This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Engel, F. B.
Right arrow Articles by von Harsdorf, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Engel, F. B.
Right arrow Articles by von Harsdorf, R.

 Previous Article  |  Next Article 

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.



This article has been cited by other articles:

  • Novoyatleva, T., Diehl, F., van Amerongen, M. J., Patra, C., Ferrazzi, F., Bellazzi, R., Engel, F. B. (2009). TWEAK is a positive regulator of cardiomyocyte proliferation. Cardiovasc Res 0: cvp360v2-cvp360 [Abstract] [Full Text]  
  • Yu, Y., Cai, J.-P., Tu, B., Wu, L., Zhao, Y., Liu, X., Li, L., McNutt, M. A., Feng, J., He, Q., Yang, Y., Wang, H., Sekiguchi, M., Zhu, W.-G. (2009). Proliferating Cell Nuclear Antigen Is Protected from Degradation by Forming a Complex with MutT Homolog2. J. Biol. Chem. 284: 19310-19320 [Abstract] [Full Text]  
  • Ebelt, H., Zhang, Y., Kampke, A., Xu, J., Schlitt, A., Buerke, M., Muller-Werdan, U., Werdan, K., Braun, T. (2008). E2F2 expression induces proliferation of terminally differentiated cardiomyocytes in vivo. Cardiovasc Res 80: 219-226 [Abstract] [Full Text]  
  • Meiners, S., Dreger, H., Fechner, M., Bieler, S., Rother, W., Gunther, C., Baumann, G., Stangl, V., Stangl, K. (2008). Suppression of Cardiomyocyte Hypertrophy by Inhibition of the Ubiquitin-Proteasome System. Hypertension 51: 302-308 [Abstract] [Full Text]  
  • Gehen, S. C., Vitiello, P. F., Bambara, R. A., Keng, P. C., O'Reilly, M. A. (2007). Downregulation of PCNA potentiates p21-mediated growth inhibition in response to hyperoxia. Am. J. Physiol. Lung Cell. Mol. Physiol. 292: L716-L724 [Abstract] [Full Text]  
  • Engel, F. B., Hsieh, P. C. H., Lee, R. T., Keating, M. T. (2006). FGF1/p38 MAP kinase inhibitor therapy induces cardiomyocyte mitosis, reduces scarring, and rescues function after myocardial infarction. Proc. Natl. Acad. Sci. USA 103: 15546-15551 [Abstract] [Full Text]  
  • Vitiello, P. F., Staversky, R. J., Gehen, S. C., Johnston, C. J., Finkelstein, J. N., Wright, T. W., O'Reilly, M. A. (2006). p21Cip1 Protection against Hyperoxia Requires Bcl-XL and Is Uncoupled from Its Ability to Suppress Growth. Am. J. Pathol. 168: 1838-1847 [Abstract] [Full Text]  
  • Engel, F. B., Schebesta, M., Duong, M. T., Lu, G., Ren, S., Madwed, J. B., Jiang, H., Wang, Y., Keating, M. T. (2005). p38 MAP kinase inhibition enables proliferation of adult mammalian cardiomyocytes. Genes Dev. 19: 1175-1187 [Abstract] [Full Text]  
  • Freund, C., Schmidt-Ullrich, R., Baurand, A., Dunger, S., Schneider, W., Loser, P., El-Jamali, A., Dietz, R., Scheidereit, C., Bergmann, M. W. (2005). Requirement of Nuclear Factor-{kappa}B in Angiotensin II- and Isoproterenol-Induced Cardiac Hypertrophy In Vivo. Circulation 111: 2319-2325 [Abstract] [Full Text]  
  • Matsuura, K., Wada, H., Nagai, T., Iijima, Y., Minamino, T., Sano, M., Akazawa, H., Molkentin, J. D., Kasanuki, H., Komuro, I. (2004). Cardiomyocytes fuse with surrounding noncardiomyocytes and reenter the cell cycle. JCB 167: 351-363 [Abstract] [Full Text]  
  • Bernier, S. G., Lazarus, D. D., Clark, E., Doyle, B., Labenski, M. T., Thompson, C. D., Westlin, W. F., Hannig, G. (2004). A methionine aminopeptidase-2 inhibitor, PPI-2458, for the treatment of rheumatoid arthritis. Proc. Natl. Acad. Sci. USA 101: 10768-10773 [Abstract] [Full Text]  
  • Maga, G., Hubscher, U. (2003). Proliferating cell nuclear antigen (PCNA): a dancer with many partners. J. Cell Sci. 116: 3051-3060 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»