Department of Biochemistry and Molecular Biology and the Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California 90033, USA.
J Biol Chem. 2011 Jan 28;286(4):2393-401. doi: 10.1074/jbc.M110.192955. Epub 2010 Nov 24.
Chronic alcohol consumption is associated with steatohepatitis and cirrhosis, enhancing the risk for hepatocellular carcinoma. RNA polymerase (pol) III transcribes a variety of small, untranslated RNAs, including tRNAs and 5S rRNAs, which determine the biosynthetic capacity of cells. Increased RNA pol III-dependent transcription, observed in transformed cells and human tumors, is required for oncogenic transformation. Given that alcohol consumption increases risk for liver cancer, we examined whether alcohol regulates this class of genes. Ethanol induces RNA pol III-dependent transcription in both HepG2 cells and primary mouse hepatocytes in a manner that requires ethanol metabolism and the activation of JNK1. This regulatory event is mediated, at least in part, through the ability of ethanol to induce expression of the TFIIIB components, Brf1, and the TATA-binding protein (TBP). Induction of TBP, Brf1, and RNA pol III-dependent gene expression is driven by enhanced c-Jun expression. Ethanol promotes a marked increase in the direct recruitment of c-Jun to TBP, Brf1, and tRNA gene promoters. Chronic alcohol administration in mice leads to enhanced expression of TBP, Brf1, tRNA, and 5S rRNA gene transcription in the liver. These alcohol-dependent increases are more pronounced in transgenic animals that express the HCV NS5A protein that display increased incidence of liver tumors. Together, these results identify a new class of genes that are regulated by alcohol through the co-regulation of TFIIIB components and define a central role for c-Jun in this process.
慢性酒精摄入与脂肪性肝炎和肝硬化有关，增加了肝细胞癌的风险。RNA 聚合酶（pol）III 转录多种小的非翻译 RNA，包括 tRNA 和 5S rRNA，这些 RNA 决定了细胞的生物合成能力。在转化细胞和人类肿瘤中观察到的 RNA pol III 依赖性转录增加是致癌转化所必需的。鉴于酒精摄入会增加肝癌的风险，我们研究了酒精是否调节这一类基因。乙醇以需要乙醇代谢和 JNK1 激活的方式诱导 HepG2 细胞和原代小鼠肝细胞中的 RNA pol III 依赖性转录。这种调节事件至少部分是通过乙醇诱导 TFIIIB 成分 Brf1 和 TATA 结合蛋白（TBP）表达的能力介导的。TBP、Brf1 和 RNA pol III 依赖性基因表达的诱导是由 c-Jun 表达增强驱动的。乙醇促进 c-Jun 直接募集到 TBP、Brf1 和 tRNA 基因启动子的显著增加。在小鼠中慢性酒精给药导致肝脏中 TBP、Brf1、tRNA 和 5S rRNA 基因转录的增强表达。在表达 HCV NS5A 蛋白的转基因动物中，这种酒精依赖性增加更为明显，这些动物表现出更高的肝癌发生率。总之，这些结果确定了一类新的基因，这些基因通过 TFIIIB 成分的共同调节被酒精调节，并定义了 c-Jun 在该过程中的核心作用。
