The decision to enter mitosis: feedback and redundancy in the mitotic entry network

The decision to enter mitosis is mediated by a network of proteins that regulate activation of the cyclin B–Cdk1 complex. Within this network, several positive feedback loops can amplify cyclin B–Cdk1 activation to ensure complete commitment to a mitotic state once the decision to enter mitosis has been made. However, evidence is accumulating that several components of the feedback loops are redundant for cyclin B–Cdk1 activation during normal cell division. Nonetheless, defined feedback loops become essential to promote mitotic entry when normal cell cycle progression is perturbed. Recent data has demonstrated that at least three Plk1-dependent feedback loops exist that enhance cyclin B–Cdk1 activation at different levels. In this review, we discuss the role of various feedback loops that regulate cyclin B–Cdk1 activation under different conditions, the timing of their activation, and the possible identity of the elusive trigger that controls mitotic entry in human cells.

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Chk1-mediated Cdc25A degradation as a critical mechanism for normal cell cycle progression

Journal of Cell Science ◽

10.1242/jcs.223123 ◽

2019 ◽

Vol 132 (2) ◽

pp. jcs223123 ◽

Cited By ~ 12

Author(s):

Hidemasa Goto ◽

Toyoaki Natsume ◽

Masato T. Kanemaki ◽

Aika Kaito ◽

Shujie Wang ◽

...

Keyword(s):

Cell Cycle ◽

Normal Cell ◽

Cell Cycle Progression ◽

Cycle Progression ◽

Normal Cell Cycle

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A novel form of Deleted in breast cancer 1 (DBC1) lacking the N-terminal domain does not bind SIRT1 and is dynamically regulated in vivo

Scientific Reports ◽

10.1038/s41598-019-50789-7 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Leonardo Santos ◽

Laura Colman ◽

Paola Contreras ◽

Claudia C. Chini ◽

Adriana Carlomagno ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Liver Regeneration ◽

Partial Hepatectomy ◽

Normal Cell ◽

Cell Cycle Progression ◽

Cycle Progression ◽

Quiescent Cells ◽

Normal Cell Cycle

Abstract The protein Deleted in Breast Cancer-1 is a regulator of several transcription factors and epigenetic regulators, including HDAC3, Rev-erb-alpha, PARP1 and SIRT1. It is well known that DBC1 regulates its targets, including SIRT1, by protein-protein interaction. However, little is known about how DBC1 biological activity is regulated. In this work, we show that in quiescent cells DBC1 is proteolytically cleaved, producing a protein (DN-DBC1) that misses the S1-like domain and no longer binds to SIRT1. DN-DBC1 is also found in vivo in mouse and human tissues. Interestingly, DN-DBC1 is cleared once quiescent cells re-enter to the cell cycle. Using a model of liver regeneration after partial hepatectomy, we found that DN-DBC1 is down-regulated in vivo during regeneration. In fact, WT mice show a decrease in SIRT1 activity during liver regeneration, coincidentally with DN-DBC1 downregulation and the appearance of full length DBC1. This effect on SIRT1 activity was not observed in DBC1 KO mice. Finally, we found that DBC1 KO mice have altered cell cycle progression and liver regeneration after partial hepatectomy, suggesting that DBC1/DN-DBC1 transitions play a role in normal cell cycle progression in vivo after cells leave quiescence. We propose that quiescent cells express DN-DBC1, which either replaces or coexist with the full-length protein, and that restoring of DBC1 is required for normal cell cycle progression in vitro and in vivo. Our results describe for the first time in vivo a naturally occurring form of DBC1, which does not bind SIRT1 and is dynamically regulated, thus contributing to redefine the knowledge about its function.

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Dynamic regulation of the PR-Set7 histone methyltransferase is required for normal cell cycle progression

Genes & Development ◽

10.1101/gad.1984210 ◽

2010 ◽

Vol 24 (22) ◽

pp. 2531-2542 ◽

Cited By ~ 88

Author(s):

S. Wu ◽

W. Wang ◽

X. Kong ◽

L. M. Congdon ◽

K. Yokomori ◽

...

Keyword(s):

Cell Cycle ◽

Normal Cell ◽

Cell Cycle Progression ◽

Histone Methyltransferase ◽

Cycle Progression ◽

Dynamic Regulation ◽

Normal Cell Cycle

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Involvement of DNA-dependent Protein Kinase in Normal Cell Cycle Progression through Mitosis

Journal of Biological Chemistry ◽

10.1074/jbc.m110.212969 ◽

2011 ◽

Vol 286 (14) ◽

pp. 12796-12802 ◽

Cited By ~ 52

Author(s):

Kyung-Jong Lee ◽

Yu-Fen Lin ◽

Han-Yi Chou ◽

Hirohiko Yajima ◽

Kazi R. Fattah ◽

...

Keyword(s):

Cell Cycle ◽

Protein Kinase ◽

Normal Cell ◽

Cell Cycle Progression ◽

Dependent Protein Kinase ◽

Cycle Progression ◽

Dependent Protein ◽

Normal Cell Cycle

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Mitochondrial reactive oxygen species originating from Romo1 exert an important role in normal cell cycle progression by regulating p27Kip1expression

Free Radical Research ◽

10.1080/10715760903038432 ◽

2009 ◽

Vol 43 (8) ◽

pp. 729-737 ◽

Cited By ~ 29

Author(s):

Jin Sil Chung ◽

Seung Baek Lee ◽

Seon Ho Park ◽

Sung Tae Kang ◽

Ah Ram Na ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Cell Cycle ◽

Normal Cell ◽

Cell Cycle Progression ◽

Reactive Oxygen ◽

Oxygen Species ◽

Mitochondrial Reactive Oxygen Species ◽

Cycle Progression ◽

Normal Cell Cycle

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Restoration of miR-193a-5p and miR-146 a-5p Expression Induces G1 Arrest in Colorectal Cancer through Targeting of MDM2/p53

Advanced Pharmaceutical Bulletin ◽

10.15171/apb.2020.017 ◽

2019 ◽

Vol 10 (1) ◽

pp. 130-134 ◽

Cited By ~ 4

Author(s):

Saeed Noorolyai ◽

Elham Baghbani ◽

Leili Aghebati Maleki ◽

Amir Baghbanzadeh Kojabad ◽

Dariush Shanehbansdi ◽

...

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Cell Cycle ◽

Tumor Suppressor ◽

Cell Cycle Progression ◽

Cyclin B ◽

G1 Arrest ◽

Cycle Progression ◽

Ht 29

Purpose: Colorectal cancer (CRC) remains a universal and lethal cancer owing to metastatic and relapsing disease. Currently, the role of microRNAs has been checked in tumorigeneses. Numerous studies have revealed that between the tumor suppressor miRNAs, the reduced expression of miR-146a-5p and -193a-5p in several cancers including CRC tissues are related with tumor progression and poor prognosis of patients. The purpose of this study is to examine the role of miR-146 a-5p and -193 a-5p in CRC cell cycle progression. Methods: The miR-193a-5p and -146 a-5p mimics were transfected into HT-29 CRC cells via jetPEI transfection reagent and their impact was assessed on p53, cyclin B, and NF-kB gene expression. The inhibitory effect of these miRNAs on cell cycle was assessed by flow cytometry. The consequence of miR-193a-5p and miR-146 a-5p on the protein expression level of Murine double minute 2 (MDM2) was assessed by western blotting. Results: miR193a-5p and -146a-5p regulated the expression of MDM2 protein and p53, cyclin B, and NF-kB gene expression in CRC cells. Treatment of HT-29 cells with miRNA-146a-5p and -193a-5p induced G1 cell cycle arrest. Conclusion: The findings of our study suggest that miR146a-5p and -193a-5p may act as a potential tumor suppressor by their influence on cell cycle progression in CRC cells. Thus, miRNA-146a-5p and -193a-5p restoration may be recommended as a potential therapeutic goal in the treatment of CRC patients.

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The highly conserved N-terminal domains of histones H3 and H4 are required for normal cell cycle progression

Molecular and Cellular Biology ◽

10.1128/mcb.11.8.4111-4120.1991 ◽

1991 ◽

Vol 11 (8) ◽

pp. 4111-4120

Author(s):

B A Morgan ◽

B A Mittman ◽

M M Smith

Keyword(s):

Cell Cycle ◽

Normal Cell ◽

Cell Cycle Progression ◽

Histone H3 ◽

Temperature Sensitive ◽

Histone H4 ◽

Cycle Progression ◽

Terminal Domain ◽

Normal Cell Cycle ◽

Terminal Domains

The N-terminal domains of the histones H3 and H4 are highly conserved throughout evolution. Mutant alleles deleted for these N-terminal domains were constructed in vitro and examined for function in vivo in Saccharomyces cerevisiae. Cells containing a single deletion allele of either histone H3 or histone H4 were viable. Deletion of the N-terminal domain of histone H4 caused cells to become sterile and temperature sensitive for growth. The normal cell cycle progression of these cells was also altered, as revealed by a major delay in progression through the G2 + M periods. Deletion of the N-terminal domain of histone H3 had only minor effects on mating and the temperature-sensitive growth of mutant cells. However, like the H4 mutant, the H3 mutants had a significant delay in completing the G2 + M periods of the division cycle. Double mutants containing N-terminal domain deletions of both histone H3 and histone H4 were inviable. The phenotypes of cells subject to this synthetic lethality suggest that the N-terminal domains are required for functions essential throughout the cell division cycle and provide genetic evidence that histones are randomly distributed during chromosome replication.

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USP48 Governs Cell Cycle Progression by Regulating the Protein Level of Aurora B

International Journal of Molecular Sciences ◽

10.3390/ijms22168508 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8508

Author(s):

Ainsley Mike Antao ◽

Kamini Kaushal ◽

Soumyadip Das ◽

Vijai Singh ◽

Bharathi Suresh ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Aurora B ◽

Deubiquitinating Enzymes ◽

Cycle Progression ◽

Protein Levels ◽

Steady State Levels ◽

Cycle Regulation ◽

Normal Cell Cycle

Deubiquitinating enzymes play key roles in the precise modulation of Aurora B—an essential cell cycle regulator. The expression of Aurora B increases before the onset of mitosis and decreases during mitotic exit; an imbalance in these levels has a severe impact on the fate of the cell cycle. Dysregulation of Aurora B can lead to aberrant chromosomal segregation and accumulation of errors during mitosis, eventually resulting in cytokinesis failure. Thus, it is essential to identify the precise regulatory mechanisms that modulate Aurora B levels during the cell division cycle. Using a deubiquitinase knockout strategy, we identified USP48 as an important candidate that can regulate Aurora B protein levels during the normal cell cycle. Here, we report that USP48 interacts with and stabilizes the Aurora B protein. Furthermore, we showed that the deubiquitinating activity of USP48 helps to maintain the steady-state levels of Aurora B protein by regulating its half-life. Finally, USP48 knockout resulted in delayed progression of cell cycle due to accumulation of mitotic defects and ultimately cytokinesis failure, suggesting the role of USP48 in cell cycle regulation.

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Differential induction of ‘metabolic genes’ after mitogen stimulation and during normal cell cycle progression

Journal of Cell Science ◽

10.1242/jcs.107.1.241 ◽

1994 ◽

Vol 107 (1) ◽

pp. 241-252 ◽

Cited By ~ 1

Author(s):

C. Burger ◽

M. Wick ◽

S. Brusselbach ◽

R. Muller

Keyword(s):

Cell Cycle ◽

Normal Cell ◽

Cell Cycle Progression ◽

S Phase ◽

Cycle Progression ◽

Genes Encoding ◽

A Cell ◽

Induced Genes ◽

Cycle Dependent ◽

Normal Cell Cycle

Mitogenic stimulation of quiescent cells not only triggers the cell division cycle but also induces an increase in cell volume, associated with an activation of cellular metabolism. It is therefore likely that genes encoding enzymes and other proteins involved in energy metabolism and biosynthetic pathways represent a major class of mitogen-induced genes. In the present study, we investigated in the non-established human fibroblast line WI-38 the induction by mitogens of 17 genes whose products play a role in different metabolic processes. We show that these genes fall into 4 different categories, i.e. non-induced genes, immediate early (IE) primary genes, delayed early (DE) secondary genes and late genes reaching peak levels in S-phase. In addition, we have analysed the regulation of these genes during normal cell cycle progression, using HL-60 cells separated by counterflow elutriation. A clear cell cycle regulation was seen with those genes that are induced in S-phase, i.e. thymidine kinase, thymidylate synthase and dihydrofolate reductase. In addition, two DE genes showed a cell cycle dependent expression. Ornithine decarboxylase mRNA increased around mid-G1, reaching maximum levels in S/G2, while hexokinase mRNA expression was highest in early G1. In contrast, the expression of other DE and IE genes did not fluctuate during the cell cycle, a result that was confirmed with elutriated WI-38 and serum-stimulated HL-60 cells. These observations suggest that G0-->S and G1-->S transition are distinct processes, exhibiting characteristic programmes of gene regulation, and merging around S-phase entry.

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