Yamada K, Tamamori-Adachi M, Goto I, Iizuka M, Yasukawa T, Aso T, Okazaki T, Kitajima S

Cyclin dependent kinase (CDK) inhibitor p21Cip1 plays a crucial role in regulating cell cycle arrest and differentiation. It is known that p21Cip1 increases during terminal differentiation of cardiomyocytes, but its expression control and biological role are not fully understood. Here we show that p21Cip1 protein is stabilized in cardiomyocytes after ...

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mitogenic stimulation, due to its increased CDK2 binding and inhibition of ubiquitylation. APC/CCdc20 complex is shown to be an E3 ligase mediating ubiquitylation of p21Cip1 at the N-terminus. CDK2, but not CDC2, suppressed the interaction of p21Cip1 with Cdc20, thereby leading to inhibition of anaphase-promoting complex/cyclosome and its activator Cdc20 (APC/CCdc20)-mediated p21Cip1 ubiquitylation. It was further demonstrated that p21Cip1 accumulation caused G2 arrest of cardiomyocytes that were forced to re-enter cell cycle. Taken together, these data show that the stability of p21Cip1 protein is actively regulated in terminally differentiated cardiomyocytes and plays a role in inhibiting their un-controlled cell cycle progression. Our study provides a novel insight on the control of p21Cip1 by ubiquitin-mediated degradation and its implication in cell cycle arrest in terminal differentiation.

Date: Nov. 01, 2011

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