Phosphorylation-dependent prolyl isomerization: a novel cell cycle regulatory mechanism

2000 ◽  
pp. 83-96 ◽  
Author(s):  
Kun Ping Lu
Keyword(s):  
Cell Cycle ◽  
Regulatory Mechanism

scholarly journals Circadian regulation of c-MYC in mice

2020 ◽  
Vol 117 (35) ◽  
pp. 21609-21617
Author(s):  
Zhenxing Liu ◽  
Christopher P. Selby ◽  
Yanyan Yang ◽  
Laura A. Lindsey-Boltz ◽  
Xuemei Cao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Circadian Clock ◽  
Tumor Suppressors ◽  
Feedback Loop ◽  
Cell Cycle Progression ◽  
Regulatory Mechanism ◽  
Clock Genes ◽  
Circadian Regulation ◽  
Cycle Progression ◽  
Insight Into

The circadian clock is a global regulatory mechanism that controls the expression of 50 to 80% of transcripts in mammals. Some of the genes controlled by the circadian clock are oncogenes or tumor suppressors. Among theseMychas been the focus of several studies which have investigated the effect of clock genes and proteins onMyctranscription and MYC protein stability. Other studies have focused on effects ofMycmutation or overproduction on the circadian clock in comparison to their effects on cell cycle progression and tumorigenesis. Here we have used mice with mutations in the essential clock genesBmal1,Cry1,andCry2to gain further insight into the effect of the circadian clock on this important oncogene/oncoprotein and tumorigenesis. We find that mutation of bothCry1andCry2, which abolishes the negative arm of the clock transcription–translation feedback loop (TTFL), causes down-regulation of c-MYC, and mutation ofBmal1,which abolishes the positive arm of TTFL, causes up-regulation of the c-MYC protein level in mouse spleen. These findings must be taken into account in models of the clock disruption–cancer connection.

scholarly journals Dynamic instability of microtubules is regulated by force

2003 ◽  
Vol 161 (6) ◽  
pp. 1029-1034 ◽  
Author(s):  
Marcel E. Janson ◽  
Mathilde E. de Dood ◽  
Marileen Dogterom
Keyword(s):  
Cell Cycle ◽  
Regulatory Mechanism ◽  
Dynamic Instability ◽  
Protein Structures ◽  
Regulatory Effects ◽  
Elongation Phase

Microtubules are long filamentous protein structures that randomly alternate between periods of elongation and shortening in a process termed dynamic instability. The average time a microtubule spends in an elongation phase, known as the catastrophe time, is regulated by the biochemical machinery of the cell throughout the cell cycle. In this light, observed changes in the catastrophe time near cellular boundaries (Brunner, D., and P. Nurse. 2000. Cell. 102:695–704; Komarova, Y.A., I.A. Vorobjev, and G.G. Borisy. 2002. J. Cell Sci. 115:3527–3539) may be attributed to regulatory effects of localized proteins. Here, we argue that the pushing force generated by a microtubule when growing against a cellular object may itself provide a regulatory mechanism of the catastrophe time. We observed an up to 20-fold, force-dependent decrease in the catastrophe time when microtubules grown from purified tubulin were polymerizing against microfabricated barriers. Comparison with catastrophe times for microtubules growing freely at different tubulin concentrations leads us to conclude that force reduces the catastrophe time only by limiting the rate of tubulin addition.

scholarly journals Feedback Control of DnaA-Mediated Replication Initiation by Replisome-Associated HdaA Protein in Caulobacter

2009 ◽  
Vol 191 (18) ◽  
pp. 5706-5716 ◽  
Author(s):  
Justine Collier ◽  
Lucy Shapiro
Keyword(s):  
Escherichia Coli ◽  
Cell Cycle ◽  
Regulatory Mechanism ◽  
Caulobacter Crescentus ◽  
Replication Initiation ◽  
Dnaa Protein ◽  
Additional Layer ◽  
Initiation Of Dna Replication ◽  
The Right ◽  
Feedback Regulatory Mechanism

ABSTRACT Chromosome replication in Caulobacter crescentus is tightly regulated to ensure that initiation occurs at the right time and only once during the cell cycle. The timing of replication initiation is controlled by both CtrA and DnaA. CtrA binds to and silences the origin. Upon the clearance of CtrA from the cell, the DnaA protein accumulates and allows loading of the replisome at the origin. Here, we identify an additional layer of replication initiation control that is mediated by the HdaA protein. In Escherichia coli, the Hda protein inactivates DnaA after replication initiation. We show that the Caulobacter HdaA homologue is necessary to restrict the initiation of DNA replication to only once per cell cycle and that it dynamically colocalizes with the replisome throughout the cell cycle. Moreover, the transcription of hdaA is directly activated by DnaA, providing a robust feedback regulatory mechanism that adjusts the levels of HdaA to inactivate DnaA.

scholarly journals Regulation of DNA Replication Initiation by Chromosome Structure

2015 ◽  
Vol 197 (21) ◽  
pp. 3370-3377 ◽  
Author(s):  
David Magnan ◽  
David Bates
Keyword(s):  
Cell Cycle ◽  
Phase Transitions ◽  
Growth Phase ◽  
Chromosome Structure ◽  
Regulatory Mechanism ◽  
Replication Initiation ◽  
Dna Replication Initiation ◽  
Genetic Switches ◽  
Structure Density ◽  
Nucleoid Structure

Recent advancements in fluorescence imaging have shown that the bacterial nucleoid is surprisingly dynamic in terms of both behavior (movement and organization) and structure (density and supercoiling). Links between chromosome structure and replication initiation have been made in a number of species, and it is universally accepted that favorable chromosome structure is required for initiation in all cells. However, almost nothing is known about whether cells use changes in chromosome structure as a regulatory mechanism for initiation. Such changes could occur during natural cell cycle or growth phase transitions, or they could be manufactured through genetic switches of topoisomerase and nucleoid structure genes. In this review, we explore the relationship between chromosome structure and replication initiation and highlight recent work implicating structure as a regulatory mechanism. A three-component origin activation model is proposed in which thermal and topological structural elements are balanced withtrans-acting control elements (DnaA) to allow efficient initiation control under a variety of nutritional and environmental conditions. Selective imbalances in these components allow cells to block replication in response to cell cycle impasse, override once-per-cell-cycle programming during growth phase transitions, and promote reinitiation when replication forks fail to complete.

scholarly journals Comprehensive Analysis Reveals the Potential Regulatory Mechanism Between Ub–Proteasome System and Cell Cycle in Colorectal Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Zhiyuan Zhang ◽  
Jingwen Chen ◽  
Wentao Tang ◽  
Qingyang Feng ◽  
Jianmin Xu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Regulatory Mechanism ◽  
Differentially Expressed ◽  
Potential Mechanism ◽  
Ppi Network ◽  
Protein Coding ◽  
Protein Protein Interaction ◽  
Differentially Expressed Protein ◽  
Cycle System

The ubiquitin (Ub)–proteasome system (UPS) is an important regulatory component in colorectal cancer (CRC), and the cell cycle is also characterized to play a significant role in CRC. In this present study, we firstly identified UPS-associated differentially expressed genes and all the differentially expressed protein-coding genes in CRC through three differential analyses. UPS-associated genes were also further analyzed via survival analysis. A weighted gene co-expression network analysis (WGCNA) was used to identify the cell cycle-associated genes. We used protein–protein interaction (PPI) network to comprehensively mine the potential mechanism of the UPS–cell cycle regulatory axis. Moreover, we constructed a signature based on UPS-associated genes to predict the overall survival of CRC patients. Our research provides a novel insight view of the UPS and cell cycle system in CRC.

scholarly journals CDK-Mediated Phosphorylation of FANCD2 Promotes Mitotic Fidelity

2020 ◽  
Author(s):  
Juan A. Cantres-Velez ◽  
Justin L. Blaize ◽  
David A. Vierra ◽  
Rebecca A. Boisvert ◽  
Jada M. Garzon ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bone Marrow ◽  
Fanconi Anemia ◽  
Genetic Disease ◽  
Regulatory Mechanism ◽  
Bone Marrow Failure ◽  
Chromosome Instability ◽  
S Phase ◽  
Rare Genetic Disease ◽  
Increased Risk

AbstractFanconi anemia (FA) is a rare genetic disease characterized by increased risk for bone marrow failure and cancer. The FA proteins function together to repair damaged DNA. A central step in the activation of the FA pathway is the monoubiquitination of the FANCD2 and FANCI proteins under conditions of cellular stress and during S-phase of the cell cycle. The regulatory mechanisms governing S-phase monoubiquitination, in particular, are poorly understood. In this study, we have identified a CDK regulatory phospho-site (S592) proximal to the site of FANCD2 monoubiquitination. FANCD2 S592 phosphorylation was detected by LC-MS/MS and by immunoblotting with a S592 phospho-specific antibody. Mutation of S592 leads to abrogated monoubiquitination of FANCD2 during S-phase. Furthermore, FA-D2 (FANCD2-/-) patient cells expressing S592 mutants display reduced proliferation under conditions of replication stress and increased mitotic aberrations, including micronuclei and multinucleated cells. Our findings describe a novel cell cycle-specific regulatory mechanism for the FANCD2 protein that promotes mitotic fidelity.Author SummaryFanconi anemia (FA) is a rare genetic disease characterized by high risk for bone marrow failure and cancer. FA has strong genetic and biochemical links to hereditary breast and ovarian cancer. The FA proteins function to repair DNA damage and to maintain genome stability. The FANCD2 protein functions at a critical stage of the FA pathway and its posttranslational modification is defective in >90% of FA patients. However, the function, and regulation of FANCD2, particularly under unperturbed cellular conditions, remains remarkably poorly characterized. In this study, we describe a novel mechanism of regulation of the FANCD2 protein during S-phase of the cell cycle. CDK-mediated phosphorylation of FANCD2 on S592 promotes the ubiquitination of FANCD2 during S-phase. Disruption of this phospho-regulatory mechanism results in compromised mitotic fidelity and an increase in mitotic chromosome instability.

scholarly journals Differential expression of receptors for Shiga and Cholera toxin is regulated by the cell cycle

2002 ◽  
Vol 115 (4) ◽  
pp. 817-826 ◽  
Author(s):  
Irina Majoul ◽  
Tobias Schmidt ◽  
Maria Pomasanova ◽  
Evgenia Boutkevich ◽  
Yuri Kozlov ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Surface ◽  
Cholera Toxin ◽  
Differential Expression ◽  
Pc12 Cells ◽  
Shiga Toxin ◽  
Regulatory Mechanism ◽  
Vero Cells ◽  
S Phase ◽  
Cycle Dependent

Cholera and Shiga toxin bind to the cell surface via glycolipid receptors GM1 and Gb3, respectively. Surprisingly, the majority of Vero cells from a non-synchronized population bind either Cholera or Shiga toxin but not both toxins. The hypothesis that the differential expression of toxin receptors is regulated by the cell cycle was tested. We find that Cholera toxin binds preferentially in G0/G1, with little binding through S-phase to telophase,whereas Shiga toxin binds maximally through G2 to telophase but does not bind during G0/G1 and S-phase. The changes result from the corresponding changes in Gb3 and GM1 synthesis, not from variations of receptor transport to the cell surface. The changes do not reflect competition of Gb3 and GM1 synthesis for lactosylceramide. Cells as diverse as Vero cells, PC12 cells and astrocytes show the same cell-cycle-dependent regulation of glycosphingolipid receptors,suggesting that this novel phenomenon is based on a conserved regulatory mechanism.

scholarly journals High Aurora Kinase and Low Dido Levels Characterizes a Sub-Group of Chronic Lymphocytic Leukemia with Chromosomal Gains and High White Blood Cell Counts: Potential Inter-Regulatory Role of E2F1 and Mir-17-92 Cluster

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2029-2029
Author(s):  
Felipe C Souza ◽  
Josiane L Schiavinato ◽  
Antonio R. Lucena-Araujo ◽  
Fabio M Oliveira ◽  
Amelia G Araújo ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Chronic Lymphocytic Leukemia ◽  
Blood Cell ◽  
White Blood Cell ◽  
Chromosomal Instability ◽  
Regulatory Mechanism ◽  
Lymphocytic Leukemia ◽  
Transcript Levels ◽  
Expression Levels

Abstract During cell cycle division Aurora kinases (AURKA and AURKB) participate in the formation and control of mitotic spindle fibers, while, protein isoforms (DIDO1, DIDO2 and DIDO3), derived by alternative splicing of the DIDO gene, assist at the junction of microtubules to kinetochores. Thus, both are relevant to cell cycle maintenance. Interestingly, overexpression (or gain of function) of AURKs or low expression (or loss of function of DIDO) are both associated with centrosomal amplification and chromosomal instability (CIN), leading to aneuploidy. Among hematological diseases with CIN records, chronic lymphocytic leukemia (CLL) can display centrosome amplification and changes in AURKs expression levels leading to aneuploidy. The Despite this, there are no studies evaluating the potential association of these genes with CIN in CLL. By evaluating their gene expression levels in CLL samples from patients with or without chromosomal aberrations, we show that increased levels of AURKA and AURKB and, conversely, reduced levels of DIDO variants, are both significantly associated with chromosomal gains and with increased white blood cell (WBC) counts. Clearly, CLL samples without any cytogenetic abnormality had expression levels similar to samples mostly harboring non-numerical aberrations. The finding that the expression levels of AURKs and DIDO variants are completely opposed, showing a discrete inter-related pattern, led us to investigate the potential regulatory mechanism behind this. Given that other have previously shown that the oncogenic miR-17-92 cluster is significantly upregulated in purified CLL patient cells expressing unmutated IGHV genes (as compared to mutated patient cells), and that miR-17 is expressed at significantly higher levels in unmutated or ZAP-70 high cases (bad prognostic cases generally associated with chromosomal instability), we investigated the potential negative regulation of DIDO variants by microRNAs from this cluster. In addition, based on the already described regulatory mechanism by which AURKA overexpression induces the E2F1-mediated transcription upregulation of the miR-17-92 cluster (with an observed expression correlation of both proteins in cancer specimens); we decided to investigate this regulatory axis in CLL. Notably, we found that all DIDO variants are predicted to be heavily targeted by several miRs of this oncogenic cluster. We show that CLL samples with low DIDO expression, in addition to the already mentioned AURK high levels, displayed significant higher levels of the transcription factor E2F1 and of its transcriptional target, the miR-17-92 primary transcript (MIR17HG). Moreover, by using the NTERA-2 cell line as a model, we show that siRNA knockdown of AURKA (at the transcript and protein level, as confirmed by qPCR and western blot) is accompanied by a striking significant reduction of E2F1 and also of MIR17HG. Furthermore, transfection of NTERA-2 cells with synthetic mimics of the miR-17~92 cluster (namely, miR-19a, miR-20a and miR-92a) results in a clear and significant reduction in the transcript levels of all DIDO variants. Finally, specific siRNA inhibition of the DIDO3 variant (but not the others) led to a significant reduction in the transcript levels of all DIDO variants, indicating an additional mechanism contributing to the downregulation of DIDO transcripts. Altogether, our results demonstrate the existence of a potential interconnected regulatory mechanism between AURK and DIDO, associated with CIN and higher WBC counts in CLL. More importantly, the high expression levels of AURKs and the associated low levels of DIDO variants are specifically associated with cytogenetic abnormalities presenting chromosomal gains, highlighting the specific cellular mechanism underlying the CIN observed in this distinct CLL group. Given the central role of CIN in cancer genesis and progression, these findings will likely have an important impact on prognosis or treatment of CLL. Funded by: FAPESP, CNPq and CAPES. Disclosures No relevant conflicts of interest to declare.

Coxsackievirus replication and the cell cycle: a potential regulatory mechanism for viral persistence/latency

2004 ◽  
Vol 193 (2-3) ◽  
pp. 83-90 ◽  
Author(s):  
Ralph Feuer ◽  
Ignacio Mena ◽  
Robb R. Pagarigan ◽  
Daniel E. Hassett ◽  
J. Lindsay Whitton
Keyword(s):  
Cell Cycle ◽  
Regulatory Mechanism ◽  
Viral Persistence

scholarly journals Phosphorylation of Threonine 61 by Cyclin A/Cdk1 Triggers Degradation of Stem-Loop Binding Protein at the End of S Phase

2008 ◽  
Vol 28 (14) ◽  
pp. 4469-4479 ◽  
Author(s):  
M. Murat Koseoglu ◽  
Lee M. Graves ◽  
William F. Marzluff
Keyword(s):  
Cell Cycle ◽  
Fusion Proteins ◽  
Regulatory Mechanism ◽  
Binding Protein ◽  
Cyclin A ◽  
S Phase ◽  
Mrna Levels ◽  
Histone Mrna ◽  
Stem Loop

ABSTRACT Histone mRNA levels are cell cycle regulated, and a major regulatory mechanism is restriction of stem-loop binding protein (SLBP) to S phase. Degradation of SLBP at the end of S phase results in cessation of histone mRNA biosynthesis, preventing accumulation of histone mRNA until SLBP is synthesized just before entry into the next S phase. Degradation of SLBP requires an SFTTP (58 to 62) and KRKL (95 to 98) sequence, which is a putative cyclin binding site. A fusion protein with the 58-amino-acid sequence of SLBP (amino acids 51 to 108) fused to glutathione S-transferase (GST) is sufficient to mimic SLBP degradation at late S phase. Using GST-SLBP fusion proteins as a substrate, we show that cyclin A/Cdk1 phosphorylates Thr61. Furthermore, knockdown of Cdk1 by RNA interference stabilizes SLBP at the end of S phase. Phosphorylation of Thr61 is necessary for subsequent phosphorylation of Thr60 by CK2 in vitro. Inhibitors of CK2 also prevent degradation of SLBP at the end of S phase. Thus, phosphorylation of Thr61 by cyclin A/Cdk1 primes phosphorylation of Thr60 by CK2 and is responsible for initiating SLBP degradation. We conclude that the increase in cyclin A/Cdk1 activity at the end of S phase triggers degradation of SLBP at S/G2.

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