Magne Laurent, Blanc Etienne, Marchand Alexandre, Fafournoux Pierre, Barouki Robert, Rouach Hélène, Garlatti Michèle
INSERM U747, Laboratoire de Pharmacologie, Toxicologie et Signalisation Cellulaire, Paris F-75006, France.
J Hepatol. 2007 Nov;47(5):691-8. doi: 10.1016/j.jhep.2007.05.018. Epub 2007 Jun 27.
BACKGROUND/AIMS: Insulin-like growth factor-binding protein-1 (IGFBP-1) modulates cell growth and metabolism in a variety of physiopathological conditions. The aim of this study was to determine the molecular mechanisms involved in IGFBP-1 upregulation by ethanol.
We studied IGFBP-1 regulation by ethanol at the protein, mRNA and gene promoter levels in the human hepatocarcinoma cell line, HepG2, which does not express significantly ethanol-metabolizing enzymes.
Ethanol (35-150mM) induced the IGFBP-1 mRNA and protein up to 5-fold in a dose-dependent manner. A similar effect was observed using primary cultures of human hepatocytes. Various inhibitors of ethanol metabolism and the antioxidant N-acetylcysteine did not prevent ethanol effects. While ethanol did not modify the IGFBP-1 gene promoter activity, it elicited a 2- to 3-fold increase in IGFBP-1 mRNA half-life and this stabilization required the 5' and the 3' untranslated mRNA region. Ethanol triggered a rapid activation of c-Jun N-terminal Kinase (JNK) in HepG2 cells and IGFBP-1 induction was significantly decreased by a specific inhibitor of JNK.
This study reveals a novel pathway of gene regulation by alcohol which involves the activation of JNK and the consequent mRNA stabilization.
背景/目的：胰岛素样生长因子结合蛋白-1（IGFBP-1）在多种生理病理条件下调节细胞生长和代谢。本研究旨在确定乙醇上调IGFBP-1所涉及的分子机制。
我们在不表达显著乙醇代谢酶的人肝癌细胞系HepG2中，从蛋白质、mRNA和基因启动子水平研究了乙醇对IGFBP-1的调节作用。
乙醇（35 - 150mM）以剂量依赖方式使IGFBP-1 mRNA和蛋白质上调达5倍。在原代培养的人肝细胞中也观察到类似效应。各种乙醇代谢抑制剂和抗氧化剂N-乙酰半胱氨酸均不能阻止乙醇的作用。虽然乙醇未改变IGFBP-1基因启动子活性，但它使IGFBP-1 mRNA半衰期增加2至3倍，这种稳定作用需要mRNA的5'和3'非翻译区。乙醇在HepG2细胞中引发c-Jun氨基末端激酶（JNK）的快速激活，JNK的特异性抑制剂可显著降低IGFBP-1的诱导。
本研究揭示了酒精调节基因的一条新途径，该途径涉及JNK的激活及随后的mRNA稳定。
