Regulation of the Hepatocyte Cell Cycle: Signaling Pathways and Protein Kinases

The adult liver exhibits the remarkable ability to “regenerate” following surgical resection or toxic liver injuries. In normal liver restoration of hepatic tissue homeostasis occurs through rapid and partially synchronous proliferation of adult mature hepatocytes. The hepatocytes expressing the liver-specific functions responsible for the crucial hepatic metabolic pathways are quiescent cells that keep the ability to reenter the cell cycle. The fact that liver regeneration is supported by the active proliferation of highly differentiated hepatocytes rather than an expansion of progenitor cells is a unique situation among adult solid tissues. The hepatocytes, which exit quiescence and proliferate for a limited number of divisions present specific proliferation signaling pathways and a peculiar cell cycle regulation. In addition, polyploidy is another characteristic feature of mammalian adult hepatocytes that contributes to the specific molecular mechanisms underlying the cell cycle in hepatocytes. The entry into and progression through G1 phase of the cell cycle are orchestrated by complex networks of extracellular stimuli and intracellular signaling pathways inducing profound modifications of the gene expression required for the exit from quiescence and the cell cycle completion of the differentiated hepatocytes. Several lines of evidences also indicate that cell cycle regulators such as the Cyclin Dependent protein Kinases (CDKs) and their functional partners the cyclins and CDK inhibitors (CDKIs) show specific expression and/or activation patterns compared to the cell cycle in others cell types.