Down-regulation of p27Kip1 promotes cell proliferation of rat neonatal cardiomyocytes induced by nuclear expression of cyclin D1 and CDK4. Evidence for impaired Skp2-dependent degradation of p27 in terminal differentiation

The Journal of Biological Chemistry
Mimi Tamamori-AdachiShigetaka Kitajima

Abstract

Mammalian cardiomyocytes lose their capacity to proliferate during terminal differentiation. We have previously reported that the expression of nuclear localization signal-tagged cyclin D1 (D1NLS) and its partner cyclin-dependent kinase 4 (CDK4) induces proliferation of rat neonatal cardiomyocytes. Here we show that the D1NLS/CDK4 cells, after their entry into the cell cycle, accumulated cyclin-dependent kinase inhibitor p27 in the nuclei and decreased the cyclin-dependent kinase 2 (CDK2) activity, leading to early cell cycle arrest. Biochemical analysis demonstrated that Skp2-dependent p27 ubiquitylation was remarkably suppressed in cardiomyocytes, whereas Skp2, a component of Skp1-Cullin-F-box protein ubiquitin ligase, was more actively ubiquitylated compared with proliferating rat fibroblasts. Specific degradation of p27 by co-expressing Skp2 or p27 small interfering RNA caused an increase of CDK2 activity and overrode the limited cell cycle. These data altogether indicate that the impaired Skp2-dependent p27 degradation is causally related to the loss of proliferation in cardiomyocytes. This provides a novel insight in understanding the molecular mechanism by which mammalian cardiomyocytes cease to proliferate during termin...Continue Reading

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Citations

Nov 10, 2009·American Journal of Physiology. Heart and Circulatory Physiology·Yigang WangAmbikaipakan Balasubramaniam
Dec 27, 2008·Biochemical and Biophysical Research Communications·Mitsuru OkadaMasato Kasuga
Mar 17, 2007·Journal of Molecular and Cellular Cardiology·Katrina A BicknellGavin Brooks
Jan 30, 2009·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Sin-Ae LeeJung Weon Lee
Mar 30, 2013·Circulation Research·Julia PaganAntonio Cittadini
Jul 2, 2005·The EMBO Journal·Kiyoshi TamuraShigetaka Kitajima
Jul 3, 2007·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Wenqi LiYong Wan
Apr 24, 2008·The Journal of Biological Chemistry·Kyoko NakamuraMasato Kasuga
Apr 28, 2007·Progress in Biophysics and Molecular Biology·Elissavet KardamiDavid C Spray
May 26, 2021·Journal of Cardiovascular Translational Research·Ya-Fei LiLian-Sheng Wang

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