Fulfilling the metabolic requirements for cell proliferation

2012 ◽  
Vol 446 (1) ◽  
pp. 1-7 ◽  
Author(s):  
Salvador Moncada ◽  
E. Annie Higgs ◽  
Sergio L. Colombo
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Ubiquitin Ligase ◽  
Cell Cycle Progression ◽  
Ubiquitin Ligases ◽  
S Phase ◽  
Simultaneous Increase ◽  
Anaphase Promoting Complex ◽  
Restriction Point ◽  
Specific Degradation

The activity of key metabolic enzymes is regulated by the ubiquitin ligases that control the function of the cyclins; therefore the activity of these ubiquitin ligases explains the coordination of cell-cycle progression with the supply of substrates necessary for cell duplication. APC/C (anaphase-promoting complex/cyclosome)-Cdh1, the ubiquitin ligase that controls G1- to S-phase transition by targeting specific degradation motifs in cell-cycle proteins, also regulates the glycolysis-promoting enzyme PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3) and GLS1 (glutaminase 1), a critical enzyme in glutaminolysis. A decrease in the activity of APC/C-Cdh1 in mid-to-late G1 releases both proteins, thus explaining the simultaneous increase in the utilization of glucose and glutamine during cell proliferation. This occurs at a time consistent with the point in G1 that has been described as the nutrient-sensitive restriction point and is responsible for the transition from G1 to S. PFKFB3 is also a substrate at the onset of S-phase for the ubiquitin ligase SCF (Skp1/cullin/F-box)-β-TrCP (β-transducin repeat-containing protein), so that the activity of PFKFB3 is short-lasting, coinciding with a peak in glycolysis in mid-to-late G1, whereas the activity of GLS1 remains high throughout S-phase. The differential regulation of the activity of these proteins indicates that a finely-tuned set of mechanisms is activated to fulfil specific metabolic demands at different stages of the cell cycle. These findings have implications for the understanding of cell proliferation in general and, in particular, of cancer, its prevention and treatment.

scholarly journals NEK7 is required for G1 progression and procentriole formation

2017 ◽  
Vol 28 (15) ◽  
pp. 2123-2134 ◽  
Author(s):  
Akshari Gupta ◽  
Yuki Tsuchiya ◽  
Midori Ohta ◽  
Gen Shiratsuchi ◽  
Daiju Kitagawa
Keyword(s):  
Cell Cycle ◽  
Ubiquitin Ligase ◽  
Cell Cycle Progression ◽  
Primary Cilia ◽  
S Phase ◽  
Cycle Progression ◽  
Restriction Point ◽  
Centriole Duplication ◽  
Abnormal Accumulation ◽  
Phase Entry

The decision to commit to the cell cycle is made during G1 through the concerted action of various cyclin–CDK complexes. Not only DNA replication, but also centriole duplication is initiated as cells enter the S-phase. The NIMA-related kinase NEK7 is one of many factors required for proper centriole duplication, as well as for timely cell cycle progression. However, its specific roles in these events are poorly understood. In this study, we find that depletion of NEK7 inhibits progression through the G1 phase in human U2OS cells via down-regulation of various cyclins and CDKs and also inhibits the earliest stages of procentriole formation. Depletion of NEK7 also induces formation of primary cilia in human RPE1 cells, suggesting that NEK7 acts at least before the restriction point during G1. G1-arrested cells in the absence of NEK7 exhibit abnormal accumulation of the APC/C cofactor Cdh1 at the vicinity of centrioles. Furthermore, the ubiquitin ligase APC/CCdh1continuously degrades the centriolar protein STIL in these cells, thus inhibiting centriole assembly. Collectively our results demonstrate that NEK7 is involved in the timely regulation of G1 progression, S-phase entry, and procentriole formation.

scholarly journals Regulation of cell cycle drivers by Cullin-RING ubiquitin ligases

2020 ◽  
Vol 52 (10) ◽  
pp. 1637-1651 ◽  
Author(s):  
Sang-Min Jang ◽  
Christophe E. Redon ◽  
Bhushan L. Thakur ◽  
Meriam K. Bahta ◽  
Mirit I. Aladjem
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Cell Cycle Progression ◽  
Ubiquitin Ligases ◽  
Anaphase Promoting Complex ◽  
Cycle Progression ◽  
Cellular Processes ◽  
Cellular Pathways ◽  
Regulation Of Cell Cycle ◽  
F Box Protein

Abstract The last decade has revealed new roles for Cullin-RING ubiquitin ligases (CRLs) in a myriad of cellular processes, including cell cycle progression. In addition to CRL1, also named SCF (SKP1-Cullin 1-F box protein), which has been known for decades as an important factor in the regulation of the cell cycle, it is now evident that all eight CRL family members are involved in the intricate cellular pathways driving cell cycle progression. In this review, we summarize the structure of CRLs and their functions in driving the cell cycle. We focus on how CRLs target key proteins for degradation or otherwise alter their functions to control the progression over the various cell cycle phases leading to cell division. We also summarize how CRLs and the anaphase-promoting complex/cyclosome (APC/C) ligase complex closely cooperate to govern efficient cell cycle progression.

scholarly journals Identification of HiNF-P, a Key Activator of Cell Cycle-Controlled Histone H4 Genes at the Onset of S Phase

2003 ◽  
Vol 23 (22) ◽  
pp. 8110-8123 ◽  
Author(s):  
Partha Mitra ◽  
Rong-Lin Xie ◽  
Ricardo Medina ◽  
Hayk Hovhannisyan ◽  
S. Kaleem Zaidi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Cyclin E ◽  
S Phase ◽  
Phase Cell ◽  
Regulatory Sequences ◽  
Histone H4 ◽  
Restriction Point ◽  
Histone H4 Gene

ABSTRACT At the G1/S phase cell cycle transition, multiple histone genes are expressed to ensure that newly synthesized DNA is immediately packaged as chromatin. Here we have purified and functionally characterized the critical transcription factor HiNF-P, which is required for E2F-independent activation of the histone H4 multigene family. Using chromatin immunoprecipitation analysis and ligation-mediated PCR-assisted genomic sequencing, we show that HiNF-P interacts with conserved H4 cell cycle regulatory sequences in vivo. Antisense inhibition of HiNF-P reduces endogenous histone H4 gene expression. Furthermore, we find that HiNF-P utilizes NPAT/p220, a substrate of the cyclin E/cyclin-dependent kinase 2 (CDK2) kinase complex, as a key coactivator to enhance histone H4 gene transcription. The biological role of HiNF-P is reflected by impeded cell cycle progression into S phase upon antisense-mediated reduction of HiNF-P levels. Our results establish that HiNF-P is the ultimate link in a linear signaling pathway that is initiated with the growth factor-dependent induction of cyclin E/CDK2 kinase activity at the restriction point and culminates in the activation of histone H4 genes through HiNF-P at the G1/S phase transition.

scholarly journals Nonperiodic Activity of the Human Anaphase-Promoting Complex–Cdh1 Ubiquitin Ligase Results in Continuous DNA Synthesis Uncoupled from Mitosis

2000 ◽  
Vol 20 (20) ◽  
pp. 7613-7623 ◽  
Author(s):  
Claus Storgaard Sørensen ◽  
Claudia Lukas ◽  
Edgar R. Kramer ◽  
Jan-Michael Peters ◽  
Jiri Bartek ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Dna Replication ◽  
Dna Synthesis ◽  
Ubiquitin Ligase ◽  
Mammalian Cells ◽  
Kinase Inhibitor ◽  
Cyclin B1 ◽  
S Phase ◽  
Anaphase Promoting Complex

ABSTRACT Ubiquitin-proteasome-mediated destruction of rate-limiting proteins is required for timely progression through the main cell cycle transitions. The anaphase-promoting complex (APC), periodically activated by the Cdh1 subunit, represents one of the major cellular ubiquitin ligases which, in Saccharomyces cerevisiae andDrosophila spp., triggers exit from mitosis and during G1 prevents unscheduled DNA replication. In this study we investigated the importance of periodic oscillation of the APC-Cdh1 activity for the cell cycle progression in human cells. We show that conditional interference with the APC-Cdh1 dissociation at the G1/S transition resulted in an inability to accumulate a surprisingly broad range of critical mitotic regulators including cyclin B1, cyclin A, Plk1, Pds1, mitosin (CENP-F), Aim1, and Cdc20. Unexpectedly, although constitutively assembled APC-Cdh1 also delayed G1/S transition and lowered the rate of DNA synthesis during S phase, some of the activities essential for DNA replication became markedly amplified, mainly due to a progressive increase of E2F-dependent cyclin E transcription and a rapid turnover of the p27Kip1 cyclin-dependent kinase inhibitor. Consequently, failure to inactivate APC-Cdh1 beyond the G1/S transition not only inhibited productive cell division but also supported slow but uninterrupted DNA replication, precluding S-phase exit and causing massive overreplication of the genome. Our data suggest that timely oscillation of the APC-Cdh1 ubiquitin ligase activity represents an essential step in coordinating DNA replication with cell division and that failure of mechanisms regulating association of APC with the Cdh1 activating subunit can undermine genomic stability in mammalian cells.

scholarly journals A Critical Role for Cyclin C in Promotion of the Hematopoietic Cell Cycle by Cooperation with c-Myc

1998 ◽  
Vol 18 (6) ◽  
pp. 3445-3454 ◽  
Author(s):  
Zhao-Jun Liu ◽  
Takahiro Ueda ◽  
Tadaaki Miyazaki ◽  
Nobuyuki Tanaka ◽  
Shinichiro Mine ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Line ◽  
Cell Cycle Progression ◽  
Critical Role ◽  
S Phase ◽  
Early Gene ◽  
Cycle Progression ◽  
Cyclin C ◽  
Growth Properties

ABSTRACT Cyclin C, a putative G1 cyclin, was originally isolated through its ability to complement a Saccharomyces cerevisiae strain lacking the G1 cyclin geneCLN1-3. Unlike cyclins D1 and E, the other two G1 cyclins obtained by the same approach and subsequently shown to play important roles during the G1/S transition, there is thus far no evidence to support the hypothesis that cyclin C is indeed critical for the promotion of cell cycle progression. In BAF-B03 cells, an interleukin 3 (IL-3)-dependent murine pro-B-cell line, cyclin C gene mRNA was induced at the G1/S phase upon IL-3 stimulation and reached a maximal level in the S phase. Enforced expression of exogenous cyclin C in this cell line failed to alter its growth properties. In the present study, we examined whether cyclin C is capable of cooperating with the cytokine-responsive immediate-early gene products c-Myc and c-Fos in the promotion of cell proliferation. We found that cyclin C is able to cooperate functionally with c-Myc, but not c-Fos, to induce both BAF-B03 cell proliferation in a cytokine-independent fashion and the formation of cell clusters. Furthermore, cyclin C was primarily responsible for the induction of cdc2 gene expression. Our data define a novel role for cyclin C in the regulation of both the G1/S and G2/M phases of the cell cycle, and this effect appears to be independent of the activity of CDK8 in the control of transcription.

The anaphase-promoting complex (APC): the sum of its parts?

2004 ◽  
Vol 32 (5) ◽  
pp. 724-727 ◽  
Author(s):  
L.A. Passmore
Keyword(s):  
Cell Cycle ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Ligases ◽  
Anaphase Promoting Complex ◽  
Activator Proteins ◽  
Related Proteins ◽  
Single Subunit ◽  
Insight Into

The APC (anaphase-promoting complex) is a multisubunit E3 ubiquitin ligase that targets cell-cycle-related proteins for degradation by the 26 S proteasome. The APC contains at least 13 subunits and is regulated by the binding of co-activator proteins and by phosphorylation. It is not known why the APC contains 13 subunits when many other ubiquitin ligases are small single-subunit enzymes. In the present study, the structures and functions of individual APC subunits are discussed. By dissecting the roles of its parts, we hope to gain insight into the mechanism of the intact APC.

scholarly journals Day/Night Separation of Oxygenic Energy Metabolism and Nuclear DNA Replication in the Unicellular Red AlgaCyanidioschyzon merolae

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Shin-ya Miyagishima ◽  
Atsuko Era ◽  
Tomohisa Hasunuma ◽  
Mami Matsuda ◽  
Shunsuke Hirooka ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Dna Replication ◽  
Energy Metabolism ◽  
Cell Cycle Progression ◽  
Nuclear Dna ◽  
S Phase ◽  
Cycle Progression ◽  
Content Type

ABSTRACTThe transition from G1to S phase and subsequent nuclear DNA replication in the cells of many species of eukaryotic algae occur predominantly during the evening and night in the absence of photosynthesis; however, little is known about how day/night changes in energy metabolism and cell cycle progression are coordinated and about the advantage conferred by the restriction of S phase to the night. Using a synchronous culture of the unicellular red algaCyanidioschyzon merolae, we found that the levels of photosynthetic and respiratory activities peak during the morning and then decrease toward the evening and night, whereas the pathways for anaerobic consumption of pyruvate, produced by glycolysis, are upregulated during the evening and night as reported recently in the green algaChlamydomonas reinhardtii. Inhibition of photosynthesis by 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU) largely reduced respiratory activity and the amplitude of the day/night rhythm of respiration, suggesting that the respiratory rhythm depends largely on photosynthetic activity. Even when the timing of G1/S-phase transition was uncoupled from the day/night rhythm by depletion of retinoblastoma-related (RBR) protein, the same patterns of photosynthesis and respiration were observed, suggesting that cell cycle progression and energy metabolism are regulated independently. Progression of the S phase under conditions of photosynthesis elevated the frequency of nuclear DNA double-strand breaks (DSB). These results suggest that the temporal separation of oxygenic energy metabolism, which causes oxidative stress, from nuclear DNA replication reduces the risk of DSB during cell proliferation inC. merolae.IMPORTANCEEukaryotes acquired chloroplasts through an endosymbiotic event in which a cyanobacterium or a unicellular eukaryotic alga was integrated into a previously nonphotosynthetic eukaryotic cell. Photosynthesis by chloroplasts enabled algae to expand their habitats and led to further evolution of land plants. However, photosynthesis causes greater oxidative stress than mitochondrion-based respiration. In seed plants, cell division is restricted to nonphotosynthetic meristematic tissues and populations of photosynthetic cells expand without cell division. Thus, seemingly, photosynthesis is spatially sequestrated from cell proliferation. In contrast, eukaryotic algae possess photosynthetic chloroplasts throughout their life cycle. Here we show that oxygenic energy conversion (daytime) and nuclear DNA replication (night time) are temporally sequestrated inC. merolae. This sequestration enables “safe” proliferation of cells and allows coexistence of chloroplasts and the eukaryotic host cell, as shown in yeast, where mitochondrial respiration and nuclear DNA replication are temporally sequestrated to reduce the mutation rate.

scholarly journals The RASSF1A Tumor Suppressor Restrains Anaphase-Promoting Complex/Cyclosome Activity during the G1/S Phase Transition To Promote Cell Cycle Progression in Human Epithelial Cells

2008 ◽  
Vol 28 (10) ◽  
pp. 3190-3197 ◽  
Author(s):  
Angelique W. Whitehurst ◽  
Rosalyn Ram ◽  
Latha Shivakumar ◽  
Boning Gao ◽  
John D. Minna ◽  
...  
Keyword(s):  
Phase Transition ◽  
Cell Cycle ◽  
Tumor Suppressor ◽  
Epithelial Cells ◽  
Cyclin D1 ◽  
Cell Cycle Progression ◽  
S Phase ◽  
Phase Cell ◽  
Anaphase Promoting Complex ◽  
Cycle Progression

ABSTRACT Multiple molecular lesions in human cancers directly collaborate to deregulate proliferation and suppress apoptosis to promote tumorigenesis. The candidate tumor suppressor RASSF1A is commonly inactivated in a broad spectrum of human tumors and has been implicated as a pivotal gatekeeper of cell cycle progression. However, a mechanistic account of the role of RASSF1A gene inactivation in tumor initiation is lacking. Here we have employed loss-of-function analysis in human epithelial cells for a detailed investigation of the contribution of RASSF1 to cell cycle progression. We found that RASSF1A has dual opposing regulatory connections to G1/S phase cell cycle transit. RASSF1A associates with the Ewing sarcoma breakpoint protein, EWS, to limit accumulation of cyclin D1 and restrict exit from G1. Surprisingly, we found that RASSF1A is also required to restrict SCFβTrCP activity to allow G/S phase transition. This restriction is required for accumulation of the anaphase-promoting complex/cyclosome (APC/C) inhibitor Emi1 and the concomitant block of APC/C-dependent cyclin A turnover. The consequence of this relationship is inhibition of cell cycle progression in normal epithelial cells upon RASSF1A depletion despite elevated cyclin D1 concentrations. Progression to tumorigenicity upon RASSF1A gene inactivation should therefore require collaborating genetic aberrations that bypass the consequences of impaired APC/C regulation at the G1/S phase cell cycle transition.

scholarly journals A Cds1-Mediated Checkpoint Protects the MBF Activator Rep2 from Ubiquitination by Anaphase-Promoting Complex/Cyclosome-Ste9 at S-Phase Arrest in Fission Yeast

2009 ◽  
Vol 29 (18) ◽  
pp. 4959-4970 ◽  
Author(s):  
Zhaoqing Chu ◽  
Majid Eshaghi ◽  
Suk Yean Poon ◽  
Jianhua Liu
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Transcriptional Activity ◽  
S Phase ◽  
Anaphase Promoting Complex ◽  
Cell Recovery ◽  
Cycle Progression ◽  
Phase Arrest ◽  
S Phase Arrest

ABSTRACT Transcription of the MluI cell cycle box (MCB) motif-containing genes at G1 phase is regulated by the MCB-binding factors (MBF) (also called DSC1) in Schizosaccharomyces pombe. Upon S-phase arrest, the MBF transcriptional activity is induced through the accumulation of the MBF activator Rep2. In this study, we show that the turnover of Rep2 is attributable to ubiquitin-mediated proteolysis. Levels of Rep2 oscillate during the cell cycle, with a peak at G1 phase, coincident with the MBF activity. Furthermore, we show that Rep2 ubiquitination requires the function of the E3 ligase anaphase-promoting complex/cyclosome (APC/C). Ste9 can be phosphorylated by the checkpoint kinase Cds1 in vitro, and its inhibition/phosphorylation at S-phase arrest is dependent on the function of Cds1. Our data indicate that the Cds1-dependent stabilization of Rep2 is achieved through the inhibition/phosphorylation of APC/C-Ste9 at the onset of S-phase arrest. Stabilization of Rep2 is important for stimulating transcription of the MBF-dependent genes to ensure a sufficient supply of proteins essential for cell recovery from S-phase arrest. We propose that oscillation of Rep2 plays a role in regulation of periodic transcription of the MBF-dependent genes during cell cycle progression.

scholarly journals Activity of the APCCdh1 form of the anaphase-promoting complex persists until S phase and prevents the premature expression of Cdc20p

2001 ◽  
Vol 154 (1) ◽  
pp. 85-94 ◽  
Author(s):  
James N. Huang ◽  
Iha Park ◽  
Eric Ellingson ◽  
Laurie E. Littlepage ◽  
David Pellman
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
S Phase ◽  
Cyclin Dependent Kinase ◽  
Anaphase Promoting Complex ◽  
Cycle Progression ◽  
Essential Step ◽  
Complete Inactivation ◽  
Regulatory Loop ◽  
Normal Cell Cycle

Cell cycle progression is driven by waves of cyclin expression coupled with regulated protein degradation. An essential step for initiating mitosis is the inactivation of proteolysis mediated by the anaphase-promoting complex/cyclosome (APC/C) bound to its regulator Cdh1p/Hct1p. Yeast APCCdh1 was proposed previously to be inactivated at Start by G1 cyclin/cyclin-dependent kinase (CDK). Here, we demonstrate that in a normal cell cycle APCCdh1 is inactivated in a graded manner and is not extinguished until S phase. Complete inactivation of APCCdh1 requires S phase cyclins. Further, persistent APCCdh1 activity throughout G1 helps to ensure the proper timing of Cdc20p expression. This suggests that S phase cyclins have an important role in allowing the accumulation of mitotic cyclins and further suggests a regulatory loop among S phase cyclins, APCCdh1, and APCCdc20.

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