scholarly journals APC/C: current understanding and future perspectives

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 725 ◽  
Author(s):  
Hiroyuki Yamano
Keyword(s):  
Cell Cycle ◽  
Molecular Mechanisms ◽  
Current Understanding ◽  
Historical Background ◽  
Cell Cycle Regulators ◽  
Anaphase Promoting Complex ◽  
Electron Microscopy Analysis ◽  
Cellular Machinery ◽  
The Many ◽  
Ubiquitin Conjugating Enzymes

The separation of sister chromatids at anaphase, which is regulated by an E3 ubiquitin ligase called the anaphase-promoting complex/cyclosome (APC/C), is arguably the most important irrevocable event during the cell cycle. The APC/C and cyclin-dependent kinase 1 (Cdk1) are just two of the many significant cell cycle regulators and exert control through ubiquitylation and phosphorylation, respectively. The temporal and spatial regulation of the APC/C is achieved by multiple mechanisms, including phosphorylation, interaction with the structurally related co-activators Cdc20 and Cdh1, loading of distinct E2 ubiquitin-conjugating enzymes, binding with inhibitors and differential affinities for various substrates. Since the discovery of APC/C 25 years ago, intensive studies have uncovered many aspects of APC/C regulation, but we are still far from a full understanding of this important cellular machinery. Recent high-resolution cryogenic electron microscopy analysis and reconstitution of the APC/C have greatly advanced our understanding of molecular mechanisms underpinning the enzymatic properties of APC/C. In this review, we will examine the historical background and current understanding of APC/C regulation.

scholarly journals Intricate Regulatory Mechanisms of the Anaphase-Promoting Complex/Cyclosome and Its Role in Chromatin Regulation

2021 ◽  
Vol 9 ◽  
Author(s):  
Tatyana Bodrug ◽  
Kaeli A. Welsh ◽  
Megan Hinkle ◽  
Michael J. Emanuele ◽  
Nicholas G. Brown
Keyword(s):  
Cell Cycle ◽  
Signaling Pathways ◽  
Biological Process ◽  
Conformational Dynamics ◽  
Intimate Relationship ◽  
Regulatory Mechanisms ◽  
Cell Cycle Regulators ◽  
Chromatin Regulation ◽  
Anaphase Promoting Complex

The ubiquitin (Ub)-proteasome system is vital to nearly every biological process in eukaryotes. Specifically, the conjugation of Ub to target proteins by Ub ligases, such as the Anaphase-Promoting Complex/Cyclosome (APC/C), is paramount for cell cycle transitions as it leads to the irreversible destruction of cell cycle regulators by the proteasome. Through this activity, the RING Ub ligase APC/C governs mitosis, G1, and numerous aspects of neurobiology. Pioneering cryo-EM, biochemical reconstitution, and cell-based studies have illuminated many aspects of the conformational dynamics of this large, multi-subunit complex and the sophisticated regulation of APC/C function. More recent studies have revealed new mechanisms that selectively dictate APC/C activity and explore additional pathways that are controlled by APC/C-mediated ubiquitination, including an intimate relationship with chromatin regulation. These tasks go beyond the traditional cell cycle role historically ascribed to the APC/C. Here, we review these novel findings, examine the mechanistic implications of APC/C regulation, and discuss the role of the APC/C in previously unappreciated signaling pathways.

The Cdk and PCNA domains on p21Cip1 both function to inhibit G1/S progression during hyperoxia

2004 ◽  
Vol 286 (3) ◽  
pp. L506-L513 ◽  
Author(s):  
Christopher E. Helt ◽  
Rhonda J. Staversky ◽  
Yi-Jang Lee ◽  
Robert A. Bambara ◽  
Peter C. Keng ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Fluorescent Protein ◽  
Nuclear Antigen ◽  
Cell Cycle Regulators ◽  
Amino Terminal ◽  
Binding Domains ◽  
Green Fluorescent

This study investigates molecular mechanisms underlying cell cycle arrest when cells are exposed to high levels of oxygen (hyperoxia). Hyperoxia has previously been shown to increase expression of the cell cycle regulators p53 and p21. In the current study, we found that p53-deficient human lung adenocarcinoma H1299 cells failed to induce p21 or growth arrest in G1 when exposed to 95% oxygen. Instead, cells arrested in S and G2. Stable expression of p53 restored induction of p21 and G1 arrest without affecting mRNA expression of the other Cip or INK4 G1 kinase inhibitors. To confirm the role of p21 in G1 arrest, we created H1299 cells with tetracycline-inducible expression of enhanced green fluorescent protein (EGFP), EGFP fused to p21 (EGFp21), or EGFP fused to p27 (EGFp27), a related cell cycle inhibitor. The amino terminus of p21 and p27 bind cyclin-dependent kinases (Cdk), whereas the carboxy terminus of p21 binds the sliding clamp proliferating cell nuclear antigen (PCNA). EGFp21 or EGFp27, but not EGFP by itself, restored G1 arrest during hyperoxia. When separately overexpressed, the amino-terminal Cdk and carboxy-terminal PCNA binding domains of p21 each prevented cells from exiting G1 during exposure. These findings demonstrate that exposure in vitro to hyperoxia exerts G1 arrest through p53-dependent induction of p21 that suppresses Cdk and PCNA activity. Because PCNA also participates in DNA repair, these results raise the possibility that p21 also affects repair of oxidized DNA.

scholarly journals JAK/STAT pathway promotes Drosophila neuroblast proliferation via the direct CycE regulation

2020 ◽  
Author(s):  
Lijuan Du ◽  
Jian Wang
Keyword(s):  
Cell Cycle ◽  
Signaling Pathway ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Control Cell ◽  
Proliferative Potential ◽  
Cell Cycle Regulators ◽  
Cycle Progression ◽  
Stat Signaling ◽  
Stat Pathway

AbstractHow neural stem cells regulate their proliferative potential and lineage diversity is a central problem in developmental neurobiology. Drosophila Mushroom bodies (MBs), centers of olfactory learning and memory, are generated by a specific set of neuroblasts (Nbs) that are born in the embryonic stage and continuously proliferate till the end of the pupal stage. Although MB presents an excellent model for studying neural stem cell proliferation, the genetic and molecular mechanisms that control the unique proliferative characteristics of the MB Nbs are largely unknown. Further, the signaling cues controlling cell cycle regulators to promote cell cycle progression in MB Nbs remain poorly understood. Here, we report that JAK/STAT signaling pathway is required for the proliferation activity and maintenance of MB Nbs. Loss of JAK/STAT activity severely reduces the later-born MB neuron types and leads to premature neuroblast termination, which can be rescued by tissue-specific overexpression of CycE and diap1. Higher JAK/STAT pathway activity in MB results in more neurons, without producing supernumerary Nbs. Furthermore, we show that JAK/STAT signaling effector Stat92E directly regulates CycE transcription in MB Nbs. Finally, MB Nb clones of loss or excess CycE phenocopy those of decreased or increased JAK/STAT signaling pathway activities. We conclude that JAK/STAT signaling controls MB Nb proliferative activity through directly regulating CycE expression to control cell cycle progression.

Cell cycle regulators in Drosophila: downstream and part of developmental decisions

1997 ◽  
Vol 110 (5) ◽  
pp. 523-528 ◽  
Author(s):  
C.F. Lehner ◽  
M.E. Lane
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Eukaryotic Cell ◽  
Embryonic Cell ◽  
Developmental Phase ◽  
Cell Cycle Regulators ◽  
Egg Extracts ◽  
Extensive Growth ◽  
New Perspective

The molecular identification of an evolutionarily conserved set of cell cycle regulators in yeast, Xenopus egg extracts, and vertebrate cell culture has opened up a new perspective for understanding the mechanisms that regulate cell proliferation during metazoan development. Now we can study how the crucial regulators of eukaryotic cell cycle progression, the various cyclin/cdk complexes (for a recent review see Nigg (1995) BioEssays 17, 471–480), are turned on or off during development. In Drosophila, this analysis is most advanced, in particular in the case of the rather rigidly programmed embryonic cell cycles that generate the cells of the larvae. In addition, this analysis has revealed how the mitotic cycle is transformed into an endocycle which allows the extensive growth of larvae and oocytes. In contrast, we know little about cyclin/cdk regulation during the imaginal proliferation that generates the cells of the adult. Nevertheless, we will also consider this second developmental phase with its conspicuous regulative character, because it will be of great interest for the analysis of the molecular mechanisms that integrate growth and proliferation during development.

scholarly journals Swm1/Apc13 Is an Evolutionarily Conserved Subunit of the Anaphase-Promoting Complex Stabilizing the Association of Cdc16 and Cdc27

2004 ◽  
Vol 24 (8) ◽  
pp. 3562-3576 ◽  
Author(s):  
Martin Schwickart ◽  
Jan Havlis ◽  
Bianca Habermann ◽  
Aliona Bogdanova ◽  
Alain Camasses ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Budding Yeast ◽  
Small Subunit ◽  
Cell Cycle Regulators ◽  
Anaphase Promoting Complex ◽  
Ubiquitin Ligase Activity ◽  
Evolutionarily Conserved ◽  
Stable Association

ABSTRACT The anaphase-promoting complex (APC/C) is a large ubiquitin-protein ligase which controls progression through anaphase by triggering the degradation of cell cycle regulators such as securin and B-type cyclins. The APC/C is an unusually complex ligase containing at least 10 different, evolutionarily conserved components. In contrast to APC/C's role in cell cycle regulation little is known about the functions of individual subunits and how they might interact with each other. Here, we have analyzed Swm1/Apc13, a small subunit recently identified in the budding yeast complex. Database searches revealed proteins related to Swm1/Apc13 in various organisms including humans. Both the human and the fission yeast homologues are associated with APC/C subunits, and they complement the phenotype of an SWM1 deletion mutant of budding yeast. Swm1/Apc13 promotes the stable association with the APC/C of the essential subunits Cdc16 and Cdc27. Accordingly, Swm1/Apc13 is required for ubiquitin ligase activity in vitro and for the timely execution of APC/C-dependent cell cycle events in vivo.

scholarly journals Cell cycle regulatory control for uterine stromal cell decidualization in implantation

Reproduction ◽  
2009 ◽  
Vol 137 (6) ◽  
pp. 889-899 ◽  
Author(s):  
Sanjoy K Das
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Stromal Cell ◽  
Molecular Mechanisms ◽  
Embryo Implantation ◽  
Regulatory Control ◽  
Cell Cycle Regulators ◽  
Cell Proliferation And Differentiation ◽  
Decidual Cells ◽  
Uterine Stromal Cell

Uterine stromal cell decidualization is integral to successful embryo implantation, which is a gateway to pregnancy establishment. This process is characterized by stromal cell proliferation and differentiation into decidual cells with polyploidy. The molecular mechanisms that are involved in these events remain poorly understood. The current concept is that locally induced factors with the onset of implantation influence uterine stromal cell proliferation and/or differentiation through modulation of core cell cycle regulators. This review will aim to address the currently available knowledge on interaction between growth factor/homeobox and cell cycle regulatory signaling in the progression of various aspects of decidualization.

DNA replication and damage checkpoints and meiotic cell cycle controls in the fission and budding yeasts

2000 ◽  
Vol 349 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Hiroshi MURAKAMI ◽  
Paul NURSE
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Replication ◽  
Fission Yeast ◽  
Molecular Mechanisms ◽  
Cell Cycle Checkpoint ◽  
Cell Cycle Regulators ◽  
Meiotic Cell ◽  
Checkpoint Proteins ◽  
Dna Damage Checkpoints

The cell cycle checkpoint mechanisms ensure the order of cell cycle events to preserve genomic integrity. Among these, the DNA-replication and DNA-damage checkpoints prevent chromosome segregation when DNA replication is inhibited or DNA is damaged. Recent studies have identified an outline of the regulatory networks for both of these controls, which apparently operate in all eukaryotes. In addition, it appears that these checkpoints have two arrest points, one is just before entry into mitosis and the other is prior to chromosome separation. The former point requires the central cell-cycle regulator Cdc2 kinase, whereas the latter involves several key regulators and substrates of the ubiquitin ligase called the anaphase promoting complex. Linkages between these cell-cycle regulators and several key checkpoint proteins are beginning to emerge. Recent findings on post-translational modifications and protein-protein interactions of the checkpoint proteins provide new insights into the checkpoint responses, although the functional significance of these biochemical properties often remains unclear. We have reviewed the molecular mechanisms acting at the DNA-replication and DNA-damage checkpoints in the fission yeast Schizosaccharomyces pombe, and the modifications of these controls during the meiotic cell cycle. We have made comparisons with the controls in fission yeast and other organisms, mainly the distantly related budding yeast.

scholarly journals APC/C Cdh1-mediated degradation of Cdh1 during meiosis in S. cerevisiae

2018 ◽  
Author(s):  
Denis Ostapenko ◽  
Mark J. Solomon
Keyword(s):  
Cell Cycle ◽  
Binding Sites ◽  
Mitotic Cell ◽  
Sporulation Medium ◽  
Cell Cycle Regulators ◽  
Anaphase Promoting Complex ◽  
Cell Cycles ◽  
Activator Proteins ◽  
Subsequent Degradation ◽  
Numerous Cell

ABSTRACTThe Anaphase-Promoting Complex/Cyclosome (APC/C) is a ubiquitin ligase that promotes the ubiquitination and subsequent degradation of numerous cell cycle regulators during mitosis and in G1. Proteins are recruited to the APC/C by activator proteins such as Cdh1. During the cell cycle, Cdh1 is subject to precise regulation so that substrates are not degraded prematurely. We have explored the regulation of Cdh1 during the developmental transition into meiosis and sporulation in the budding yeast S. cerevisiae. Transition to sporulation medium triggers the degradation of Cdh1. Degradation requires that cells be of the a/a mating type and be starved for glucose, but they do not actually need to enter into the meiotic program. Degradation requires an intact SNF1 protein kinase complex (orthologous to the mammalian AMPK nutritional sensor), which is activated by the absence of glucose. Cdh1 degradation is mediated by the APC/C itself in a ‘trans’ mechanism in which one molecule of Cdh1 recruits a second molecule of Cdh1 to the APC/C for ubiquitination. However, Cdh1-Cdh1 recognition does not depend on the degradation motifs or binding sites involved in the recognition of typical APC/C substrates. We hypothesize that Cdh1 degradation is necessary for the preservation of cell cycle regulators and chromosome cohesion proteins between the reductional and equational meiotic divisions, which occur without the intervening Gap or S phases found in mitotic cell cycles.

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