NFκB1 (p50) suppresses SOD2 expression by inhibiting FoxO3a transactivation in a miR190/PHLPP1/Akt-dependent axis.
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.
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987 Department of Occupational and Environmental Health, School of Public Health, Fourth Military Medical University, Shanxi 710032, China Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical College, Wenzhou, Zhejiang 325035, China.
Kejun
K
Du
Yonghui
Y
Yu
Dongyun
D
Zhang
Wenjing
W
Luo
Haishan
H
Huang
Jingyuan
J
Chen
Jimin
J
Gao
Chuanshu
C
Huang
D000818:Animals; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000172:deficiency / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D000099156:Superoxide Dismutase 2
D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D008156:Luciferases; D035683:MicroRNAs; D052002:NF-kappa B p50 Subunit; D009687:Nuclear Proteins; D010749:Phosphoprotein Phosphatases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C474033:FoxO3 protein, mouse; C546705:MIRN190 microRNA, mouse; C519282:PHLPP1 protein, mouse