The liver plays a pivotal role in energy homeostasis by orchestrating biochemical pathways of carbohydrate, fat, and protein metabolism and exhibits inherent compensatory regeneration capacity to regain partially lost metabolic functions. It is unclear, however, as to how cell proliferation and metabolism are interconnected and coregulated in liver. In this context, transcription coactivator Med1 (also known as PBP/TRAP220/DRIP205), a key subunit of the mammalian Mediator complex, interacts with nuclear hormone receptors and transcription factor CCAAT/enhancer-binding protein- (CEBPB) that are critical for liver development and metabolism. The Mediator complex is necessary for the expression of RNA polymerase II (PoI II)-transcribed genes. Studies with conditional Med1 null mutation have established that Med1 is required for fatty acid oxidation and glucose metabolism. Med1 also controls liver regeneration and the development of hepatocellular carcinoma (HCC), in that hepatocytes lacking Med1 fail to regenerate and fail to give rise to liver tumors. The proposed research is based on exciting preliminary studies showing that adenovirally-driven overexpression of Med1 (adeno-Med1) in mouse liver stimulates hepatocyte DNA replication and regeneration. Gene expression profiling revealed that Med1 upregulates many genes that are important for lipogenesis and gluconeogenesis. These processes, when unconstrained, are linked to metabolic abnormalities and cancer. Our preliminary data indicate that Med1 is phosphorylated by energy sensor, adenosine monophosphate (AMP)-activated protein kinase (AMPK). Given that nuclear receptors and transcription factors CEBPB and forkhead box protein M1 (FOXM1), play critical roles in metabolism and proliferation of hepatocytes, increased expression of Med1 is an efficient way to simultaneously enhance their function. We focus on Med1 because it is necessary for liver regeneration and sufficient by itself for inducing hepatocellular proliferation. Therefore, we hypothesize that Med1 integrates the regulation of liver cell proliferation and metabolism and its persistent and unconstrained overexpression accelerates liver tumorigenesis. Our objective is to firmly establish that Med1 is a pivotal regulator of liver regeneration, and metabolic functions that contribute to liver tumorigenesis and elucidate the molecular mechanisms.
Our specific aims are to: 1) delineate the mechanisms by which Med1 overexpression in hepatocytes induces liver cell proliferation; 2) determine how Med1-mediated functions of cell proliferation and metabolism are regulated by AMPK-mediated phosphorylation; and 3) characterize and use a transgenic mouse model in which Med1 can be expressed conditionally in hepatocytes to establish that overexpression of Med1 augments hepatocellular proliferation and hepatocarcinogenesis. These studies will establish the critical role of transcription coactivator Med1 in hepatocellular proliferation, metabolism, and hepatocarcinogenesis, and reveal Med1-associated signaling mediators that have promise as targets for new therapies.
Liver cancer, the third most common cause of cancer-related death, accounts for an estimated 700,000 deaths annually worldwide. In the United States, liver cancer incidence and mortality rates are continuing to rise in the past two decades, attributable, in part, to end-stage cirrhotic liver disease resulting from hepatitis C virus (HCV) infection and obesity-associated nonalcoholic fatty liver disease. Liver regeneration and metabolic functions are interconnected to impact on liver tumor development and our studies will provide a deeper understanding of the role of Med1 subunit of the Mediator complex, a key regulator of gene transcription that could uncover new strategies for therapies.
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