CYCLIN D1/CDK4 COMPLEX IN HEPATOCYTE PROLIFERATION

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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.