Med1 in Liver Metabolism, Regeneration and Cancer

描述（由申请人提供）：肝脏通过协调碳水化合物、脂肪和蛋白质代谢的生化途径在能量稳态中起关键作用，并表现出固有的代偿性再生能力，以恢复部分丧失的代谢功能。然而，目前尚不清楚细胞增殖和代谢在肝脏中是如何相互关联和共同调节的。在这种情况下，转录辅激活因子Med1（也称为PBP/TRAP220/DRIP205），哺乳动物介体复合物的关键亚基，与核激素受体和转录因子CCAAT/增强子结合蛋白-<$（CEBPB）相互作用，这对肝脏发育和代谢至关重要。介体复合物是RNA聚合酶II（PoI II）转录基因表达所必需的。条件性Med1无效突变的研究已经确定Med1是脂肪酸氧化和葡萄糖代谢所必需的。Med1还控制肝再生和肝细胞癌（HCC）的发展，因为缺乏Med1的肝细胞不能再生，也不能产生肝肿瘤。这项研究是基于令人兴奋的初步研究，表明在小鼠肝脏中腺病毒驱动的Med1（adeno-Med1）过表达刺激肝细胞DNA复制和再生。基因表达谱分析显示，Med1上调许多基因，这些基因对脂肪生成和脂肪生成很重要。这些过程，如果不受约束，与代谢异常和癌症有关。我们的初步数据表明，Med1是由能量传感器，腺苷一磷酸（AMP）激活的蛋白激酶（AMPK）磷酸化。鉴于核受体和转录因子CEBPB和叉头盒蛋白M1（FOXM1）在肝细胞的代谢和增殖中起关键作用，增加Med1的表达是同时增强其功能的有效方法。我们专注于Med1，因为它是肝再生所必需的，并且本身足以诱导肝细胞增殖。因此，我们假设Med1整合了肝细胞增殖和代谢的调节，其持续和不受约束的过表达加速了肝脏肿瘤的发生。我们的目标是确定Med1是肝再生的关键调节因子，以及有助于肝肿瘤发生的代谢功能，并阐明其分子机制。我们的具体目标是：1）描述肝细胞中Med1过表达诱导肝细胞增殖的机制; 2）确定Med1介导的细胞增殖和代谢功能如何受AMPK介导的磷酸化调节; 3）表征并使用转基因小鼠模型，其中Med1可以在肝细胞中有条件地表达，以确定Med1的过表达增强肝细胞增殖和肝癌发生。这些研究将确立转录辅激活因子Med1在肝细胞增殖、代谢和肝癌发生中的关键作用，并揭示Med1相关的信号传导介质，这些介质有望成为新疗法的靶点。

DESCRIPTION (provided by applicant): 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.