title: p38/p53/miR-200a-3p feedback loop promotes oxidative stress-mediated liver cell death.
abstract: Although our previous studies have provided evidence that oxidative stress has an essential role in total parenteral nutrition (TPN)-associated liver injury, the mechanisms involved are incompletely understood. Here, we show the existence of crosstalk between the miR-200 family of microRNAs and oxidative stress. The members of the miR-200 family are markedly enhanced in hepatic cells by hydrogen peroxide (H2O2) treatment. The upregulation of miR-200-3p in turn modulates the H2O2-mediated oxidative stress response by targeting p38α. The enhanced expression of miR-200-3p mimics p38α deficiency and promotes H2O2-induced cell death. Members of the miR-200 family that are known to inhibit the epithelial to mesenchymal transition (EMT) are induced by the tumor suppressor p53. Here, we show that p53 phosphorylation at Ser 33 contributes to H2O2-induced miR-200s transcription. In addition, we show that p38α can directly phosphorylate p53 at serine 33 upon H2O2 exposure. Thus, we suggest that in liver cells, the oxidative stress-induced, p38α-mediated phosphorylation of p53 at Ser33 is essential for the functional regulation of oxidative stress-induced miR-200 transcription by p53. Collectively, our data indicate that the p53-dependent expression of miR-200a-3p promotes cell death by inhibiting a p38/p53/miR-200 feedback loop.
authors: a Department of Pediatric Surgery ; Xinhua Hospital; School of Medicine; Shanghai Jiao Tong University ; Shanghai , China.
authors: Yongtao
authors: Y
authors: Xiao
authors: Weihui
authors: W
authors: Yan
authors: Lina
authors: L
authors: Lu
authors: Ying
authors: Y
authors: Wang
authors: Wei
authors: W
authors: Lu
authors: Yi
authors: Y
authors: Cao
authors: Wei
authors: W
authors: Cai
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D006861:Hydrogen Peroxide; D048308:Mitogen-Activated Protein Kinase 14
keywords: 3′-UTR; 3′-untranslated region; ChIP; MAPK; MMP; ROS; TPN; chromatin immunoprecipitation; liver injury; microRNA; mitochondrial membrane potential; mitogen-activated protein kinase; oxidative stress; p38; p53; reactive oxygen species; total parenteral nutrition