scholarly journals Protein Phosphatases in G1 Regulation

2020 ◽  
Vol 21 (2) ◽  
pp. 395 ◽  
Author(s):  
Ruth Martín ◽  
Vilte Stonyte ◽  
Sandra Lopez-Aviles
Keyword(s):  
Cell Cycle ◽  
Protein Phosphatases ◽  
Eukaryotic Cells ◽  
Signalling Pathways ◽  
Cyclin Dependent Kinase ◽  
Restriction Point ◽  
Environmental Signals ◽  
Substrate Phosphorylation ◽  
Cell Cycle Machinery

Eukaryotic cells make the decision to proliferate, to differentiate or to cease dividing during G1, before passage through the restriction point or Start. Keeping cyclin-dependent kinase (CDK) activity low during this period restricts commitment to a new cell cycle and is essential to provide the adequate timeframe for the sensing of environmental signals. Here, we review the role of protein phosphatases in the modulation of CDK activity and as the counteracting force for CDK-dependent substrate phosphorylation, in budding and fission yeast. Moreover, we discuss recent findings that place protein phosphatases in the interface between nutritional signalling pathways and the cell cycle machinery.

scholarly journals The Role of Cdh1p in Maintaining Genomic Stability in Budding Yeast

Genetics ◽  
2003 ◽  
Vol 165 (2) ◽  
pp. 489-503 ◽  
Author(s):  
Karen E Ross ◽  
Orna Cohen-Fix
Keyword(s):  
Cell Cycle ◽  
Chromosome Segregation ◽  
Spindle Assembly Checkpoint ◽  
Chromosome Loss ◽  
Cyclin Dependent Kinase ◽  
Anaphase Promoting Complex ◽  
Growth Defects ◽  
Genes Encoding ◽  
Specificity Factor

Abstract Cdh1p, a substrate specificity factor for the cell cycle-regulated ubiquitin ligase, the anaphase-promoting complex/cyclosome (APC/C), promotes exit from mitosis by directing the degradation of a number of proteins, including the mitotic cyclins. Here we present evidence that Cdh1p activity at the M/G1 transition is important not only for mitotic exit but also for high-fidelity chromosome segregation in the subsequent cell cycle. CDH1 showed genetic interactions with MAD2 and PDS1, genes encoding components of the mitotic spindle assembly checkpoint that acts at metaphase to prevent premature chromosome segregation. Unlike cdh1Δ and mad2Δ single mutants, the mad2Δ cdh1Δ double mutant grew slowly and exhibited high rates of chromosome and plasmid loss. Simultaneous deletion of PDS1 and CDH1 caused extensive chromosome missegregation and cell death. Our data suggest that at least part of the chromosome loss can be attributed to kinetochore/spindle problems. Our data further suggest that Cdh1p and Sic1p, a Cdc28p/Clb inhibitor, have overlapping as well as nonoverlapping roles in ensuring proper chromosome segregation. The severe growth defects of both mad2Δ cdh1Δ and pds1Δ cdh1Δ strains were rescued by overexpressing Swe1p, a G2/M inhibitor of the cyclin-dependent kinase, Cdc28p/Clb. We propose that the failure to degrade cyclins at the end of mitosis leaves cdh1Δ mutant strains with abnormal Cdc28p/Clb activity that interferes with proper chromosome segregation.

scholarly journals Budding yeast relies on G1 cyclin specificity to couple cell cycle progression with morphogenetic development

2021 ◽  
Vol 7 (23) ◽  
pp. eabg0007
Author(s):  
Deniz Pirincci Ercan ◽  
Florine Chrétien ◽  
Probir Chakravarty ◽  
Helen R. Flynn ◽  
Ambrosius P. Snijders ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Budding Yeast ◽  
Quantitative Model ◽  
Cyclin Dependent Kinase ◽  
Cycle Progression ◽  
Model Cell ◽  
Mitotic Cyclin ◽  
Substrate Phosphorylation ◽  
The Cost

Two models have been put forward for cyclin-dependent kinase (Cdk) control of the cell cycle. In the qualitative model, cell cycle events are ordered by distinct substrate specificities of successive cyclin waves. Alternatively, in the quantitative model, the gradual rise of Cdk activity from G1 phase to mitosis leads to ordered substrate phosphorylation at sequential thresholds. Here, we study the relative contributions of qualitative and quantitative Cdk control in Saccharomyces cerevisiae. All S phase and mitotic cyclins can be replaced by a single mitotic cyclin, albeit at the cost of reduced fitness. A single cyclin can also replace all G1 cyclins to support ordered cell cycle progression, fulfilling key predictions of the quantitative model. However, single-cyclin cells fail to polarize or grow buds and thus cannot survive. Our results suggest that budding yeast has become dependent on G1 cyclin specificity to couple cell cycle progression to essential morphogenetic events.

scholarly journals Review of rationale and progress toward targeting cyclin-dependent kinase 2 (CDK2) for male contraception†

2020 ◽  
Vol 103 (2) ◽  
pp. 357-367
Author(s):  
Erik B Faber ◽  
Nan Wang ◽  
Gunda I Georg
Keyword(s):  
Cell Cycle ◽  
Binding Site ◽  
Knockout Mice ◽  
Male Contraception ◽  
Cyclin Dependent Kinase ◽  
Compensatory Mechanisms ◽  
Binding Partner ◽  
Male Contraceptive ◽  
Clinical Stages

Abstract Cyclin-dependent kinase 2 (CDK2) is a member of the larger cell cycle regulating CDK family of kinases, activated by binding partner cyclins as its name suggests. Despite its canonical role in mitosis, CDK2 knockout mice are viable but sterile, suggesting compensatory mechanisms for loss of CDK2 in mitosis but not meiosis. Here, we review the literature surrounding the role of CDK2 in meiosis, particularly a cyclin-independent role in complex with another activator, Speedy 1 (SPY1). From this evidence, we suggest that CDK2 could be a viable nonhormonal male contraceptive target. Finally, we review the literature of pertinent CDK2 inhibitors from the preclinical to clinical stages, mostly developed to treat various cancers. To date, there is no potent yet selective CDK2 inhibitor that could be repurposed as a contraceptive without appreciable off-target toxicity. To achieve selectivity for CDK2 over closely related kinases, developing compounds that bind outside the conserved adenosine triphosphate-binding site may be necessary.

scholarly journals A comprehensive model for the proliferation–quiescence decision in response to endogenous DNA damage in human cells

2018 ◽  
Vol 115 (10) ◽  
pp. 2532-2537 ◽  
Author(s):  
Frank S. Heldt ◽  
Alexis R. Barr ◽  
Sam Cooper ◽  
Chris Bakal ◽  
Béla Novák
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Kinase Inhibitor ◽  
Human Cells ◽  
Cyclin Dependent Kinase ◽  
Restriction Point ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Serum Stimulation ◽  
G1 Cells ◽  
External Stimuli

Human cells that suffer mild DNA damage can enter a reversible state of growth arrest known as quiescence. This decision to temporarily exit the cell cycle is essential to prevent the propagation of mutations, and most cancer cells harbor defects in the underlying control system. Here we present a mechanistic mathematical model to study the proliferation–quiescence decision in nontransformed human cells. We show that two bistable switches, the restriction point (RP) and the G1/S transition, mediate this decision by integrating DNA damage and mitogen signals. In particular, our data suggest that the cyclin-dependent kinase inhibitor p21 (Cip1/Waf1), which is expressed in response to DNA damage, promotes quiescence by blocking positive feedback loops that facilitate G1 progression downstream of serum stimulation. Intriguingly, cells exploit bistability in the RP to convert graded p21 and mitogen signals into an all-or-nothing cell-cycle response. The same mechanism creates a window of opportunity where G1 cells that have passed the RP can revert to quiescence if exposed to DNA damage. We present experimental evidence that cells gradually lose this ability to revert to quiescence as they progress through G1 and that the onset of rapid p21 degradation at the G1/S transition prevents this response altogether, insulating S phase from mild, endogenous DNA damage. Thus, two bistable switches conspire in the early cell cycle to provide both sensitivity and robustness to external stimuli.

scholarly journals Cell Cycle Control of Schwann Cell Proliferation: Role of Cyclin-Dependent Kinase-2

2000 ◽  
Vol 20 (12) ◽  
pp. 4627-4634 ◽  
Author(s):  
Ravi Tikoo ◽  
George Zanazzi ◽  
Dov Shiffman ◽  
James Salzer ◽  
Moses V. Chao
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Schwann Cell ◽  
Cell Cycle Control ◽  
Cyclin Dependent Kinase

Role of the p16 tumor suppressor gene in cancer.

1998 ◽  
Vol 16 (3) ◽  
pp. 1197-1206 ◽  
Author(s):  
W H Liggett ◽  
D Sidransky
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Human Cancer ◽  
Suppressor Gene ◽  
Premalignant Lesions ◽  
Early Event ◽  
Cyclin Dependent Kinase ◽  
Primary Tumors

Since its discovery as a CDKI (cyclin-dependent kinase inhibitor) in 1993, the tumor suppressor p16 (INK4A/MTS-1/CDKN2A) has gained widespread importance in cancer. The frequent mutations and deletions of p16 in human cancer cell lines first suggested an important role for p16 in carcinogenesis. This genetic evidence for a causal role was significantly strengthened by the observation that p16 was frequently inactivated in familial melanoma kindreds. Since then, a high frequency of p16 gene alterations were observed in many primary tumors. In human neoplasms, p16 is silenced in at least three ways: homozygous deletion, methylation of the promoter, and point mutation. The first two mechanisms comprise the majority of inactivation events in most primary tumors. Additionally, the loss of p16 may be an early event in cancer progression, because deletion of at least one copy is quite high in some premalignant lesions. p16 is a major target in carcinogenesis, rivaled in frequency only by the p53 tumor-suppressor gene. Its mechanism of action as a CDKI has been elegantly elucidated and involves binding to and inactivating the cyclin D-cyclin-dependent kinase 4 (or 6) complex, and thus renders the retinoblastoma protein inactive. This effect blocks the transcription of important cell-cycle regulatory proteins and results in cell-cycle arrest. Although p16 may be involved in cell senescence, the physiologic role of p16 is still unclear. Future work will focus on studies of the upstream events that lead to p16 expression and its mechanism of regulation, and perhaps lead to better therapeutic strategies that can improve the clinical course of many lethal cancers.

scholarly journals The Role of the Cell Cycle Machinery in Resumption of Postembryonic Development

2004 ◽  
Vol 137 (1) ◽  
pp. 127-140 ◽  
Author(s):  
Rosa Maria Barrôco ◽  
Kris Van Poucke ◽  
Jan H.W. Bergervoet ◽  
Lieven De Veylder ◽  
Steven P.C. Groot ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Postembryonic Development ◽  
Cell Cycle Machinery
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