© 1999 American Heart Association, Inc.
Original Contribution |
E2F-1 Overexpression in Cardiomyocytes Induces Downregulation of p21CIP1 and p27KIP1 and Release of Active Cyclin-Dependent Kinases in the Presence of Insulin-Like Growth Factor I
From the Department of Cardiology (R.v.H., L.H., F.M., U.W., R.D.), Franz Volhard Clinic, Humboldt University; the Max Delbrück Center for Molecular Medicine (M.C.C.), Berlin, Germany.
Correspondence to Rüdiger v. Harsdorf, MD, Franz-Volhard-Klinik, Medizinische Fakultät der Charité, Humboldt-Universität, Wiltbergstr 50, 13125 Berlin. E-mail rharsdo{at}mdc-berlin.de
Abstract—The heart is a postmitotic organ unable to regenerate after injury. The mechanisms controlling cell cycle arrest in cardiomyocytes are still unknown. Adenoviral delivery of E2F-1 to primary rat cardiomyocytes resulted in an increase in the expression of key cell cycle activators and apoptosis in >90% of the cells. However, insulin-like growth factor I (IGF-I) rescued cardiomyocytes from E2F-1–induced apoptosis. Furthermore, overexpression of E2F-1 in the presence of IGF-I induced the specific downregulation of total p21CIP1 and p27KIP1 protein levels and their dissociation from cyclin-dependent kinases (cdks). In contrast, p16INK4 and p57KIP2 protein levels and their association with cdks remained unaltered. The dissociation of p21CIP1 and p27KIP1 from their cdk complexes correlated well with the activation of cdk2, cdk4, and cdk6 and the release from cell cycle arrest. Under these circumstances, the number of cardiomyocytes in S phase rose from 1.2% to 23%. These results indicate that IGF-I renders cardiomyocytes permissive for cell cycle reentry. Finally, the specific downregulation of p21CIP1 and p27KIP1 further suggests their key role in the maintenance of cell cycle arrest in cardiomyocytes.
Key Words: cell cycle • E2F-1 • cardiomyocyte • apoptosis • insulin-like growth factor I
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