Mechanism of Alcohol-induced RNA pol III dependent transcription

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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.