CYCLIN AND CYCLIN-DEPENDENT KINASE-1 MESSENGER-RNA EXPRESSION IN MODELS OF REGENERATING LIVER AND HUMAN LIVER-DISEASES

There is compelling evidence that the eukaryotic cell cycle is control led by a family of proteins called cyclins, which complex with cyclin- dependent kinases (CDK) to modulate key events during cell division. W e have examined the regulation of these genes in models of experimenta l liver regeneration and their expression in human liver diseases. Sev enty percent partial hepatectomy (PH) was performed on rats and normal BALB/c and athymic nude mice to determine patterns of cyclin and CDK1 mRNA expression. It has been previously shown by [H-3]thymidine incor poration that athymic nude mice manifest impaired regeneration after P H. Our results demonstrate a sequential pattern of cyclin and CDK1 tra nscript expression in each of the models. Cyclin D1 was the most abund ant mRNA steady-state transcript in the regenerating livers. CDK1 and cyclins associated with later stages of the cell cycle showed delayed and diminished expression in nude mice compared with normals. Nuclear run-off assays performed at key time points post-PH revealed little ch ange in transcription rates, suggesting that steady-state mRNA express ion of the cyclin genes is regulated primarily by posttranscriptional events. Human liver tissue from various acute and chronic hepatic dise ases showed increased expression of cyclins A and D1. We conclude that the regenerating liver post-PH offers an excellent in vivo model for studying cyclin and CDK gene expression. Impaired regeneration in the nude mouse is associated with altered cyclin and CDK1 mRNA transcript expression. Furthermore, cyclins may eventually provide clinically rel evant molecular markers of regenerative activity in human liver diseas es.