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논문 기본 정보

자료유형
학술저널
저자정보
Je-Hyun Yoon (University of South Carolina) Hyejin Mun (University of South Carolina) Sungyul Lee (Seoul National University) Suyoung Choi (Chungnam National University) Ji-Hoon Jeong (University of Oklahoma) Seungbeom Ko (Medical University of South Carolina) Yoo Lim Chun (Medical University of South Carolina) Benjamin Deaton (Medical University of South Carolina) Clay T. Yeager (Medical University of South Carolina) Audrey Boyette (Medical University of South Carolina) Juliana Palmera (Medical University of South Carolina) London Newman (Medical University of South Carolina) Ping Zhou (Cincinnati Children's Hospital Medical Center) Soona Shin (Cincinnati Children's Hospital Medical Center) Dong-Chan Kim (Division of Medical Device R) Cari A. Sagum (The University of Texas MD, Anderson Cancer Center) Mark T. Bedford (The University of Texas MD, Anderson Cancer Center) Young-Kook Kim (Chonnam National University Medical School) Jaeyul Kwon (Chungnam National University) Junyang Jung (College of Medicine, Kyung Hee University) Jeong Ho Chang (Kyungpook National University)
저널정보
한국분자세포생물학회 Molecules and Cells Molecules and Cells Vol.47 No.1
발행연도
2024.1
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1 - 16 (16page)

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Although binge alcohol-induced gut leakage has been studied extensively in the context of reactive oxygen species−mediated signaling, it was recently revealed that post-transcriptional regulation plays an essential role as well. Ethanol (EtOH)-inducible cytochrome P450-2E1 (CYP2E1), a key enzyme in EtOH metabolism, promotes alcohol-induced hepatic steatosis and inflammatory liver disease, at least in part by mediating changes in intestinal permeability. For instance, gut leakage and elevated intestinal permeability to endotoxins have been shown to be regulated by enhancing CYP2E1 mRNA and CYP2E1 protein levels. Although it is understood that EtOH promotes CYP2E1 induction and activation, the mechanisms that regulate CYP2E1 expression in the context of intestinal damage remain poorly defined. Specific miRNAs, including miR-132, miR-212, miR-378, and miR-552, have been shown to repress the expression of CYP2E1, suggesting that these miRNAs contribute to EtOH-induced intestinal injury. Here, we have shown that CYP2E1 expression is regulated post-transcriptionally through miRNA-mediated degradation, as follows: (1) the RNA-binding protein AU-binding factor 1 (AUF1) binds mature miRNAs, including CYP2E1-targeting miRNAs, and this binding modulates the degradation of corresponding target mRNAs upon EtOH treatment; (2) the serine/threonine kinase mammalian Ste20-like kinase 1 (MST1) mediates oxidative stress-induced phosphorylation of AUF1. Those findings suggest that reactive oxygen species−mediated signaling modulates AUF1/miRNA interaction through MST1-mediated phosphorylation. Thus, our study demonstrates the critical functions of AUF1 phosphorylation by MST1 in the decay of miRNAs targeting CYP2E1, the stabilization of CYP2E1 mRNA in the presence of EtOH, and the relationship of this pathway to subsequent intestinal injury.

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