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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Meiotic resumption (G2/M transition) and progression through meiosis I (MI) are two key stages for producing fertilization-competent eggs. Here, we report that CenpH, a component of the kinetochore inner plate, is responsible for G2/M transition in meiotic mouse oocytes. Depletion of CenpH by morpholino injection decreased cyclin B1 levels, resulting in attenuation of maturation-promoting factor (MPF) activation, and severely compromised meiotic resumption. CenpH protects cyclin B1 from destruction by competing with the action of APC/CCdh1 Impaired G2/M transition after CenpH depletion could be rescued by expression of exogenous cyclin B1. Unexpectedly, blocking CenpH did not affect spindle organization and meiotic cell cycle progression after germinal vesicle breakdown. Our findings reveal a novel role of CenpH in regulating meiotic G2/M transition by acting via the APC/CCdh1-cyclin B1 pathway.
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PMID:CenpH regulates meiotic G2/M transition by modulating the APC/CCdh1-cyclin B1 pathway in oocytes. 2799 78

Cellular transitions are achieved by the concerted actions of regulated degradation pathways. In the case of the cell cycle, ubiquitin mediated degradation ensures unidirectional transition from one phase to another. For instance, turnover of the cell cycle regulator cyclin B1 occurs after metaphase to induce mitotic exit. To better understand pathways controlling cyclin B1 turnover, the N-terminal domain of cyclin B1 was fused to luciferase to generate an N-cyclin B1-luciferase protein that can be used as a reporter for protein turnover. Prior studies demonstrated that cell-based screens using this reporter identified small molecules inhibiting the ubiquitin ligase controlling cyclin B1-turnover. Our group adapted this approach for the G2-M regulator Wee1 where a Wee1-luciferase construct was used to identify selective small molecules inhibiting an upstream kinase that controls Wee1 turnover. In the present study we present a screening approach where cell cycle regulators are fused to luciferase and overexpressed with cDNAs to identify specific regulators of protein turnover. We overexpressed approximately 14,000 cDNAs with the N-cyclin B1-luciferase fusion protein and determined its steady-state level relative to other luciferase fusion proteins. We identified the known APC/C regulator Cdh1 and the F-box protein Fbxl15 as specific modulators of N-cyclin B1-luciferase steady-state levels and turnover. Collectively, our studies suggest that analyzing the steady-state levels of luciferase fusion proteins in parallel facilitates identification of specific regulators of protein turnover.
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PMID:A cell based screening approach for identifying protein degradation regulators. 2829 22

Human chorionic gonadotropin (hCG) mimics the action of luteinizing hormone (LH) and triggers meiotic maturation and ovulation in mammals. The mechanism by which hCG triggers meiotic resumption in mammalian oocytes remains poorly understood. We aimed to find out the impact of hCG surge on morphological changes, adenosine 3',5'-cyclic monophosphate (cAMP), guanosine 3',5'-cyclic monophosphate (cGMP), cell division cycle 25B (Cdc25B), Wee1, early mitotic inhibitor 2 (Emi2), anaphase-promoting complex/cyclosome (APC/C), meiotic arrest deficient protein 2 (MAD2), phosphorylation status of cyclin-dependent kinase 1 (Cdk1), its activity and cyclin B1 expression levels during meiotic resumption from diplotene as well as metaphase-II (M-II) arrest in cumulus oocyte complexes (COCs). Our data suggest that hCG surge increased cyclic nucleotides level in encircling granulosa cells but decreased their level in oocyte. The reduced intraoocyte cyclic nucleotides level is associated with the decrease of Cdc25B, Thr161 phosphorylated Cdk1 and Emi2 expression levels. On the other hand, hCG surge increased Wee1, Thr14/Tyr15 phosphorylated Cdk1, APC/C as well as MAD2 expression levels. The elevated APC/C activity reduced cyclin B1 level. The changes in phosphorylation status of Cdk1 and reduced cyclin B1 level might have resulted in maturation promoting factor (MPF) destabilization. The destabilized MPF finally triggered resumption of meiosis from diplotene as well as M-II arrest in rat oocytes.
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PMID:Maturation promoting factor destabilization mediates human chorionic gonadotropin induced meiotic resumption in rat oocytes. 2881 66

The correct temporal regulation of mitosis underpins genomic stability because it ensures the alignment of chromosomes on the mitotic spindle that is required for their proper segregation to the two daughter cells. Crucially, sister chromatid separation must be delayed until all the chromosomes have attached to the spindle; this is achieved by the Spindle Assembly Checkpoint (SAC) that inhibits the Anaphase Promoting Complex/Cyclosome (APC/C) ubiquitin ligase. In many species the first embryonic M-phase is significantly prolonged compared to the subsequent divisions, but the reason behind this has remained unclear. Here, we show that the first M-phase in the mouse embryo is significantly extended due to a delay in APC/C activation. Unlike in somatic cells, where the APC/C first targets cyclin A2 for degradation at nuclear envelope breakdown (NEBD), we find that in zygotes cyclin A2 remains stable for a significant period of time after NEBD. Our findings that the SAC prevents cyclin A2 degradation, whereas over-expressed Plk1 stimulates it, support our conclusion that the delay in cyclin A2 degradation is caused by low APC/C activity. As a consequence of delayed APC/C activation cyclin B1 stability in the first mitosis is also prolonged, leading to the unusual length of the first M-phase.
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PMID:Delayed APC/C activation extends the first mitosis of mouse embryos. 2885 45

A series of new 1,3,4-oxadiazole-2(3H)-thione analogues (3a to 3o) have been designed, synthesized and evaluated for their anticancer activity. Four different cancerous cell lines viz. HeLa (cervical), U-87 (glioblastoma), Panc (pancreatic) and MCF-7 (breast) were used to assess the potency of the synthesized compounds as anticancer agents. Among them 3i and 3j showed promising cytotoxicity against HeLa cell line. Further, 3i and 3j successfully inhibited cell cycle progression and displayed cell death in HeLa cells via apoptosis as visualized by Annexin V APC and DNA fragmentation assay. 3i and 3j induced caspase-3 activation, PARP cleavage, increase in expression of proapoptotic protein Bax and decrease in the expression of antiapoptotic protein Bcl-2. Also, 3i and 3j induced overexpression of p21 and decreased expression of cyclin B1 indicating the arrest of cells in G2-M phase of the cell cycle. Therefore, new lead compounds are being suggested having anticancer activity through cell cycle inhibition and apoptosis.
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PMID:Development of 1,3,4-oxadiazole thione based novel anticancer agents: Design, synthesis and in-vitro studies. 2888 9

HDAC inhibitors (HDACis) have been demonstrated with profound antiproliferative activities in various tumor types. Previously, we screened several polyoxometalate HDACis based on our p21 luciferase promoter system and demonstrated that such HDACis have antitumor activity. Here, we further investigate the antitumor mechanism of PAC-320, a compound among the polyoxometalates, in human prostate cancer. We demonstrate that PAC-320 is a broad-spectrum HDACi and could inhibit growth of prostate cancer cells in vitro and in vivo. Furthermore, we find that PAC-320 induces cell cycle arrest at G2/M phase and apoptosis. Mechanically, PAC-320 induced cell cycle arrest is associated with an increase of p21 and decrease of cyclin A and cyclin B1, while PAC-320 induced apoptosis is mediated through mitochondria apoptotic pathway and is closely associated with increase of BH3-only proteins Noxa and Hrk. Meanwhile, we demonstrate that p38 MAPK pathway is involved in PAC-320 induced antiproliferative activities in prostate cancer. Taken together, our data indicates that PAC-320 has potent prostate cancer inhibitory activity in vitro and in vivo, which is mediated by G2/M cell cycle arrest and apoptosis.
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PMID:HDAC inhibitor PAC-320 induces G2/M cell cycle arrest and apoptosis in human prostate cancer. 2941 32

Although it is known that in most angiosperms mitosis in early endosperm development is syncytial and synchronized, it is unclear how the synchronization is regulated. We showed previously that APC11, also named ZYG1, in Arabidopsis activates zygote division by interaction and degradation of cyclin B1. Here, we report that the mutation in APC11/ZYG1 led to unsynchronized mitosis and over-accumulation of cyclin B1-GUS in the endosperm. Mutations in two other APC subunits showed similar defects. Transgenic expression of stable cyclin B1 in the endosperm also caused unsynchronized mitosis. Further, downregulation of APC11 generated multi-nucleate somatic cells with unsynchronized mitotic division. Together, our results suggest that APC/C-mediated cyclin B1 degradation is critical for cell cycle synchronization.
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PMID:ANAPHASE PROMOTING COMPLEX/CYCLOSOME-mediated cyclin B1 degradation is critical for cell cycle synchronization in syncytial endosperms. 2942 75

The cysteine protease separase opens the cohesin ring by cleaving its kleisin subunit and is a pivotal cell cycle factor for the transition from metaphase to anaphase. It is inhibited by forming a complex with the chaperone securin, and in vertebrates, also by the Cdk1-cyclin B1 complex. Separase is activated upon the destruction of securin or cyclin B1 by the proteasome, after ubiquitination by the anaphase-promoting complex/cyclosome (APC/C). Here we review recent structures of the active protease segment of Chaetomium thermophilum separase in complex with a substrate-mimic inhibitor and full-length Saccharomyces cerevisiae and Caenorhabditis elegans separase in complex with securin. These structures define the mechanism for substrate recognition and catalysis by separase, and show that securin has extensive contacts with separase, consistent with its chaperone function. They confirm that securin inhibits separase by binding as a pseudo substrate.
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PMID:Structural biology of the separase-securin complex with crucial roles in chromosome segregation. 2945 22

Separation of sister chromatids is a drastic and irreversible step in the cell cycle. The key biochemistry behind this event is the proteolysis mediated by the ubiquitin ligase called the anaphase promoting complex, or APC/C. Securin and cyclin B1 are the two established substrates for APC/C whose degradation releases separase and inactivates cyclin B1-dependent kinase 1 (cdk1), respectively, at the metaphase-to-anaphase transition. In this study, we have combined biochemical quantifications with mathematical simulations to characterize the kinetic regulation of securin and cyclin B1, in the cytoplasmic and chromosomal compartments, and found that they are differentially distributed and degraded with different rates. Modeling their interaction with separase predicted that activation timing of separase well coincides with the decline of securin-separase concentration in the cytoplasm. Notably, it also coincides with the peak of cyclin B1-separase level on chromosomes, which appeared crucial to coordinate the timing for separase activation and cdk1 inhibition. We have also conducted phosphoproteomic analysis and identified Ki67 as a chromosomal cdk1 substrate whose dephosphorylation is facilitated by cyclin B1-separase interaction in anaphase.
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PMID:Quantitative analyses of the metaphase-to-anaphase transition reveal differential kinetic regulation for securin and cyclin B1. 2966 86

ATP depletion inhibits cell cycle progression, especially during the G1 phase and the G2 to M transition. However, the effect of ATP depletion on mitotic progression remains unclear. We observed that the reduction of ATP after prometaphase by simultaneous treatment with 2-deoxyglucose and NaN3 did not arrest mitotic progression. Interestingly, ATP depletion during nocodazole-induced prometaphase arrest resulted in mitotic slippage, as indicated by a reduction in mitotic cells, APC/C-dependent degradation of cyclin B1, increased cell attachment, and increased nuclear membrane reassembly. Additionally, cells successfully progressed through the cell cycle after mitotic slippage, as indicated by EdU incorporation and time-lapse imaging. Although degradation of cyclin B during normal mitotic progression is primarily regulated by APC/CCdc20, we observed an unexpected decrease in Cdc20 prior to degradation of cyclin B during mitotic slippage. This decrease in Cdc20 was followed by a change in the binding partner preference of APC/C from Cdc20 to Cdh1; consequently, APC/CCdh1, but not APC/CCdc20, facilitated cyclin B degradation following ATP depletion. Pulse-chase analysis revealed that ATP depletion significantly abrogated global translation, including the translation of Cdc20 and Cdh1. Additionally, the half-life of Cdh1 was much longer than that of Cdc20. These data suggest that ATP depletion during mitotic arrest induces mitotic slippage facilitated by APC/CCdh1-dependent cyclin B degradation, which follows a decrease in Cdc20 resulting from reduced global translation and the differences in the half-lives of the Cdc20 and Cdh1 proteins.
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PMID:ATP depletion during mitotic arrest induces mitotic slippage and APC/CCdh1-dependent cyclin B1 degradation. 2970 Feb 88


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