The Med1 Subunit of the Mediator Complex Induces Liver Cell Proliferation and Is Phosphorylated by AMP Kinase*
The Med1 Subunit of the Mediator Complex Induces Liver Cell Proliferation and Is Phosphorylated by AMP Kinase*
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DOI：
10.1074/jbc.m113.486696
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发表时间：
2013-08
期刊：
影响因子：
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通讯作者：
N. Viswakarma;Yuzhi Jia;Liang Bai;Q. Gao;B. Lin;Xiaohong Zhang;P. Misra;A. Rana;S. Jain;F. Gonzalez;Yi-jun Zhu;B. Thimmapaya;J. Reddy
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文献类型：
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作者：
N. Viswakarma;Yuzhi Jia;Liang Bai;Q. Gao;B. Lin;Xiaohong Zhang;P. Misra;A. Rana;S. Jain;F. Gonzalez;Yi-jun Zhu;B. Thimmapaya;J. Reddy
背景：介体复合体的MED1亚单位协调能量代谢的代谢途径。结果：MED1在肝脏中的过表达促进了肝细胞的增殖，细胞能量感受器AMPK使MED1磷酸化。结论：MED1对肝细胞的增殖和AMPK下游的能量平衡是必需的。意义：MED1及其被AMPK的磷酸化可能在肝脏的病理生理学中具有重要意义。介体是一个大的多亚基蛋白质复合体，通过将基因特异的转录因子与前起始复合体和RNA聚合酶II连接在一起，在基因转录中发挥关键作用。在肝脏中，介体复合体的关键亚单位MED1与几个核受体和转录因子相互作用，指导基因的特异性转录。在肝脏中条件性敲除MED_1的结果表明，缺乏MED_1的肝细胞在肝部分切除或某些核受体激活剂治疗后不能再生，并且在致癌物的刺激下也不能产生肿瘤。我们现在报道，腺病毒驱动的MED1在小鼠肝脏的过表达促进了肝细胞DNA的合成，增强了DNA复制、细胞周期控制和肝脏特异基因的表达，表明MED1单独对肝细胞增殖是必要的和充分的。重要的是，我们证明了AMP激活的蛋白激酶(AMPK)是一种重要的细胞能量感受器，在体外与丝氨酸656、丝氨酸756和丝氨酸796相互作用并直接磷酸化MED1。AMPK还在小鼠肝脏、培养的原代肝细胞以及HEK293和HeLa细胞中磷酸化MED1。此外，我们在体内证明了PPARMED1激活剂增加了AMPK介导的α的磷酸化。化合物C抑制AMPK可抑制MED1PPARα激活剂非诺贝特和Wy-14,643诱导的肝细胞增殖。化合物C联合治疗可减轻肝脏中PPARα激活剂诱导的β氧化。我们的结果表明，通过与AMPK的结合，MED1磷酸化调控肝细胞的增殖和脂肪酸氧化，很可能是PPARα和AMPK的下游效应分子。
Background: The Med1 subunit of the Mediator complex orchestrates metabolic pathways of energy metabolism. Results: Overexpression of Med1 in liver enhances hepatocyte proliferation and the cellular energy sensor AMPK phosphorylates Med1. Conclusion: Med1 is essential for hepatocellular proliferation and energy homeostasis downstream to AMPK. Significance: Med1 and its phosphorylation by AMPK may have important implications in the pathophysiology of liver. Mediator, a large multisubunit protein complex, plays a pivotal role in gene transcription by linking gene-specific transcription factors with the preinitiation complex and RNA polymerase II. In the liver, the key subunit of the Mediator complex, Med1, interacts with several nuclear receptors and transcription factors to direct gene-specific transcription. Conditional knock-out of Med1 in the liver showed that hepatocytes lacking Med1 did not regenerate following either partial hepatectomy or treatment with certain nuclear receptor activators and failed to give rise to tumors when challenged with carcinogens. We now report that the adenovirally driven overexpression of Med1 in mouse liver stimulates hepatocyte DNA synthesis with enhanced expression of DNA replication, cell cycle control, and liver-specific genes, indicating that Med1 alone is necessary and sufficient for liver cell proliferation. Importantly, we demonstrate that AMP-activated protein kinase (AMPK), an important cellular energy sensor, interacts with, and directly phosphorylates, Med1 in vitro at serine 656, serine 756, and serine 796. AMPK also phosphorylates Med1 in vivo in mouse liver and in cultured primary hepatocytes and HEK293 and HeLa cells. In addition, we demonstrate that PPARα activators increase AMPK-mediated Med1 phosphorylation in vivo. Inhibition of AMPK by compound C decreased hepatocyte proliferation induced by Med1 and also by the PPARα activators fenofibrate and Wy-14,643. Co-treatment with compound C attenuated PPARα activator-inducible fatty acid β-oxidation in liver. Our results suggest that Med1 phosphorylation by its association with AMPK regulates liver cell proliferation and fatty acid oxidation, most likely as a downstream effector of PPARα and AMPK.