CYCLIN D1/CDK4 COMPLEX IN HEPATOCYTE PROLIFERATION

正常肝脏在急性肝损伤后有显著的再生能力。 导致实质细胞丧失的损伤，但这种反应 在许多肝病中是减少的。在健康的动物中，生长 70%肝部分切除(PH)等刺激诱导 分化的肝细胞进入细胞周期并迅速恢复 功能性肝脏肿块。肝脏再生已经得到了广泛的研究， 对复杂的细胞外环境有了重大的了解 以及控制这一过程的细胞内事件。然而， 导致肝细胞进展的细胞内因子通过 细胞周期的G1期还没有得到彻底的描述。 因为生长刺激和抑制信号经常控制 通过G1期调节细胞增殖，这是突出的 研究细胞周期这一阶段的分子调控。一位高度 保守的激酶复合体家族，由细胞周期蛋白和细胞周期蛋白组成。 依赖蛋白激酶(CDKs)在真核细胞中调节细胞周期。 细胞周期蛋白与CDKs的不同结合形成全酶复合体 它们控制着细胞周期不同阶段的进程。 细胞周期蛋白D1/CDK4复合体似乎是一种关键的决定因素 通过细胞周期的G1期进展，并可能是焦点 生长点产生的刺激和抑制信号 细胞外刺激。细胞周期蛋白D1/CDK4复合体的活性为 受CDK抑制(CKI)蛋白控制，包括p21和p27。我们的 初步研究表明，细胞周期蛋白D1/CDK4复合体、p21和 P27通过G1期调控肝细胞的进程 再生肝中细胞周期的阶段。我们建议研究 Cyclins、CDKs和CKIs在大鼠肝细胞增殖中的作用 在体外和体内再生的肝脏中。我们的具体目标是： (1)确定p21和p27调节活性的机制 细胞周期蛋白D1/CDK4和细胞周期蛋白E/CDK2复合体在再生中的作用 活体肝脏，以及(2)确定转化为 生长因子β与生长抑制细胞外基质 (ECM)条件下调细胞周期蛋白/cdk复合体的活性。 这些研究旨在提供对分子控制的洞察。 肝再生，并研究肝细胞的潜在机制 人类肝病中的生长抑制。

Normal liver has a remarkable capacity to regenerate after acute injuries that result in the loss of parenchymal cells, but this response is diminished in many liver diseases. In healthy animals, growth stimulus such as 70 percent partial hepatectomy (PH) induces differentiated hepatocytes to enter the cell cycle and rapidly restore functional liver mass. Liver regeneration has been studied extensively, and significant insight has been gained into the complex extracellular and intracellular events that control this process. However, the intracellular factors that lead to progression of hepatocytes through G1 phase of the cell cycle have not been as thoroughly characterized. Because growth stimulatory and inhibitory signals frequently control proliferation by regulating progression through G1 phase, it is salient to study the molecular control of this stage of the cell cycle. A highly conserved family of kinase complexes, consisting of cyclins and cyclin- dependent kinases (cdks), regulate the cell cycle in eukaryotic cells. Different combinations of cyclins and cdks form holoenzyme complexes which control progression through different stages of the cell cycle. The cyclin D1/cdk4 complex appears to be a critical determinant of progression through G1 phase of the cell cycle, and may be the focal point of growth stimulatory and inhibitory signals arising from extracellular stimuli. The activity of the cyclin D1/cdk4 complex is controlled by cdk-inhibitory (CKI) proteins, including p21 and p27. Our preliminary studies suggest that the cyclin D1/cdk4 complex, p21, and p27 play a role in regulating the progression of hepatocytes through G1 phase of the cell cycle in the regenerating liver. We propose to study the role of cyclins, cdks, and CKIs during hepatocyte proliferation in vitro and in the regenerating liver in vivo. Our specific goals are to: (1) Identify the mechanisms by which p21 and p27 regulate the activity of the cyclin D1/cdk4 and cyclin E/cdk2 complexes in the regenerating liver in vivo, and (2) identify the mechanisms by which transforming growth factor Beta (TGF Beta) and growth inhibitory extracellular matrix (ECM) conditions downregulate the activity of the cyclin/cdk complexes. These studies are intended to provide insight into the molecular control of liver regeneration, and to examine potential mechanisms of hepatocyte growth inhibition in human liver diseases.