时间：
2009-01-16
影响因子：
3.1
通讯作者：
Cardozo, Christopher
中科院分区：
文献类型：
--
作者：
Zhao, Weidong;Qin, Weiping;Cardozo, Christopher
肌肉泛素连接酶MAFbx和MuRF1在肌肉萎缩中上调并促进肌肉萎缩。糖皮质激素对MAFbx和MuRF1的上调与Akt活性降低导致的FOXO 1和FOXO 3A活化有关。我们确定了C2C12细胞中这些生物反应对糖皮质激素受体（GR）的需求，在C2C12细胞中，GR表达被稳定表达的shRNA敲低。GR的丢失阻止了地塞米松诱导的蛋白质催化剂的增加。GR的丧失或用RU486抑制配体与GR的结合，阻止了地塞米松对MAFbx和MuRF1的上调。GR的丢失也阻止了地塞米松诱导的Akt磷酸化的减少，以及未磷酸化的FOXO 1部分的增加。这一发现确立了GR在激活促进肌肉蛋白质催化的分子信号中的需要。爱思唯尔公司出版
The muscle ubiquitin ligases MAFbx and MuRF1 are upregulated in and promote muscle atrophy. Upregulation of MAFbx and MuRF1 by glucocorticoids has been linked to activation of FOXO1 and FOXO3A resulting from reduced Akt activity. We determined the requirements for the glucocorticoid receptor (GR) in these biological responses in C2C12 cells in which GR expression was knocked down by stable expression of an shRNA. Loss of GR prevented dexamethasone-induced increases in protein catabolism. Loss of GR. or inhibition of ligand binding to GR with RU486, prevented upregulation of MAFbx and MuRF1 by dexamethasone. Loss of GR also prevented dexamethasone-induced decreases in Akt phosphorylation, and increases in the fraction of FOXO1 that was unphosphorylated. The findings establish a requirement for the GR in activating molecular signals that promote muscle protein catabolism. Published by Elsevier Inc.