Evidence for a regulatory role of Cullin-RING E3 ubiquitin ligase 7 in insulin signaling.
Evidence for a regulatory role of Cullin-RING E3 ubiquitin ligase 7 in insulin signaling.
复制标题
DOI：
10.1016/j.cellsig.2013.11.005
复制
发表时间：
2014-02
影响因子：
4.8
通讯作者：
Sarikas A
中科院分区：
文献类型：
--
作者：
Scheufele F;Wolf B;Kruse M;Hartmann T;Lempart J;Mühlich S;Pfeiffer AFH;Field LJ;Charron MJ;Pan ZQ;Engelhardt S;Sarikas A
胰岛素受体下游信号通路的功能失调在胰岛素抵抗和2型糖尿病的发病机制中起着关键作用。在这项研究中，我们报告了Cullin-RING E3泛素连接酶7（CRL 7）在调节胰岛素信号传导和葡萄糖稳态中的作用的体外和体内实验证据。我们发现Cul 7 −/−小鼠胚胎成纤维细胞在胰岛素刺激后显示出增强的AKT和Erk MAP激酶磷酸化。在C2 C12肌管中通过RNA干扰消耗CUL 7导致胰岛素信号传导途径和细胞葡萄糖摄取的活化增加，以及这些细胞执行胰岛素诱导的胰岛素受体底物1（IRS 1）降解的能力降低。在体内，与野生型对照相比，Cul 7或Fbxw 8（CRL 7的两个关键组分）的杂合性导致胰岛素刺激后骨骼肌组织中PI 3激酶/ AKT活化升高。最后，Cul 7 +/−或Fbxw 8 +/−小鼠表现出增强的胰岛素敏感性和血浆葡萄糖清除率。总的来说，我们的研究结果指出，在胰岛素介导的葡萄糖稳态的控制，通过抑制骨骼肌细胞中的PI 3激酶/ AKT活性的CRL 7尚未认识到的作用。
Dysfunctional regulation of signalling pathways downstream of the insulin receptor plays a pivotal role in the pathogenesis of insulin resistance and type 2 diabetes. In this study we report both in vitro and in vivo experimental evidence for a role of Cullin-RING E3 ubiquitin ligase 7 (CRL7) in the regulation of insulin signalling and glucose homeostasis. We show that Cul7−/− mouse embryonic fibroblasts displayed enhanced AKT and Erk MAP kinase phosphorylation upon insulin stimulation. Depletion of CUL7 by RNA interference in C2C12 myotubes led to increased activation of insulin signalling pathways and cellular glucose uptake, as well as a reduced capacity of these cells to execute insulin-induced degradation of insulin receptor substrate 1 (IRS1). In vivo, heterozygosity of either Cul7 or Fbxw8, both key components of CRL7, resulted in elevated PI3 kinase / AKT activation in skeletal muscle tissue upon insulin stimulation when compared to wild-type controls. Finally, Cul7+/− or Fbxw8+/− mice exhibited enhanced insulin sensitivity and plasma glucose clearance. Collectively, our findings point to a yet unrecognized role of CRL7 in insulin-mediated control of glucose homeostasis by restraining PI3 kinase / AKT activities in skeletal muscle cells.
登录
查看更多内容
影响因子：
158.5
作者：
SHULMAN, GI;ROTHMAN, DL;SHULMAN, RG
通讯作者：
SHULMAN, RG
影响因子：
7.7
作者：
Pederson, TM;Kramer, DL;Rondinone, CM
通讯作者：
Rondinone, CM
DOI：
10.1073/pnas.1733908100
发表时间：
2003-08-19
影响因子：
11.1
作者：
Arai, T;Kasper, JS;DeCaprio, JA
通讯作者：
DeCaprio, JA
影响因子：
82.9
作者：
Stenbit, AE;Tsao, TS;Charron, MJ
通讯作者：
Charron, MJ
影响因子：
7.7
作者：
Sun, XJ;Goldberg, JL;Mitchell, JJ
通讯作者：
Mitchell, JJ