NFκB1 (p50) suppresses SOD2 expression by inhibiting FoxO3a transactivation in a miR190/PHLPP1/Akt-dependent axis

Author:

Du Kejun12,Yu Yonghui1,Zhang Dongyun1,Luo Wenjing2,Huang Haishan13,Chen Jingyuan2,Gao Jimin3,Huang Chuanshu13

Affiliation:

1. Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987

2. Department of Occupational and Environmental Health, School of Public Health, Fourth Military Medical University, Shanxi 710032, China

3. Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical College, Wenzhou, Zhejiang 325035, China

Abstract

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.

Publisher

American Society for Cell Biology (ASCB)

Subject

Cell Biology,Molecular Biology

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