Abstract
Aurora-A, a serine-threonine kinase, is frequently overexpressed in human cancers, including hepatocellular carcinoma. To study the phenotypic effects of Aurora-A overexpression on liver regeneration and tumorigenesis, we generated transgenic mice overexpressing human Aurora-A in the liver. The overexpression of Aurora-A after hepatectomy caused an earlier entry into S phase, a sustaining of DNA synthesis, and premitotic arrest in the regenerating liver. These regenerating transgenic livers show a relative increase in binuclear hepatocytes compared with regenerating wild-type livers; in addition, multipolar segregation and trinucleation could be observed only in the transgenic hepatocytes after hepatectomy. These results together suggest that defects accumulated after first round of the hepatocyte cell cycle and that there was a failure to some degree of cytokinesis. Interestingly, the p53-dependent checkpoint was activated by these abnormalities, indicating that p53 plays a crucial role during liver regeneration. Indeed, the premitotic arrest and abnormal cell death, mainly necrosis, caused by Aurora-A overexpression were genetically rescued by p53 knockout. However, trinucleation of hepatocytes remained in the regenerating livers of the transgenic mice with a p53 knockout background, indicating that the abnormal mitotic segregation and cytokinesis failure were p53 independent. Moreover, overexpression of Aurora-A in transgenic liver led to a low incidence (3.8%) of hepatic tumor formation after a long latency period. This transgenic mouse model provides a useful system that allows the study of the physiologic effects of Aurora-A on liver regeneration and the genetic pathways of Aurora-A-mediated tumorigenesis in liver.
Highlights
Aurora-A is a serine-threonine kinase that plays a series of important roles in the regulation of mitotic progression in various organisms
Our data showed that expression of the Aurora-A mRNA was transiently induced at 2 days after hepatectomy, which coincides with G2-M phase during hepatocyte cell cycle progression, and rapidly decreased to basal level 3 days after hepatectomy (Fig. 1B)
Because a significantly lower percentage of the mitotic hepatocytes was observed over the complete mitotic period from 2 to 4 days after hepatectomy in the transgenic mice (Fig. 3B), these results indicated that Aurora-A overexpression accelerated hepatocytes entering into G2 phase, but these cells showed an impaired progression across the G2-M transition and this resulted in premitotic arrest
Summary
Aurora-A is a serine-threonine kinase that plays a series of important roles in the regulation of mitotic progression in various organisms. The various functions of Aurora-A correlate with various different cell cycle events, including centrosome maturation and separation, bipolar spindle assembly, chromosome alignment, and the transition from prophase to metaphase as well as cytokinesis [1, 2]. Previous studies have indicated that cytokinesis failure is one of the most significant defects induced by Aurora-A overexpression in a cell culture system and leads to centrosome amplification and polyploidy after the first round of the cell cycle [9, 10]. Aurora-A overexpression can override the checkpoint induced by defective spindle assembly and DNA damage, which leads to aneuploidy [11]. These events may all contribute to the carcinogenic transforming activity of Aurora-A
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