Degradation of p21Cip1 through Anaphase-promoting Complex/Cyclosome and Its Activator Cdc20 (APC/CCdc20) Ubiquitin Ligase Complex-mediated Ubiquitylation Is Inhibited by Cyclin-dependent Kinase 2 in Cardiomyocytes

Yamada, Kazuhiko; Tamamori‐Adachi, Mimi; Goto, I; Iizuka, Masaru; Yasukawa, Takashi; Aso, Teijiro; Okazaki, Taro; Kitajima, Shigetaka

doi:10.1074/jbc.m111.236711

Cited by 9 publications

(8 citation statements)

References 57 publications

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“…These observations suggest that dephosphorylation of p21 is the pre-requisite for its ubiquitination. More importantly, the interaction between Cdk2 and p21 has been shown to inhibit the APC/C Cdc20 -mediated degradation of p21 during G2/M progression [46]. These findings further supports our hypothesis that p21 is dephosphorylated as the cell exit mitosis.…”

Section: Discussionsupporting

confidence: 87%

“…Moreover, we found that p21 accumulated rapidly in Bat3 -KD cells released from a nocodazole arrest, whereas the phosphorylation of p21 was reduced. Degradation of p21 by APC/C Cdc20 during G2/M progression has also been reported to occur during prometaphase and the interaction between Cdk2 and p21 inhibits this process [17] , [46] . These findings suggest that the decreased p21 phosphorylation in the Bat3 -KD cells results in continuous p21 synthesis.…”

Section: Discussionmentioning

confidence: 99%

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A Novel, Non-Apoptotic Role for Scythe/BAT3: A Functional Switch between the Pro- and Anti-Proliferative Roles of p21 during the Cell Cycle

Yong

Wang

2012

PLoS ONE

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BackgroundScythe/BAT3 is a member of the BAG protein family whose role in apoptosis has been extensively studied. However, since the developmental defects observed in Bat3-null mouse embryos cannot be explained solely by defects in apoptosis, we investigated whether BAT3 is also involved in cell-cycle progression.Methods/Principal FindingsUsing a stable-inducible Bat3-knockdown cellular system, we demonstrated that reduced BAT3 protein level causes a delay in both G1/S transition and G2/M progression. Concurrent with these changes in cell-cycle progression, we observed a reduction in the turnover and phosphorylation of the CDK inhibitor p21, which is best known as an inhibitor of DNA replication; however, phosphorylated p21 has also been shown to promote G2/M progression. Our findings indicate that in Bat3-knockdown cells, p21 continues to be synthesized during cell-cycle phases that do not normally require p21, resulting in p21 protein accumulation and a subsequent delay in cell-cycle progression. Finally, we showed that BAT3 co-localizes with p21 during the cell cycle and is required for the translocation of p21 from the cytoplasm to the nucleus during the G1/S transition and G2/M progression.Conclusion:Our study reveals a novel, non-apoptotic role for BAT3 in cell-cycle regulation. By maintaining a low p21 protein level during the G1/S transition, BAT3 counteracts the inhibitory effect of p21 on DNA replication and thus enables the cells to progress from G1 to S phase. Conversely, during G2/M progression, BAT3 facilitates p21 phosphorylation by cyclin A/Cdk2, an event required for G2/M progression. BAT3 modulates these pro- and anti-proliferative roles of p21 at least in part by regulating cyclin A abundance, as well as p21 translocation between the cytoplasm and the nucleus to ensure that it functions in the appropriate intracellular compartment during each phase of the cell cycle.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

A Novel, Non-Apoptotic Role for Scythe/BAT3: A Functional Switch between the Pro- and Anti-Proliferative Roles of p21 during the Cell Cycle

Yong

Wang

2012

PLoS ONE

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“…[62][63][64] In prometaphase, p21 is recognized at its D-box motif by APC/C Cdc20 when bound to Cdk1/cyclin B, 65 which is counteracted by the overexpression of Cdk2, at least in cardiomyocytes. 67 Interestingly, Skp2 silencing induces a slight accumulation of p21 probably representing another degradation pathway of p21 during mitosis. 65 Recently, it has been shown that a fourth E3 ligase CRL2 LRR1 (Cullin 2-RING ubiquitin ligase/leucinerich repeat protein) is acting only and specialized in the cytoplasm.…”

Section: Phosphorylationmentioning

confidence: 99%

Less understood issues: p21Cip1 in mitosis and its therapeutic potential

2014

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p21(Cip1) is a multifunctional protein and a key player in regulating different cellular processes. The transcription of p21 is regulated by p53-dependent and -independent pathways. The expression of p21 is increased in response to various cellular stresses to arrest the cell cycle and ensure genomic stability. p21 has been shown to be a tumor suppressor and an oncogene as well. The function of p21 in mitosis has been proposed but not systematically studied. We have recently shown that p21 binds to and inhibits the activity of Cdk1/cyclin B1, and is important for a fine-tuned mitotic progression. Loss of p21 prolongs the duration of mitosis and results in severe mitotic defects like chromosome segregation and cytokinesis failures promoting consequently genomic instability. Moreover, p21 is dramatically stabilized in mitotic tumor cells upon treatment with mitotic agents like paclitaxel or mitotic kinase inhibitors. Increased p21 is mainly localized in the cytoplasm and associates with cell survival indicating a crucial role of p21 in susceptibility to mitotic agents in tumor cells. In this review we will briefly summarize the structure and general physiological functions as well as regulation of p21, discuss in detail its role in mitosis and its potential to serve as a therapeutic target.

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“…40) CDK2 was shown to suppress the interaction of p21 with CDC20 and facilitate the degradation of p21, thus regulating mitosis. [41][42][43] KRAS is a member of the p21 small GTPase family and numerous investigations have reported that the overexpression of p21 proteins encoded by KRAS was detected in the cardiovascular disease. [44][45][46] As reported previously, polymorphisms in estrogen receptor (ER)-α were correlated with increased risk of MI, and the activation of ER-α was regulated by p21-activated kinase 1.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Gene Expression During the Development of Congestive Heart Failure After Myocardial Infarction in Rat Models

Zhang

et al. 2015

Int. Heart J.

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SummaryOur study aimed to investigate the gene expression at different myocardial infarction (MI) phases and to understand the development mechanisms of congestive heart failure (CHF) after MI. Dataset GSE1957 including 24 samples of rat left ventricles at 1-day post MI or sham operation and 7-day post MI or sham operation was downloaded from Gene Expression Ominibus. The data were normalized with an affyPLM package and differentially expressed genes (DEGs) were identified with a Linear Models for Microarray Data package. Heat maps of the DEGs were constructed using Cluster 3.0. GO (Gene Ontology) enrichment analysis of the DEGs was performed in Database for Annotation, Visualization, and Integrated Discovery. A protein-protein interaction (PPI) network was constructed by Biomolecular Interaction Network Database and visualized by Cytoscape, and a subnetwork was analyzed using plugin ClusterONE in Cytoscape. A total of 5 DEGs at 1-day post-MI, 5 DEGs at 7-day post-MI, and 7 DEGs between the MI and sham groups at 1-day and 7-day post-MI were identified. For the GO category analysis, DEGs at 1-day post-MI were enriched in response to cytokine stimulus. DEGs at 7-day post-MI were enriched in response to inorganic substance and chemical homeostasis. DEGs between 1-day and 7-day post-MI including CDK2 and CDC20 were significantly enriched in mitosis. CDK2, ANXA1, CDC20, and AQP2 were included in the PPI network, and CDK2 was the only DEG included in the subnetwork. In conclusion, the induction of DEGs at 7-day post-MI might participate in the response to a hormone and endogenous stimulus to regulate the development of CHF after MI. (Int Heart J 2015; 56: 444-449) Key words: Differentially expressed gene, Interaction network, CDK2, AQP2 M yocardial infarction (MI) is commonly known as heart attack. MI is a leading cause of heart failure and one of the major causes of the death and disability, and is a chronic disease and can even go undetected, eventually leading to a sudden death.1,2) Patients with MI sometimes have chest pain while 64% of the cases may not even have any symptoms.3) Therefore, an urgent task is to develop diagnostic and therapeutic methods for MI.In recent years, studies on genes have provided us with information for disease diagnosis and therapy due to their high sensitivity, specificity, and fast speed. The relation between gene expression and MI has been studied extensively, and the progression of congestive heart failure (CHF) after MI is complex and related to several changes. [4][5][6][7] For example, the variants of gene ALOX5AP which encodes 5-lipoxygenase activating protein are associated with the pathogenesis of MI by increasing leukotriene production and inflammation. 4) Andersson, et al reported that the expression of 10 neuronal type regulated genes including muscarinic m4, ATP receptor P2rx4, nerve growth factor receptor, and cardiac Kcne1 were all increased in 7-day post-MI CHF hearts, while fewer genes were differentially expressed at 1-day post MI. 6) However, the underlying funct...

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Degradation of p21Cip1 through Anaphase-promoting Complex/Cyclosome and Its Activator Cdc20 (APC/CCdc20) Ubiquitin Ligase Complex-mediated Ubiquitylation Is Inhibited by Cyclin-dependent Kinase 2 in Cardiomyocytes

Cited by 9 publications

References 57 publications

A Novel, Non-Apoptotic Role for Scythe/BAT3: A Functional Switch between the Pro- and Anti-Proliferative Roles of p21 during the Cell Cycle

A Novel, Non-Apoptotic Role for Scythe/BAT3: A Functional Switch between the Pro- and Anti-Proliferative Roles of p21 during the Cell Cycle

Less understood issues: p21Cip1 in mitosis and its therapeutic potential

Analysis of Gene Expression During the Development of Congestive Heart Failure After Myocardial Infarction in Rat Models

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