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

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.

DOI: 10.1091/mbc.E13-06-0343

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@inproceedings{Du2013NFB1S, title={NFκB1 (p50) suppresses SOD2 expression by inhibiting FoxO3a transactivation in a miR190/PHLPP1/Akt-dependent axis}, author={Kejun Du and Yonghui Yu and Dongyun Zhang and Wenjing Luo and Haishan Huang and Jing-Yuan Chen and Jimin Gao and Chuanshu Huang}, booktitle={Molecular biology of the cell}, year={2013} }