Cyclin D1/CDK4 Complex in Hepatocyte Proliferation

描述（由申请人提供）：现在认识到代谢的改变在增殖和恶性细胞中起关键作用。为了提供生长和增殖所需的能量和合成代谢，细胞必须通过尚未完全表征的机制进行大量的代谢适应。在我的R01拨款续期申请中，我们建议研究cyclin D1如何调节肝脏和肝细胞癌（HCC）代谢的关键方面。Cyclin D1是一种细胞周期控制蛋白，通过G1期的关键检查点促进进展，也是人类癌症（包括HCC）中最普遍的癌基因之一。它在正常肝脏中表达水平较低，但在肝细胞增殖和肿瘤中被显著诱导。我们前期的研究表明，cyclin D1在肝细胞的细胞周期中起着重要的作用，事实上在缺乏其他cyclin D1的情况下，cyclin D1足以促进肝细胞的增殖和肝脏的生长

DESCRIPTION (provided by applicant): It is now recognized that alterations in metabolism play a critical role in proliferating and malignant cells. In order to provide for the energy and anabolic requirements of growth and proliferation, cells must undergo substantial metabolic adaptations through mechanisms that are incompletely characterized. In this application for a renewal of my R01 grant, we propose to examine how cyclin D1 regulates key aspects of metabolism in the liver and hepatocellular carcinoma (HCC). Cyclin D1 is a cell cycle control protein that promotes progression through critical checkpoints in G1 phase and is also one of the most prevalent oncogenes in human cancers (including HCC). It is expressed at low levels in normal liver, but is markedly induced during hepatocyte proliferation and in cancer. Our prior studies have shown that cyclin D1 plays an important role in the hepatocyte cell cycle, and in fact is sufficient to promote proliferation of these cells and liver growth in the absence of other stimuli. Our more recent data have found that cyclin D1 regulates metabolism through direct repression of two key transcription factors, HNF4? and PPAR?, which play an important role in the liver. The modulation of these transcription factors by cyclin D1 has several potentially important implications, including a shift in metabolism away from activities that support systemic homeostasis and decreased fatty acid oxidation, leading to fatty liver. Our data also indicate that cyclin D1 promotes glycolysis, a key anabolic feature of growth. In Aim 1A of this proposal, we will examine the regulation of HNF4? by cyclin D1, which has implications for broad aspects of homeostatic metabolism in the regenerating liver and HCC. In Aim 1B, we will examine the mechanisms by which cyclin D1 regulates PPAR? activity, which plays an important role in lipid utilization. In Aim 2, we will use biochemical and advanced metabolomic techniques to study the mechanisms by which cyclin D1 regulates lipid homeostasis, and to define how this protein modulates the flux of glucose and glutamine into key metabolic pathways. We believe that these studies will significantly advance the understanding of how cyclin D1 promotes growth, proliferation, and cancer through metabolic regulation.