HuR inhibits apoptosis by amplifying Akt signaling through a positive feedback loop.
HuR inhibits apoptosis by amplifying Akt signaling through a positive feedback loop.
复制标题
DOI：
10.1002/jcp.24120
复制
发表时间：
2013-01
影响因子：
5.6
通讯作者：
Lee, Beth S.
中科院分区：
文献类型：
--
作者：
Singh, Mamata;Martinez, Alaina R.;Govindaraju, Suman;Lee, Beth S.
人类抗原R(Hur)是一种转录后的基因表达调节因子，在细胞应激过程中稳定mRNAs，提高存活率方面起着关键作用。HUR的表达通过多个转录和转录后调控受到严格调控。虽然已知HUR可以稳定参与细胞生存的mRNAs的一个子集，但它在PI3-K/Akt信号的生存途径中的作用尚不清楚。在这里，我们表明，在肾近端小管细胞中，HUR通过在正反馈环中放大Akt信号而在细胞存活中发挥核心作用。这个反馈环的关键是Hur介导的编码Grb10的mRNA的稳定，Grb10是一种接头蛋白，其表达对Akt的激活至关重要。通过与Grb10相互作用来刺激Akt，然后激活NF-κB，从而进一步增强Hur基因和蛋白的表达。这种反馈环在非应激细胞中是活跃的，但它的影响在应激过程中会增强。因此，本研究证明了HUR在Akt信号转导中的核心作用，并揭示了HUR水平低于或高于正常水平的轻微变化可能被放大，从而潜在地导致细胞死亡或细胞转化的机制。
Human antigen R (HuR) is a post-transcriptional regulator of gene expression that plays a key role in stabilizing mRNAs during cellular stress, leading to enhanced survival. HuR expression is tightly regulated through multiple transcription and post-transcriptional controls. Although HuR is known to stabilize a subset of mRNAs involved in cell survival, its role in the survival pathway of PI3-kinase/Akt signaling is unclear. Here, we show that in renal proximal tubule cells, HuR performs a central role in cell survival by amplifying Akt signaling in a positive feedback loop. Key to this feedback loop is HuR-mediated stabilization of mRNA encoding Grb10, an adaptor protein whose expression is critical for Akt activation. Stimulation of Akt by interaction with Grb10 then activates NF-κB, which further enhances HuR mRNA and protein expression. This feedback loop is active in unstressed cells, but its effects are increased during stress. Therefore, this study demonstrates a central role for HuR in Akt signaling and reveals a mechanism by which modest changes in HuR levels below or above normal may be amplified, potentially resulting in cell death or cellular transformation.
登录
查看更多内容
影响因子：
4.1
作者：
Guo X;Wu Y;Hartley RS
通讯作者：
Hartley RS
DOI：
10.4161/cc.9.7.11164
发表时间：
2010-04-01
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Abdelmohsen K;Kim MM;Srikantan S;Mercken EM;Brennan SE;Wilson GM;Cabo Rd;Gorospe M
通讯作者：
Gorospe M
影响因子：
4.5
作者：
Gallouzi, IE;Brennan, CM;Steitz, JA
通讯作者：
Steitz, JA
DOI：
10.1073/pnas.1532175100
发表时间：
2003-07-08
影响因子：
11.1
作者：
Charalambous, M;Smith, FM;Ward, A
通讯作者：
Ward, A
影响因子：
2.8
作者：
Hu, Zhi-qian;Zhang, Jia-yi;Mao, Yu-min
通讯作者：
Mao, Yu-min