Loss of p27Kip1 accelerates DNA replication after partial hepatectomy in mice

Background. Liver regeneration after partial hepatectomy (PH) is accomplished by a synchronous replication of hepatocytes. Both positive and negative regulators of cyclin-dependent protein kinase (Cdk) have been implicated in hepatocyte proliferation, but their specific roles in vivo remain to be clarified. To investigate the specific role of p27(Kip1), a member of the Cip/Kip family of Cdk inhibitors, in cell-cycle regulation during liver regeneration, p27-knockout mice were studied after PH. Materials and methods. Under ether anesthesia, mice were subjected to 70% PH. Animals were sacrificed at intervals after the surgery, and the remnant liver was harvested and analyzed. Results. In p27-deficient mice, the timing of DNA synthesis was significantly accelerated with a perturbation in the ordered distribution of proliferating cells in the hepatic lobule. p27 deficiency, however, did not affect the whole population of cycling cells, the number of apoptotic cells, or liver injury and mortality after PH. Conclusion. These data provide in vivo evidence that p27 functions as a brake in the start of the hepatocyte cell cycle, thereby coordinating temporally and spatially the onset of DNA synthesis of hepatocytes within the hepatic lobules. (C) 2003 Elsevier Inc. All rights reserved.