CDK inhibitors, p21Cip1 and p27Kip1, participate in cell cycle exit of mammalian cardiomyocytes

Abstract

Mammalian cardiomyocytes actively proliferate during embryonic stages, following which cardiomyocytes exit their cell cycle after birth. The irreversible cell cycle exit inhibits cardiac regeneration by the proliferation of pre-existing cardiomyocytes. Exactly how the cell cycle exit occurs remains largely unknown. Previously, we showed that cyclin E- and cyclin A-CDK activities are inhibited before the CDKs levels decrease in postnatal stages. This result suggests that factors such as CDK inhibitors (CKIs) inhibit CDK activities, and contribute to the cell cycle exit. In the present study, we focused on a Cip/Kip family, which can inhibit cyclin E- and cyclin A-CDK activities. Expression of p21(Cip1) and p27(Kip1) but not p57(Kip2) showed a peak around postnatal day 5, when cyclin E- and cyclin A-CDK activities start to decrease. p21(Cip1) and p27(Kip1) bound to cyclin E, cyclin A and CDK2 at postnatal stages. Cell cycle distribution patterns of postnatal cardiomyocytes in p21(Cip1) and p27(Kip1) knockout mice showed failure in the cell cycle exit at G1-phase, and endoreplication. These results indicate that p21(Cip1) and p27(Kip) play important roles in the cell cycle exit of postnatal cardiomyocytes.

Effects of ginsenoside Rg1 on the senescence of vascular smooth muscle cells

“…In this way, the binding of CDK2 to cyclinE is inhibited, and Rb phosphorylation is prevented. E2f cannot be released, and the cell cycle is arrested in the G1 phase, permitting DNA damage to be repaired (Fenouille et al, 2011;Tane et al, 2014). In addition, p16 can increase the stability of p21, which can then induce the expression of the p16 gene via the transcription factor Spl.…”

The exosome complex establishes a barricade to erythroid maturation

“…37,41,42,[61][62][63] Cdkn1b appears to be important for erythroid maturation, because it is induced by GATA-1 36 and accumulates upon terminal erythroid maturation. 60 Ectopic Cdkn1b expression promotes erythroid maturation of K562 erythroleukemia cells.…”

“…Cdkn1b controls cyclin-dependent kinases that bind cyclin D and cyclin E, arresting cells in G 1 . 41,42 Ddit3 (CHOP) is a DNA damage-inducible G 1 /S transition inhibitor. 43,44 Trp53inp1 functions downstream of p53 and p73 to induce G 1 arrest and to enhance apoptosis.…”

Protein phosphatase 2A promotes the transition to G0 during terminal differentiation in Drosophila

“…This suggests that mechanisms regulating Cyclin/Cdk2 activity during the final cell cycle in vivo could impact the timing and robustness of cell cycle exit in tissues. Consistent with this hypothesis, the loss of CKIs that inhibit Cyclin E/Cdk2 complexes or loss of the F-box protein Fbw7 (Fbxw7), which regulates Cyclin E stability, can partially delay proper cell cycle exit in certain tissues (Chen and Segil, 1999;de Nooij et al, 1996;Fero et al, 1996;Kiyokawa et al, 1996;Lane et al, 1996;Minella et al, 2008;Moberg et al, 2001;Tane et al, 2014). But even in the presence of aberrantly high Cyclin E/Cdk2, cell cycle exit is most often only delayed by one or two cell cycles in vivo, demonstrating the robustness of developmentally controlled quiescence (Baumgardt et al, 2014;Buttitta et al, 2010;Loeb et al, 2005;Nakayama et al, 1996).…”