A kinase-independent role for unoccupied insulin and IGF-1 receptors in the control of apoptosis.
A kinase-independent role for unoccupied insulin and IGF-1 receptors in the control of apoptosis.
复制标题
DOI：
10.1126/scisignal.2001173
复制
发表时间：
2010-12-07
影响因子：
7.3
通讯作者：
Kahn CR
中科院分区：
文献类型：
--
作者：
Boucher J;Macotela Y;Bezy O;Mori MA;Kriauciunas K;Kahn CR
胰岛素和胰岛素样生长因子1（IGF-1）作为抗凋亡激素。我们意外地发现，缺乏胰岛素和IGF-1受体（分别为IR和IGF 1 R）的双敲除（DKO）细胞对通过内源性或外源性途径诱导的细胞凋亡具有抗性。这种对凋亡的抗性与促凋亡蛋白Bax的丰度降低和抗凋亡蛋白Bcl-2、Bcl-xL、XIAP和Flip的丰度增加有关。这些蛋白质丰度的变化主要涉及转录后机制。胰岛素或IGF-1受体对DKO细胞的恢复也恢复了它们对凋亡的敏感性。值得注意的是，胰岛素受体的催化失活突变形式的表达也恢复了对细胞凋亡的易感性。因此，胰岛素和IGF-1受体在控制细胞存活方面具有双向作用，并且可以被视为先前未鉴定的依赖性受体。胰岛素和IGF-1结合刺激受体酪氨酸激酶活性并阻断细胞凋亡，而未配体的胰岛素和IGF-1受体通过独立于其催化活性的机制起作用，对细胞死亡产生容许作用。
Insulin and insulin-like growth factor 1 (IGF-1) act as anti-apoptotic hormones. We found that, unexpectedly, double knockout (DKO) cells that lacked both insulin and IGF-1 receptors (IR and IGF1R, respectively), were resistant to apoptosis induced through either the intrinsic or extrinsic pathway. This resistance to apoptosis was associated with decreased abundance of the pro-apoptotic protein Bax and increases in abundance of the anti-apoptotic proteins Bcl-2, Bcl-xL, XIAP, and Flip. These changes in protein abundance involved primarily post-transcriptional mechanisms. Restoration of the insulin or IGF-1 receptor to DKO cells also restored their sensitivity to apoptosis. Notably, expression of a catalytically inactive mutant form of the insulin receptor also restored susceptibility to apoptosis. Thus, the insulin and IGF-1 receptors have bidirectional roles in the control of cell survival and can be viewed as previously-unidentified dependence receptors. Insulin and IGF-1 binding stimulates receptor tyrosine kinase activity and blocks apoptosis, whereas unliganded insulin and IGF-1 receptors, acting through a mechanism independent of their catalytic activity, exert a permissive effect on cell death.
登录
查看更多内容
影响因子：
64.5
作者：
Du, CY;Fang, M;Wang, XD
通讯作者：
Wang, XD
影响因子：
5.3
作者：
Laustsen, Palle G.;Russell, Steven J.;Kahn, C. Ronald
通讯作者：
Kahn, C. Ronald
影响因子：
64.8
作者：
Irmler, M;Thome, M;Tschopp, J
通讯作者：
Tschopp, J
影响因子：
2.7
作者：
Louvi, A;Accili, D;Efstratiadis, A
通讯作者：
Efstratiadis, A
影响因子：
3.7
作者：
Navarro, P;Valverde, AM;Lorenzo, M
通讯作者：
Lorenzo, M