Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sister-chromatid separation and exit from mitosis require ubiquitin-mediated proteolysis of cell cycle regulators such as cyclin B and securin. The specificity of the reaction is controlled by an ubiquitin-ligase multiprotein complex known as APC (Anaphase Promoting Complex). Comparison of the coding sequences of Arabidopsis genes with the Genbank database reveals extensive homology of the predicted ORFs with the corresponding proteins of other eukaryotes, indicating that the APC is well conserved in plants. However, different from other eukaryotes, the Arabidopsis genes have some particular characteristics, such as the presence of two copies of the CDC27 gene. Furthermore, expression analyses of the AtAPC genes disclose complex profiles that differ, depending on the tissue examined. In actively dividing cell suspensions there is a direct correspondence between the rates of proliferation and mRNA levels from the AtAPC components. On the other hand, in plant organs, dark-grown seedlings and during leaf growth, this correlation is lost and the AtAPC genes are highly expressed in tissues with low overall cell division. Moreover, expression patterns diverge between the subunit genes, raising the possibility that there could be more than one form of the APC, which would execute distinct functions during plant development. The results suggest that an important layer of regulation of APC/C in plants could operate through subunit availability in specific tissues and/or cellular compartments.
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PMID:The Arabidopsis anaphase promoting complex (APC): regulation through subunit availability in plant tissues. 1694 Jul 52

Regulated protein degradation is essential for eukaryotic cell cycle progression. The anaphase-promoting complex/cyclosome (APC/C) is responsible for the protein destruction required for the initiation of anaphase and the exit from mitosis, including the degradation of securin and B-type cyclins. We initiated a study of the APC/C in the multinucleated, filamentous ascomycete Ashbya gossypii to understand the mechanisms underlying the asynchronous mitosis observed in these cells. These experiments were motivated by previous work which demonstrated that the mitotic cyclin AgClb1/2p persists through anaphase, suggesting that the APC/C may not be required for the division cycle in A. gossypii. We have now found that the predicted APC/C components AgCdc23p and AgDoc1p and the targeting factors AgCdc20p and AgCdh1p are essential for growth and nuclear division. Mutants lacking any of these factors arrest as germlings with nuclei blocked in mitosis. A likely substrate of the APC/C is the securin homologue AgPds1p, which is present in all nuclei in hyphae except those in anaphase. The destruction box sequence of AgPds1p is required for this timed disappearance. To investigate how the APC/C may function to degrade AgPds1p in only the subset of anaphase nuclei, we localized components and targeting subunits of the APC/C. Remarkably, AgCdc23p, AgDoc1p, and AgCdc16p were found in all nuclei in all cell cycle stages, as were the APC/C targeting factors AgCdc20p and AgCdh1p. These data suggest that the AgAPC/C may be constitutively active across the cell cycle and that proteolysis in these multinucleated cells may be regulated at the level of substrates rather than by the APC/C itself.
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PMID:The anaphase-promoting complex/cyclosome is required for anaphase progression in multinucleated Ashbya gossypii cells. 1715 35

The spindle assembly checkpoint (SAC) governs the timing of metaphase-to-anaphase transition and is essential for genome stability. The Caenorhabditis elegans mutant strain gk2 carries a deletion within the mdf-1/MAD1 gene that results in death of the homozygous strain after two or three generations. Here we describe 11 suppressors of the mdf-1(gk2) lethality, 10 identified in an ethyl methanesulfonate (EMS) mutagenesis screen and 1 isolated using the dog-1(gk10) (deletions of guanine-rich DNA) mutator strain. Using time-lapse imaging of early embryonic cells and germline mitotic division, we demonstrate that there are two classes of suppressors. Eight suppressors compensate for the loss of the checkpoint by delaying mitotic progression, which coincides with securin (IFY-1/Pds1) accumulation; three suppressors have normal IFY-1/Pds1 levels and normal anaphase onset. Furthermore, in the class of suppressors with delayed mitotic progression, we have identified four alleles of known suppressors emb-30/APC4 and fzy-1/CDC20, which are components of the anaphase-promoting complex/cyclosome (APC/C). In addition, we have identified another APC/C component capable of bypassing the checkpoint requirement that has not previously been described in C. elegans. The such-1/APC5-like mutation, h1960, significantly delays anaphase onset both in germline and in early embryonic cells.
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PMID:Suppressors of spindle checkpoint defect (such) mutants identify new mdf-1/MAD1 interactors in Caenorhabditis elegans. 1723 15

The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase mediating targeted proteolysis through ubiquitination of protein substrates to control the progression of mitosis. The APC/C recognizes its substrates through two adapter proteins, Cdc20 and Cdh1, which contain similar C-terminal domains composed of seven WD-40 repeats believed to be involved in interacting with their substrates. During the transition from metaphase to anaphase, APC/C-Cdc20 mediates the ubiquitination of securin and cyclin B1, allowing the activation of separase and the onset of anaphase and mitotic exit. APC/C-Cdc20 and APC/C-Cdh1 have overlapping substrates. It is unclear whether they are redundant for mitosis. Using a gene-trapping approach, we have obtained mice which lack Cdc20 function. These mice show failed embryogenesis. The embryos were arrested in metaphase at the two-cell stage with high levels of cyclin B1, indicating an essential role of Cdc20 in mitosis that is not redundant with that of Cdh1. Interestingly, Cdc20 and securin double mutant embryos could not maintain the metaphase arrest, suggesting a role of securin in preventing mitotic exit.
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PMID:Loss of Cdc20 causes a securin-dependent metaphase arrest in two-cell mouse embryos. 1732 31

Orderly progression through mitosis is regulated by the anaphase-promoting complex/cyclosome (APC/C), a large multiprotein E3 ubiquitin ligase that targets key mitotic regulators for destruction by the proteasome. APC/C has two activating subunits, Cdc20 and Cdh1. The well-established view is that Cdc20 activates APC/C from the onset of mitosis through the metaphase-anaphase transition, and that Cdh1 does so from anaphase through G1. Recent work, however, indicates that Cdh1 also activates APC/C in early mitosis and that this APC/C pool targets the anaphase inhibitor securin. To prevent premature degradation of securin, the nuclear transport factors Nup98 and Rae1 associate with APC/C(Cdh1)-securin complexes. In late metaphase, when all kinetochores are attached to spindle microtubules and the spindle assembly checkpoint is satisfied, Nup98 and Rae1 are released from these complexes, thereby allowing for prompt ubiquitination of securin by APC/C(Cdh1). This, and other mechanisms by which the catalytic activity of APC/C is tightly regulated to ensure proper timing of degradation of each of its mitotic substrates, are highlighted.
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PMID:Mitotic regulation of the anaphase-promoting complex. 1733 50

Diallyl trisulfide (DATS), a cancer chemopreventive constituent of garlic, inhibits growth of cancer cells by interfering with cell cycle progression, but the mechanism is not fully understood. Here, we show the existence of a novel ataxia-telangiectasia mutated and Rad3 related (ATR)/checkpoint kinase 1 (Chk1)-dependent checkpoint partially responsible for DATS-mediated prometaphase arrest in cancer cells, which is different from the recently described gamma irradiation-induced mitotic exit checkpoint. The PC-3 human prostate cancer cells synchronized in prometaphase by nocodazole treatment and released to DATS-containing medium remained arrested in prometaphase, whereas the cells released to normal medium exited mitosis and resumed cell cycle. The mitotic arrest was maintained even after 4 h of culture of DATS-treated cells (4-h treatment) in drug-free medium. The DATS-arrested mitotic cells exhibited accumulation of anaphase-promoting complex/cyclosome (APC/C) substrates cyclin A and cyclin B1 and hyperphosphorylation of securin, which was accompanied by increased phosphorylation of the APC/C regulatory subunits Cdc20 and Cdh1. The DATS-mediated accumulation of cyclin B1 and hyperphosphorylation of securin, Cdc20, and Cdh1 were partially but markedly attenuated by knockdown of Chk1 or ATR protein. The U2OS osteosarcoma cells expressing doxycycline-inducible kinase dead ATR were significantly more resistant not only to DATS-mediated prometaphase arrest but also to the accumulation of cyclin B1 and hyperphosphorylation of securin, Cdc20, and Cdh1 compared with cells expressing wild-type ATR. However, securin protein knockdown failed to rescue cells from DATS-induced prometaphase arrest. In conclusion, the present study describes a novel signaling pathway involving ATR/Chk1 in the regulation of DATS-induced prometaphase arrest.
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PMID:Activation of a novel ataxia-telangiectasia mutated and Rad3 related/checkpoint kinase 1-dependent prometaphase checkpoint in cancer cells by diallyl trisulfide, a promising cancer chemopreventive constituent of processed garlic. 1740 33

Mitotic progression is controlled by proteolytic destruction of securin and cyclin. The mitotic E3 ubiquitin ligase, known as the anaphase promoting complex or cyclosome (APC/C), in partnership with its activators Cdc20p and Cdh1p, targets these proteins for degradation. In the presence of defective kinetochore-microtubule interactions, APC/C(Cdc20) is inhibited by the spindle checkpoint, thereby delaying anaphase onset and providing more time for spindle assembly. Cdc20p interacts directly with Mad2p, and its levels are subject to careful regulation, but the precise mode(s) of APC/C( Cdc20) inhibition remain unclear. The mitotic checkpoint complex (MCC, consisting of Mad3p, Mad2p, Bub3p and Cdc20p in budding yeast) is a potent APC/C inhibitor. Here we focus on Mad3p and how it acts, in concert with Mad2p, to efficiently inhibit Cdc20p. We identify and analyse the function of two motifs in Mad3p, KEN30 and KEN296, which are conserved from yeast Mad3p to human BubR1. These KEN amino acid sequences resemble 'degron' signals that confer interaction with APC/C activators and target proteins for degradation. We show that both Mad3p KEN boxes are necessary for spindle checkpoint function. Mutation of KEN30 abolished MCC formation and stabilised Cdc20p in mitosis. In addition, mutation of Mad3-KEN30, APC/C subunits, or Cdh1p, stabilised Mad3p in G1, indicating that the N-terminal KEN box could be a Mad3p degron. To determine the significance of Mad3p turnover, we analysed the consequences of MAD3 overexpression and found that four-fold overproduction of Mad3p led to chromosome bi-orientation defects and significant chromosome loss during recovery from anti-microtubule drug induced checkpoint arrest. In conclusion, Mad3p KEN30 mediates interactions that regulate the proteolytic turnover of Cdc20p and Mad3p, and the levels of both of these proteins are critical for spindle checkpoint signaling and high fidelity chromosome segregation.
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PMID:Mad3 KEN boxes mediate both Cdc20 and Mad3 turnover, and are critical for the spindle checkpoint. 1740 66

The fidelity of cell division is dependent on the accumulation and ordered destruction of critical protein regulators. By triggering the appropriately timed, ubiquitin-dependent proteolysis of the mitotic regulatory proteins securin, cyclin B, aurora A kinase, and polo-like kinase 1, the anaphase promoting complex/cyclosome (APC/C) ubiquitin ligase plays an essential role in maintaining genomic stability. Misexpression of these APC/C substrates, individually, has been implicated in genomic instability and cancer. However, no comprehensive survey of the extent of their misregulation in tumors has been performed. Here, we analyzed more than 1600 benign and malignant tumors by immunohistochemical staining of tissue microarrays and found frequent overexpression of securin, polo-like kinase 1, aurora A, and Skp2 in malignant tumors. Positive and negative APC/C regulators, Cdh1 and Emi1, respectively, were also more strongly expressed in malignant versus benign tumors. Clustering and statistical analysis supports the finding that malignant tumors generally show broad misregulation of mitotic APC/C substrates not seen in benign tumors, suggesting that a "mitotic profile" in tumors may result from misregulation of the APC/C destruction pathway. This profile of misregulated mitotic APC/C substrates and regulators in malignant tumors suggests that analysis of this pathway may be diagnostically useful and represent a potentially important therapeutic target.
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PMID:Oncogenic regulators and substrates of the anaphase promoting complex/cyclosome are frequently overexpressed in malignant tumors. 1745 82

Anaphase-promoting complex or cyclosome (APC/C) controls the metaphase-to-anaphase transition and mitosis exit by triggering the degradation of key cell cycle regulators such as securin and B-type cyclins. However, little is known about the functions of individual APC/C subunits and how they might regulate APC/C activity in space and time. Here, we report that two potential Cdk1 kinase phosphorylation sites are required for the chromosomal localisation of GFP::Cdc27 during mitosis. Either or both of the highly conserved proline residues in the Cdk1 phosphorylation consensus sequence motifs were mutated to alanine (Cdc27 P304A or P456A). The singly mutated fusion proteins, GFP::Cdc27P304A and GFP::Cdc27P456A, can still localise to mitotic chromosomes in a manner identical to wild-type GFP::Cdc27 and are functional in that they can rescue the phenotype of the cdc27L7123 mutant in vivo. However, when both of the Cdk1 phosphorylation sequence motifs were mutated, the resulting GFP::Cdc27P304A,P456A construct was not localised to the chromosomes during mitosis and was no longer functional, as it failed to rescue mutant phenotypes of the cdc27L7123 gene. High levels of cyclin B and cyclin A were detected in mutant third instar larvae brain samples compared with its wild-type control. These results show for the first time that the two potential Cdk1 phosphorylation sites on Drosophila Cdc27 are required for its chromosomal localisation during mitosis and imply that these localisations specific to Cdc27 are crucial for APC/C functions.
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PMID:Cdk1 phosphorylation sites on Cdc27 are required for correct chromosomal localisation and APC/C function in syncytial Drosophila embryos. 1751 85

HTLV-1 Tax is a potent activator of viral transcription and NF-kappaB. Recent data indicate that Tax activates the anaphase promoting complex/cyclosome (APC/C) ahead of schedule, causing premature degradation of cyclin A, cyclin B1, securin, and Skp2. Premature loss of these mitotic regulators is accompanied by mitotic aberrations and leads to rapid senescence and cell cycle arrest in HeLa and S. cerevisiae cells. Tax-induced rapid senescence (tax-IRS) of HeLa cells is mediated primarily by a dramatic stabilization of p27KIP and is also accompanied by a great surge in the level of p21CIP1mRNA and protein. Deficiencies in p27KIP prevent Tax-IRS. A collection of tax point mutants that permit normal growth of S. cerevisiae have been isolated. Like wild-type tax, many of them (C23W, A108T, L159F, and L235F) transactivate both the HTLV-LTR and the NF-kappaB reporters. One of them, V19M, preferentially activates NF-kappaB, but is attenuated for LTR activation. None of the mutants significantly elevated the levels of p21CIP1and p27KIP1, indicating that the dramatic surge in p21CIP1/WAF1and p27KIP 1induced by Tax is brought about by a mechanism distinct from NF-kappaB or LTR activation. Importantly, the ability of these mutants to activate APC/C is attenuated or abrogated. These data indicate that Tax-induced rapid senescence is causally associated with APC/C activation.
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PMID:HTLV-1 Tax mutants that do not induce G1 arrest are disabled in activating the anaphase promoting complex. 1753 28


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