NFκB1 (p50) suppresses SOD2 expression by inhibiting FoxO3a transactivation in a miR190/PHLPP1/Akt-dependent axis.
NFκB1 (p50) suppresses SOD2 expression by inhibiting FoxO3a transactivation in a miR190/PHLPP1/Akt-dependent axis.
复制标题
DOI：
10.1091/mbc.e13-06-0343
复制
发表时间：
2013-11
影响因子：
3.3
通讯作者：
Huang C
中科院分区：
文献类型：
--
作者：
Du K;Yu Y;Zhang D;Luo W;Huang H;Chen J;Gao J;Huang C
本研究报道了p50通过不依赖nfκ b的途径调控SOD2转录的新功能。p50调控的FoxO3a磷酸化和反式激活有助于SOD2转录，p50下调的PHLPP1通过miR190翻译负责Akt和FoxO3a的激活。核因子κB1 （NFκB1; p50）由于缺乏转录结构域，其生物学功能尚未像NFκB家族其他成员那样得到广泛研究。我们最近的研究表明，p50通过抑制GADD45α蛋白降解和增加p53蛋白翻译而发挥凋亡介质的作用。在这里，我们报道了p50通过不依赖nfκ b的途径调节超氧化物歧化酶2 （SOD2）转录的新功能。我们发现，小鼠胚胎成纤维细胞（MEFs; p50−/−）中p50的缺失在蛋白和mRNA水平上上调了SOD2的表达。与野生型（WT） MEF （p50+/+）细胞相比，p50−/−细胞中SOD2启动子驱动的荧光素酶也上调，表明p50在转录水平上调控SOD2。我们的研究结果还表明，与WT细胞相比，p50缺陷特异性地导致磷酸化下调和FoxO3a的反激活增加。进一步研究表明，p50下调FoxO3a磷酸化是由活化的Akt通过上调microRNA 190 （miR190）介导的，从而抑制PH结构域和富亮氨酸重复蛋白磷酸酶1 （PHLPP1）的翻译。我们的研究共同确定了p50通过调节miR190/PHLPP1/Akt-FoxO3a通路调控SOD2转录的新功能，这为p50的生理功能提供了重要的见解。
This study reports a novel function of p50 in its regulation of SOD2 transcription via an NFκB-independent pathway. p50-regulated FoxO3a phosphorylation and transactivation contributes to SOD2 transcription, and p50–down-regulated PHLPP1 translation via miR190 is responsible for activation of Akt and FoxO3a. The biological functions of nuclear factor κB1 (NFκB1; p50) have not been studied as often as those of other members of the NFκB family due to its lack of a transcriptional domain. Our recent studies showed that p50 functions as an apoptotic mediator via its inhibition of GADD45α protein degradation and increase in p53 protein translation. Here we report a novel function of p50 in its regulation of superoxide dismutase 2 (SOD2) transcription via an NFκB-independent pathway. We find that deletion of p50 in mouse embryonic fibroblasts (MEFs; p50−/−) up-regulates SOD2 expression at both protein and mRNA levels. SOD2 promoter–driven luciferase is also up-regulated in p50−/− cells compared with wild-type (WT) MEF (p50+/+) cells, suggesting p50 regulation of SOD2 at the transcriptional level. Our results also show that p50 deficiency specifically results in down-regulation of phosphorylation and increased transactivation of FoxO3a compared with WT cells. Further studies indicate that p50–down-regulated FoxO3a phosphorylation is mediated by activated Akt via up-regulation of microRNA 190 (miR190), in turn inhibiting PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1) translation. Together our studies identify a novel p50 function in the regulation of SOD2 transcription by modulating the miR190/PHLPP1/Akt-FoxO3a pathway, which provides significant insight into the physiological function of p50.