Reactivation of the mitosis-promoting factor in postmitotic cardiomyocytes.
Cardiomyocytes cease to divide shortly after birth and an irreversible cell cycle arrest is evident accompanied by the downregulation of cyclin-dependent kinase activities. To get a better understanding of the cardiac cell cycle and its regulation, the effect of functional recovery of the mitosis-promoting factor (MPF) consisting of cyclin B1 and the cyclin-dependent kinase Cdc2 was assessed in primary cultures of postmitotic ventricular adult rat cardiomyocytes (ARC). Gene transfer into ARC was achieved using the adenovirus-enhanced transferrinfection system that was characterized by the absence of cytotoxic events. Simultaneous ectopic expression of wild-type versions of cyclin B1 and Cdc2 was sufficient to induce MPF activity. Reestablished MPF resulted in a mitotic phenotype, marked by an abnormal condensation of the nuclei, histone H3 phosphorylation and variable degree of decay of the contractile apparatus. Although a complete cell division was not observed, the results provided conclusive evidence that cell cycle-related events in postmitotic cardiomyocytes could be triggered by genetic intervention downstream of the G1/S checkpoint. This will be of importance to design novel strategies to overcome the proliferation arrest in adult cardiomyocytes.
Dätwyler
Daniel A
DA
Institute of Cell Biology, Swiss Federal Institute of Technology, Zürich, Switzerland.
Magyar
Josef P
JP
Weikert
Christian
C
Wightman
Lionel
L
Wagner
Ernst
E
Eppenberger
Hans M
HM
D000818:Animals; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D019926:Cyclin B / Q000235:genetics / Q000378:metabolism; D056744:Cyclin B1; D005260:Female; D016193:G1 Phase / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D018014:Gene Transfer Techniques; D018816:Genes, cdc / Q000502:physiology; D006321:Heart / Q000254:growth & development*; D006801:Humans; D016200:Maturation-Promoting Factor / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D016196:S Phase / Q000235:genetics
C534699:CCNB1 protein, human; C534701:Ccnb1 protein, rat; D019926:Cyclin B; D056744:Cyclin B1; D016203:CDC2 Protein Kinase; D016200:Maturation-Promoting Factor