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Mechanism of Alcohol-induced RNA pol III dependent transcription

酒精诱导RNA pol III依赖性转录的机制

基本信息

批准号：
7847685
负责人：
Shuping Zhong
金额：
$ 24.31万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7847685
关键词：
Address Affect Alcohol consumption Alcohol dehydrogenase Alcoholic Liver Diseases Alcohols Antibodies Biological Assay Biological Models C57BL/6 Mouse Cell Culture Techniques Cell Line Cell Nucleolus Cells Chemicals Chronic Cirrhosis Co-Immunoprecipitations Cytochrome P-450 CYP2E1 DNA Polymerase I Data Development Disease Engineering Ethanol Event Gene Expression Genes Genetic Transcription Hepatitis C virus Hepatocyte Histopathology Human Hypertrophy Immunoblot Analysis In Situ In Vitro Infusion procedures Leucine-Specific tRNA Link Liver Liver Fibrosis Liver diseases Liver neoplasms Longitudinal Studies MAP Kinase Gene MAPK14 gene MAPK9 gene Malignant Neoplasms Malignant neoplasm of liver Measures Mediating Messenger RNA Mitogen-Activated Protein Kinases Modeling Molecular Mus Oncogene Deregulation Pathogenesis Pathway interactions Pharmaceutical Preparations Phosphorylation Polymerase Primary carcinoma of the liver cells Production Protein Isoforms Proteins RNA RNA Polymerase III Recovery Reporter Genes Reverse Transcriptase Polymerase Chain Reaction Ribonucleases Ribosomal RNA Risk Role Signal Transduction Pathway Steatohepatitis Stress TATA-Box Binding Protein Testing Time Tissues Transcription Factor TFIIIB Transfer RNA Transgenic Mice Tyrosine-Specific tRNA Untranslated RNA alcohol effect cancer cell cell growth cell transformation chromatin immunoprecipitation extracellular signal-regulated kinase 3 feeding in vivo in vivo Model inhibitor/antagonist insight mouse model novel therapeutics promoter protein protein interaction protein structure public health relevance research study response stress-activated protein kinase 1 transcription factor transcription factor TFIIIC tumor

项目摘要

DESCRIPTION (provided by applicant): Alcohol consumption is generally thought to enhance liver fibrosis. Alcohol-induced liver fibrosis promotes formation of cirrhosis, which increases a risk of liver cancer. Cancer cells have a consistent cytological feature of nucleolar hypertrophy, enlarged nucleoli, where rRNAs are synthesized by RNA pol I and pol III. This implies that transformation in situ is closely linked to the deregulation of RNA pol I- and III-dependent transcription, because the size of the nucleolus reflects the levels of rRNA synthesis. RNA pol III genes encode a variety of untranslated RNAs, including tRNAs and 5S rRNAs. Deregulation of RNA pol III-dependent transcription, enhancing cellular tRNAs and 5S rRNAs production, leads to an increase in translational capacity to promote cell transformation. Although alcohol has been widely studied, nothing is yet known as to whether the transcription of RNA pol III-dependent genes might be affected by alcohol. Since deregulation of RNA pol III-dependent transcription is closely associated with cancers, addressing how alcohol affects this transcription will dramatically elevate our understanding of liver cancer development. Studies have shown that alcohol is able to activate MAP kinases, which are tightly linked to human cancers. Our hypothesis is that alcohol induces stress, activates MAP kinases, particularly the c-Jun N-terminal kinase-1 (JNK1), and increases RNA pol III- dependent transcription, leading to tumor development. First, we will test whether alcohol induces a major class of genes of RNA pol III-dependent transcription, tRNAs, in vivo and in vitro. Second, we will identify alcohol- induced changes in machinery of RNA pol III transcription. Third, we will further investigate the specific signal transduction pathways mediating the alcohol-induced deregulation of RNA pol III-dependent transcription. In addition, we will use liver tissues from chronically alcohol-fed NS5A transgenic mice and intragastric ethanol infusion mice to further identify the changes in RNA pol III-dependent transcription in vivo. Elucidating these key molecular events triggered by alcohol will provide new insights into the pathogenesis of alcohol-induced liver cancer to develop new therapeutic strategies for recovery from liver cancer. Public Health Relevance: The project seeks to elucidate the mechanism of alcohol-induced RNA pol III-dependent transcription in liver cancer and identify the specific pathway by determining MAP kinases, JNK1 and JNK2. Our new discovers of alcohol-induced changes in RNA pol III transcription machinery and our preliminary studies will provide valuable information to develop new drugs to therapy alcohol-associate liver diseases.

描述（由申请人提供）：通常认为饮酒会增强肝纤维化。酒精诱导的肝纤维化促进肝硬化的形成，从而增加肝癌的风险。癌细胞具有一致的核仁肥大、核仁扩大的细胞学特征，其中rRNA由RNA pol I和pol III合成。这意味着原位转化与RNA聚合酶I和III依赖性转录的失调密切相关，因为核仁的大小反映了rRNA合成的水平。RNA pol III基因编码多种非翻译RNA，包括tRNA和5S rRNA。RNA pol III依赖性转录的失调，增强细胞tRNA和5S rRNA的产生，导致翻译能力的增加，以促进细胞转化。虽然酒精已经被广泛研究，但还不知道RNA pol III依赖基因的转录是否会受到酒精的影响。由于RNA pol III依赖性转录的失调与癌症密切相关，因此解决酒精如何影响这种转录将大大提高我们对肝癌发展的理解。研究表明，酒精能够激活与人类癌症密切相关的MAP激酶。我们的假设是，酒精诱导应激，激活MAP激酶，特别是c-Jun N-末端激酶-1（JNK 1），并增加RNA pol III依赖性转录，导致肿瘤发展。首先，我们将测试酒精是否诱导RNA聚合酶III依赖性转录，tRNA，在体内和体外的主要类别的基因。其次，我们将鉴定酒精诱导的RNA聚合酶III转录机制的变化.第三，我们将进一步研究特定的信号转导途径介导的酒精诱导的RNA聚合酶III依赖的转录失调。此外，我们将使用长期酒精喂养的NS 5A转基因小鼠和胃内乙醇灌注小鼠的肝组织，以进一步确定体内RNA pol III依赖性转录的变化。阐明这些由酒精引发的关键分子事件将为酒精诱导的肝癌的发病机制提供新的见解，以开发新的治疗策略，从肝癌中恢复。公共卫生相关性：该项目旨在阐明肝癌中酒精诱导的RNA pol III依赖性转录的机制，并通过确定MAP激酶JNK 1和JNK 2来确定特定途径。我们对酒精诱导的RNA pol III转录机制改变的新发现和初步研究将为开发治疗酒精相关性肝病的新药提供有价值的信息。