scholarly journals Down-Regulation of CK2α Leads toUp-Regulation of the Cyclin-Dependent Kinase Inhibitor p27KIP1 in Conditions Unfavorable for the Growth of Myoblast Cells

2020 ◽  
Vol 54 (6) ◽  
pp. 1177-1198
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Cell Growth ◽  
Knockout Mouse ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Kinase Inhibitor ◽  
Cyclin Dependent Kinase ◽  
Cycle Progression ◽  
Cyclin Dependent Kinase Inhibitor

BACKGROUND/AIMS: Compelling evidence indicates that CK2α, which is one of the two catalytic isoforms of protein kinase CK2, is required for cell viability and plays an important role in cell proliferation and differentiation. While much is known on CK2 in the context of disease states, particularly cancer, its critical role in non-cancerous cell growth has not been extensively investigated. METHODS: In the present study, we have employed a cell line derived from rat heart with inducible down-regulation of CK2α and CK2α-knockout mouse tissue to identify CK2-mediated molecular mechanisms regulating cell growth. For this, we have performed Incucyte® live-cell analysis and applied flow cytometry, western blot, immunoprecipitation, immunohistochemistry, RT-qPCR and luciferase-based methods. RESULTS: Here, we show that lack of CK2α results in significantly delayed cell cycle progression through G1, inhibition of cyclin E-CDK2 complex, decreased phosphorylation of Rb protein at S795, and inactivation of E2F transcription factor. These events are accompanied by nuclear accumulation and up-regulation of the cyclin-dependent kinase inhibitor p27KIP1 in cells and CK2α-knockout mouse tissues. We found that increased levels of p27KIP1 are mainly attributable to post-translational modifications, namely phosphorylation at S10 and T197 amino acid residues catalyzed by Dyrk1B and AMPK, respectively, as silencing of FoxO3A transcription factor, which activates CDKN1B the gene coding for p27KIP1, does not result in markedly decreased expression levels of the corresponding protein. Interestingly, simultaneous silencing of CK2α and p27KIP1 significantly impairs cell cycle progression without increasing cell death. CONCLUSION: Taken together, our study sheds light on the molecular mechanisms controlling cell cycle progression through G1 phase when myoblasts proliferation potential is impaired by CK2α depletion. Our results suggest that elevated levels of p27KIP1,which follows CK2α depletion, contribute to delay the G1-to-S phase transition. Effects seen when p27KIP1 is down-regulated are independent of CK2α and reflect the protective role exerted by p27KIP1 under unfavorable cell growth conditions.

scholarly journals Transcriptional Downregulation of p27KIP1 through Regulation of E2F Function during LMP1-Mediated Transformation

2009 ◽  
Vol 83 (24) ◽  
pp. 12671-12679 ◽  
Author(s):  
David N. Everly ◽  
Bernardo A. Mainou ◽  
Nancy Raab-Traub
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Kinase Inhibitor ◽  
Cyclin Dependent Kinase ◽  
Mobility Shift ◽  
Cycle Progression ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Phenotypic Transformation ◽  
Electrophoretic Mobility Shift Assays ◽  
Posttranscriptional Level

ABSTRACT LMP1 induces the phenotypic transformation of fibroblasts and affects regulators of the cell cycle during this process. LMP1 decreases expression of the cyclin-dependent kinase inhibitor p27 and increases the levels and phosphorylation of cyclin-dependent kinase 2 and the retinoblastoma protein. In the present study, the effects of LMP1 on cell cycle progression and the mechanism of p27 downregulation by LMP1 were determined. Although p27 is frequently regulated at the posttranscriptional level during cell cycle progression and in cancer, LMP1 did not decrease ectopically expressed p27. However, LMP1 did decrease p27 RNA levels and inhibited the activity of p27 promoter reporters. The LMP1-regulated promoter element was mapped to a region containing two E2F sites. Electrophoretic mobility shift assays determined that the regulated cis element bound an inhibitory E2F complex containing E2F4 and p130. These findings indicate that LMP1 decreases p27 transcription through effects on E2F family transcription factors. This property likely contributes to the ability of LMP1 to stimulate cell cycle progression.

scholarly journals FOXO target gene CTDSP2 regulates cell cycle progression through Ras and p21Cip1/Waf1

2015 ◽  
Vol 469 (2) ◽  
pp. 289-298 ◽  
Author(s):  
David E.A. Kloet ◽  
Paulien E. Polderman ◽  
Astrid Eijkelenboom ◽  
Lydia M. Smits ◽  
Miranda H. van Triest ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Kinase Inhibitor ◽  
Cyclin Dependent Kinase ◽  
Cycle Progression ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Altered Gene Expression ◽  
Forkhead Box ◽  
Altered Gene ◽  
Regulate Cell Cycle Progression

Growth factor controlled activity of forkhead box O transcription factors results in altered gene expression, including expression of CTDSP2 (C-terminal domain small phosphatase 2). CTDSP2 can regulate cell cycle progression through Ras and the cyclin-dependent kinase inhibitor p21Cip1/Waf1.

scholarly journals The Role of the Cyclin Dependent Kinase Inhibitor p21cip1/waf1 in Targeting Cancer: Molecular Mechanisms and Novel Therapeutics

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1475 ◽  
Author(s):  
Al Bitar ◽  
Gali-Muhtasib
Keyword(s):  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Kinase Inhibitor ◽  
Biological Activities ◽  
Cyclin Dependent Kinase ◽  
Cycle Progression ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Multiple Signaling ◽  
Made In

p21cip1/waf1 mediates various biological activities by sensing and responding to multiple stimuli, via p53-dependent and independent pathways. p21 is known to act as a tumor suppressor mainly by inhibiting cell cycle progression and allowing DNA repair. Significant advances have been made in elucidating the potential role of p21 in promoting tumorigenesis. Here, we discuss the involvement of p21 in multiple signaling pathways, its dual role in cancer, and the importance of understanding its paradoxical functions for effectively designing therapeutic strategies that could selectively inhibit its oncogenic activities, override resistance to therapy and yet preserve its tumor suppressive functions.

scholarly journals Alsterpaullone, a Cyclin-Dependent Kinase Inhibitor, Mediated Toxicity in HeLa Cells through Apoptosis-Inducing Effect

2013 ◽  
Vol 2013 ◽  
pp. 1-5 ◽  
Author(s):  
Chunying Cui ◽  
Yuji Wang ◽  
Yaonan Wang ◽  
Ming Zhao ◽  
Shiqi Peng
Keyword(s):  
Cell Cycle ◽  
Hela Cells ◽  
Cell Cycle Progression ◽  
Caspase 3 ◽  
Kinase Inhibitor ◽  
Cdk Inhibitor ◽  
Cyclin Dependent Kinase ◽  
Cycle Progression ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Dose Dependent

Alsterpaullone, a small molecule cyclin-dependent kinase (CDK) inhibitor, regulates the cell cycle progression. Beyond death-inducing properties, we identified the effect of alsterpaullone on cycle procedure and apoptosis of HeLa cell. It was found that alsterpaullone inhibited HeLa cells in a time-dependent (0–72 h) and dose-dependent (0–30 μM) manner. In the presence of alsterpaullone, HeLa cells were arrested in G2/M prior to undergoing apoptosis via a mechanism that is involved in the regulation of various antiapoptotic genes, DNA-repair, transcription, and cell cycle progression. Compared to controls, alsterpaullone effectively prevented HeLa cells from entering S-phase. These potential therapeutic efficacies could be correlated with the activation of caspase-3.

scholarly journals Combination Gene Delivery of the Cell Cycle Inhibitor p27 with Thymidine Kinase Enhances Prodrug Cytotoxicity

1998 ◽  
Vol 72 (11) ◽  
pp. 9201-9207 ◽  
Author(s):  
Xavier Danthinne ◽  
Kazunori Aoki ◽  
Akiko L. Kurachi ◽  
Gary J. Nabel ◽  
Elizabeth G. Nabel
Keyword(s):  
Cell Cycle ◽  
Gene Transfer ◽  
Thymidine Kinase ◽  
Cell Cycle Progression ◽  
Kinase Inhibitor ◽  
Genetically Modified ◽  
Cyclin Dependent Kinase ◽  
Cycle Progression ◽  
Cyclin Dependent Kinase Inhibitor

ABSTRACT Cytoxicity induced by the herpesvirus thymidine kinase (TK) gene in combination with prodrugs is dependent on cell growth and leads to the elimination of genetically modified cells, thus limiting the duration of expression and efficacy of this treatment in vivo. Here, an effort was made to enhance TK/prodrug efficacy by coexpression of a cyclin-dependent kinase inhibitor (CKI), p27, to render cells resistant to TK/prodrug by inhibiting DNA synthesis. Expression of p27 by transfection substantially reduced cell cycle progression, and its activity was enhanced by mutations designed to stabilize the protein. Coexpression of p27 and TK or a p27/TK fusion protein led to greater prodrug cytotoxicity than that produced by TK alone in the Renca cell line, which is sensitive to bystander killing. Combination gene transfer of this CKI with TK therefore sustained the synthesis of TK by genetically modified cells to enhance the susceptibility of bystander cells to prodrug cytotoxicity and increased the efficacy of this gene transfer approach.

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