scholarly journals Mammalian egg activation: from Ca2+ spiking to cell cycle progression

Reproduction ◽  
2005 ◽  
Vol 130 (6) ◽  
pp. 813-823 ◽  
Author(s):  
Keith T Jones
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Polar Body ◽  
Signal Transduction Pathway ◽  
Cyclin B1 ◽  
Egg Activation ◽  
Anaphase Promoting Complex ◽  
Sister Chromatids ◽  
Dependent Protein ◽  
Second Polar Body

Mammalian eggs arrest at metaphase of the second meiotic division (MetII). Sperm break this arrest by inducing a series of Ca2+spikes that last for several hours. During this time cell cycle resumption is induced, sister chromatids undergo anaphase and the second polar body is extruded. This is followed by decondensation of the chromatin and the formation of pronuclei. Ca2+spiking is both the necessary and solely sufficient sperm signal to induce full egg activation. How MetII arrest is established, how the Ca2+spiking is induced and how the signal is transduced into cell cycle resumption are the topics of this review. Although the roles of most components of the signal transduction pathway remain to be fully investigated, here I present a model in which a sperm-specific phospholipase C (PLCζ) generates Ca2+spikes to activate calmodulin-dependent protein kinase II and so switch on the Anaphase-Promoting Complex/Cyclosome (APC/C). APC/C activation leads to securin and cyclin B1 degradation and in so doing allows sister chromatids to be segregated and to decondense.

scholarly journals Pseudosubstrate Inhibition of the Anaphase-Promoting Complex by Acm1: Regulation by Proteolysis and Cdc28 Phosphorylation

2008 ◽  
Vol 28 (15) ◽  
pp. 4653-4664 ◽  
Author(s):  
Denis Ostapenko ◽  
Janet L. Burton ◽  
Ruiwen Wang ◽  
Mark J. Solomon
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Budding Yeast ◽  
Anaphase Promoting Complex ◽  
Inhibitory Protein ◽  
Ubiquitin Ligase Activity ◽  
Dependent Protein ◽  
Apc Mutation

ABSTRACT The ubiquitin ligase activity of the anaphase-promoting complex (APC)/cyclosome needs to be tightly regulated for proper cell cycle progression. Substrates are recruited to the APC by the Cdc20 and Cdh1 accessory proteins. The Cdh1-APC interaction is inhibited through phosphorylation of Cdh1 by Cdc28, the major cyclin-dependent protein kinase in budding yeast. More recently, Acm1 was reported to be a Cdh1-binding and -inhibitory protein in budding yeast. We found that although Acm1 is an unstable protein and contains the KEN-box and D-box motifs typically found in APC substrates, Acm1 itself is not an APC substrate. Rather, it uses these motifs to compete with substrates for Cdh1 binding, thereby inhibiting their recruitment to the APC. Mutation of these motifs prevented Acm1-Cdh1 binding in vivo and rendered Acm1 inactive both in vitro and in vivo. Acm1 stability was critically dependent on phosphorylation by Cdc28, as Acm1 was destabilized following inhibition of Cdc28, mutation of consensus Cdc28 phosphorylation sites in Acm1, or deletion of the Bmh1 and Bmh2 phosphoprotein-binding proteins. Thus, Cdc28 serves dual roles in inhibiting Cdh1-dependent APC activity during the cell cycle: stabilization of the Cdh1 inhibitor Acm1 and direct phosphorylation of Cdh1 to prevent its association with the APC.

scholarly journals Glypican-1 Regulates Anaphase Promoting Complex/Cyclosome Substrates and Cell Cycle Progression in Endothelial Cells

2008 ◽  
Vol 19 (7) ◽  
pp. 2789-2801 ◽  
Author(s):  
Dianhua Qiao ◽  
Xinhai Yang ◽  
Kristy Meyer ◽  
Andreas Friedl
Keyword(s):  
Cell Cycle ◽  
Endothelial Cells ◽  
Cell Cycle Progression ◽  
Cyclin B1 ◽  
Anaphase Promoting Complex ◽  
Cycle Progression ◽  
Cycle Arrest ◽  
Flow Cytometric ◽  
Biochemical Analyses

Glypican-1 (GPC1), a member of the mammalian glypican family of heparan sulfate proteoglycans, is highly expressed in glioma blood vessel endothelial cells (ECs). In this study, we investigated the role of GPC1 in EC replication by manipulating GPC1 expression in cultured mouse brain ECs. Moderate GPC1 overexpression stimulates EC growth, but proliferation is significantly suppressed when GPC1 expression is either knocked down or the molecule is highly overexpressed. Flow cytometric and biochemical analyses show that high or low expression of GPC1 causes cell cycle arrest at mitosis or the G2 phase of the cell cycle, accompanied by endoreduplication and consequently polyploidization. We further show that GPC1 inhibits the anaphase-promoting complex/cyclosome (APC/C)–mediated degradation of mitotic cyclins and securin. High levels of GPC1 induce metaphase arrest and centrosome overproduction, alterations that are mimicked by overexpression of cyclin B1 and cyclin A, respectively. These observations suggest that GPC1 regulates EC cell cycle progression at least partially by modulating APC/C-mediated degradation of mitotic cyclins and securin.

scholarly journals 011.Waking up the egg. How the sperm regulates exit out of the meiotic cell cycle

2004 ◽  
Vol 16 (9) ◽  
pp. 11
Author(s):  
K. T. Jones
Keyword(s):  
Cell Cycle ◽  
Polar Body ◽  
Cyclin B1 ◽  
26S Proteasome ◽  
Calcium Signal ◽  
Calcium Spikes ◽  
M Phase ◽  
Second Polar Body ◽  
Polar Body Extrusion ◽  
Mammalian Eggs

A series of calcium spikes are induced in the mammalian egg cytoplasm at fertilisation. These calcium spikes, which last for several hours, are the necessary and sufficient signal that stimulates the egg to escape from arrest at metaphase of the second meiotic division. Metaphase arrest is achieved by preventing the destruction of cyclin B1, the regulatory component of Maturation (M-Phase) Promoting Factor, and securin, which prevents segregation of sister chromatids. Both these proteins are destroyed by tagging with ubiquitin, using an E3 ligase the Anaphase-Promoting Complex (APC). Ubiquitination tags them for proteolysis by the 26S proteasome. Work from my lab has demonstrated that the sperm calcium signal works through activating the APC, not the 26S proteasome. Although we do not know which APC component is affected by calcium, this activation appears specific to a metaphase-arrested cell cycle state. More recently we have found that the APC is differently regulated at specific points during exit from meiosis II. Before extrusion of the second polar body it is the APC activator cdc20 that regulates APC activity. However, following extrusion of the second polar body cdh1 appears the major regulator. It is probable, therefore, that the calcium spiking affects the activity of both APCcdc20 and APCcdh1. This swap in APC activator at the time of second polar body extrusion has not been reported in eggs of other species, in fact non-mammalian eggs all lack cdh1. Since APCcdc20 and APCcdh1 have different substrate specificities, the function of APCcdh1 in mammalian eggs warrants further investigation.

PTTG has a Dual Role of Promotion-Inhibition in the Development of Pituitary Adenomas

2019 ◽  
Vol 26 (11) ◽  
pp. 800-818
Author(s):  
Zujian Xiong ◽  
Xuejun Li ◽  
Qi Yang
Keyword(s):  
Cell Cycle ◽  
Pituitary Adenoma ◽  
Pituitary Adenomas ◽  
Cell Cycle Progression ◽  
Key Factors ◽  
Cycle Progression ◽  
Sister Chromatids ◽  
Regulation Of Cell Cycle ◽  
Late Stages

Pituitary Tumor Transforming Gene (PTTG) of human is known as a checkpoint gene in the middle and late stages of mitosis, and is also a proto-oncogene that promotes cell cycle progression. In the nucleus, PTTG works as securin in controlling the mid-term segregation of sister chromatids. Overexpression of PTTG, entering the nucleus with the help of PBF in pituitary adenomas, participates in the regulation of cell cycle, interferes with DNA repair, induces genetic instability, transactivates FGF-2 and VEGF and promotes angiogenesis and tumor invasion. Simultaneously, overexpression of PTTG induces tumor cell senescence through the DNA damage pathway, making pituitary adenoma possessing the potential self-limiting ability. To elucidate the mechanism of PTTG in the regulation of pituitary adenomas, we focus on both the positive and negative function of PTTG and find out key factors interacted with PTTG in pituitary adenomas. Furthermore, we discuss other possible mechanisms correlate with PTTG in pituitary adenoma initiation and development and the potential value of PTTG in clinical treatment.

scholarly journals The Saccharomyces cerevisiae Anaphase-Promoting Complex Interacts with Multiple Histone-Modifying Enzymes To Regulate Cell Cycle Progression

2010 ◽  
Vol 9 (10) ◽  
pp. 1418-1431 ◽  
Author(s):  
Emma L. Turner ◽  
Mackenzie E. Malo ◽  
Marnie G. Pisclevich ◽  
Megan D. Dash ◽  
Gerald F. Davies ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Chromatin Assembly ◽  
Temperature Sensitive ◽  
Anaphase Promoting Complex ◽  
Cycle Progression ◽  
Ubiquitin Ligase Complex ◽  
Genes Encoding ◽  
Dependent Cell ◽  
Histone Modifying Enzymes

ABSTRACT The anaphase-promoting complex (APC), a large evolutionarily conserved ubiquitin ligase complex, regulates cell cycle progression through mitosis and G1. Here, we present data suggesting that APC-dependent cell cycle progression relies on a specific set of posttranslational histone-modifying enzymes. Multiple APC subunit mutants were impaired in total and modified histone H3 protein content. Acetylated H3K56 (H3K56Ac) levels were as reduced as those of total H3, indicating that loading histones with H3K56Ac is unaffected in APC mutants. However, under restrictive conditions, H3K9Ac and dimethylated H3K79 (H3K79me2) levels were more greatly reduced than those of total H3. In a screen for histone acetyltransferase (HAT) and histone deacetylase (HDAC) mutants that genetically interact with the apc5 CA (chromatin assembly) mutant, we found that deletion of GCN5 or ELP3 severely hampered apc5 CA temperature-sensitive (ts) growth. Further analyses showed that (i) the elp3Δ gcn5Δ double mutant ts defect was epistatic to that observed in apc5 CA cells; (ii) gcn5Δ and elp3Δ mutants accumulate in mitosis; and (iii) turnover of the APC substrate Clb2 is not impaired in elp3Δ gcn5Δ cells. Increased expression of ELP3 and GCN5, as well as genes encoding the HAT Rtt109 and the chromatin assembly factors Msi1 and Asf1, suppressed apc5 CA defects, while increased APC5 expression partially suppressed elp3Δ gcn5Δ growth defects. Finally, we demonstrate that Gcn5 is unstable during G1 and following G1 arrest and is stabilized in APC mutants. We present our working model in which Elp3/Gcn5 and the APC work together to facilitate passage through mitosis and G1. To progress into S, we propose that at least Gcn5 must then be targeted for degradation in an APC-dependent fashion.

scholarly journals Mouse Emi2 is required to enter meiosis II by reestablishing cyclin B1 during interkinesis

2006 ◽  
Vol 174 (6) ◽  
pp. 791-801 ◽  
Author(s):  
Suzanne Madgwick ◽  
David V. Hansen ◽  
Mark Levasseur ◽  
Peter K. Jackson ◽  
Keith T. Jones
Keyword(s):  
Fluorescent Protein ◽  
Polar Body ◽  
Cyclin B1 ◽  
Anaphase Promoting Complex ◽  
Morpholino Knockdown ◽  
Short Time ◽  
Mitotic Inhibitor ◽  
Antisense Morpholino ◽  
Meiosis I

During interkinesis, a metaphase II (MetII) spindle is built immediately after the completion of meiosis I. Oocytes then remain MetII arrested until fertilization. In mouse, we find that early mitotic inhibitor 2 (Emi2), which is an anaphase-promoting complex inhibitor, is involved in both the establishment and the maintenance of MetII arrest. In MetII oocytes, Emi2 needs to be degraded for oocytes to exit meiosis, and such degradation, as visualized by fluorescent protein tagging, occurred tens of minutes ahead of cyclin B1. Emi2 antisense morpholino knockdown during oocyte maturation did not affect polar body (PB) extrusion. However, in interkinesis the central spindle microtubules from meiosis I persisted for a short time, and a MetII spindle failed to assemble. The chromatin in the oocyte quickly decondensed and a nucleus formed. All of these effects were caused by the essential role of Emi2 in stabilizing cyclin B1 after the first PB extrusion because in Emi2 knockdown oocytes a MetII spindle was recovered by Emi2 rescue or by expression of nondegradable cyclin B1 after meiosis I.

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.

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