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Molecular and Cellular Biology, January 2003, p. 555-565, Vol. 23, No. 2
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.2.555-565.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

p21CIP1 Controls Proliferating Cell Nuclear Antigen Level in Adult Cardiomyocytes

Felix B. Engel,1,{dagger} Ludger Hauck,1 Manfred Boehm,2 Elizabeth G. Nabel,2 Rainer Dietz,1 and Rüdiger von Harsdorf1*

Department of Cardiology, Campus Virchow Clinic, Charité, Humboldt University, Max Delbrück Center for Molecular Medicine, Berlin, Germany,1 Cardiovascular Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 208922

Received 15 February 2002/ Returned for modification 1 May 2002/ Accepted 27 September 2002

Cell cycle withdrawal associated with terminal differentiation is responsible for the incapability of many organs to regenerate after injury. Here, we employed a cell-free system to analyze the molecular mechanisms underlying cell cycle arrest in cardiomyocytes. In this assay, incubation of S phase nuclei mixed with cytoplasmic extract of S phase cells and adult primary cardiomyocytes results in a dramatic reduction of proliferating cell nuclear antigen (PCNA) protein levels. This effect was blocked by the proteasome inhibitors MG132 and lactacystin, whereas actinomycin D and cycloheximide had no effect. Immunodepletion and addback experiments revealed that the effect of cardiomyocyte extract on PCNA protein levels is maintained by p21 but not p27. In serum-stimulated cardiomyocytes PCNA expression was reconstituted, whereas the protein level of p21 but not that of p27 was reduced. Cytoplasmic extract of serum-stimulated cardiomyocytes did not influence the PCNA protein level in S phase nuclei. Moreover, the hypertrophic effect of serum stimulation was blocked by ectopic expression of p21 and the PCNA protein level was found to be upregulated in adult cardiomyocytes derived from p21 knockout mice. Our data provide evidence that p21 regulates the PCNA protein level in adult cardiomyocytes, which has implications for cardiomyocyte growth control.

* Corresponding author. Mailing address: Universitätsklinikum Charité, Medizinische Klinik mit Schwerpunkt Kardiologie, Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. Phone: 49-30-450 553747. Fax: 49-30-450 553977. E-mail: rharsdo{at}mdc-berlin.de.

{dagger} Present address: Department of Cardiology, Children's Hospital, Department of Cell Biology, Harvard Medical School, Howard Hughes Medical Institute, Boston, MA 02115.

Molecular and Cellular Biology, January 2003, p. 555-565, Vol. 23, No. 2
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.2.555-565.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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