CYCLIN D1/CDK4 COMPLEX IN HEPATOCYTE PROLIFERATION

正常肝脏在急性损伤后具有显著的再生能力。 导致实质细胞损失的损伤，但这种反应 在许多肝脏疾病中减少。 在健康的动物中， 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 肝再生已被广泛研究， 并且对于复杂的细胞外 以及控制这一过程的细胞内事件。 但 导致肝细胞进展的细胞内因子 细胞周期的G1期尚未被彻底表征。 因为生长刺激和抑制信号经常控制 通过调节G1期的进展来增殖，这是显著的 来研究细胞周期这一阶段的分子控制。一个高度 激酶复合物的保守家族，由细胞周期蛋白和细胞周期蛋白组成， 依赖性激酶（CDK）调节真核细胞中的细胞周期。 细胞周期蛋白和cdk的不同组合形成全酶复合物 其控制细胞周期的不同阶段的进展。 细胞周期蛋白D1/cdk 4复合物似乎是一个关键的决定因素， 通过细胞周期的G1期进展，并可能是病灶 生长刺激和抑制信号点， 细胞外刺激 细胞周期蛋白D1/cdk 4复合物的活性是 由cdk抑制（CKI）蛋白控制，包括p21和p27。 我们 初步研究表明，细胞周期蛋白D1/cdk 4复合物，p21， p27在调节肝细胞通过G1期的进展中起作用 再生肝脏中细胞周期的一个阶段。我们建议研究 细胞周期蛋白、cdks和CKIs在肝细胞增殖中的作用 体外和体内再生肝中。 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/cdk 4和细胞周期蛋白E/cdk 2复合物在再生中的表达 肝脏在体内，和（2）确定的机制，通过转化 生长因子β（TGF β）和生长抑制性细胞外基质 (ECM)条件下调细胞周期蛋白/CDK复合物的活性。 这些研究旨在提供深入了解分子控制 肝再生，并检查肝细胞的潜在机制， 在人类肝脏疾病中的生长抑制。

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.