Cyclin D1/CDK4 Complex in Hepatocyte Proliferation

描述(申请人提供)：现已认识到新陈代谢的改变在细胞增殖和恶性过程中起着关键作用。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描述的机制进行实质性的代谢适应。在我的R01拨款续期申请中，我们建议研究细胞周期蛋白D1如何调节肝脏和肝细胞癌(HCC)中代谢的关键方面。细胞周期蛋白D1是一种细胞周期控制蛋白，在G1期通过关键的检查点促进进展，也是人类癌症(包括肝癌)中最常见的癌基因之一。它在正常肝脏中低水平表达，但在肝细胞增殖和癌症中显著诱导。我们先前的研究表明，细胞周期蛋白D1在肝细胞周期中起着重要作用，事实上在没有其他刺激的情况下，它足以促进这些细胞的增殖和肝脏的生长。我们最近的数据发现，细胞周期蛋白D1通过直接抑制两个关键转录因子HNF4α和PPARα来调节新陈代谢，这两个转录因子在肝脏中发挥着重要作用。Cyclin D1对这些转录因子的调节有几个潜在的重要意义，包括代谢从支持全身动态平衡的活动转移到减少脂肪酸氧化，从而导致脂肪肝。我们的数据还表明， 细胞周期蛋白D1促进糖酵解，这是生长的一个关键的合成代谢特征。在本提案的目标1A中，我们将研究细胞周期蛋白D1对HNF4α的调节，这对再生肝和肝细胞癌的动态平衡代谢具有广泛的意义。在目标1B中，我们将研究细胞周期蛋白D1调节PPARα活性的机制，该活性在脂质利用中起着重要作用。在目标2中，我们将使用生化和高级代谢组学技术来研究细胞周期蛋白D1调节脂质稳态的机制，并确定该蛋白如何调节葡萄糖和谷氨酰胺的流量进入关键的代谢途径。我们相信，这些研究将极大地促进对细胞周期蛋白D1如何通过代谢调节促进生长、增殖和癌症的理解。

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, HNF4α and PPARα, 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 HNF4α 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 PPARα 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.