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

Coordination of events required for cell cycle progression is orchestrated in large part by the ubiquitin (Ub)-mediated destruction of key regulatory proteins such as cyclins and their inhibitors. Until now, the G1/S and mitotic phases of the cell cycle were thought to be controlled by discrete families of multisubunit Ub-ligases: SCF ligases controlled the G1 to S transition, whereas APC ligases controlled the onset and exit from mitosis. New work, published in the March 11 issue of Nature, challenges this concept by revealing that an essential function of APC is to limit SCF activity during the G1 phase of the cell cycle.
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PMID:Crashing waves of destruction: the cell cycle and APC(Cdh1) regulation of SCF(Skp2). 1509 36

Early mitotic inhibitor 1 (Emi1) inhibits the activity of the anaphase promoting complex/cyclosome (APC/C), which is a multisubunit ubiquitin ligase that targets mitotic regulators for degradation in exit from mitosis. Levels of Emi1 oscillate in the cell cycle: it accumulates in the S phase and is rapidly degraded in prometaphase. The degradation of Emi1 in early mitosis is necessary for the activation of APC/C in late mitosis. Previous studies have shown that Emi1 is targeted for degradation in mitosis by a Skp1-Cullin1 F-box protein (SCF) ubiquitin ligase complex that contains the F-box protein beta-TrCP. As with other substrates of SCF(beta-TrCP), the phosphorylation of Emi1 on a DSGxxS sequence is required for this process. However, the protein kinase(s) involved has not been identified. We find that Polo-like kinase 1 (Plk1), a protein kinase that accumulates in mitosis, markedly stimulates the ligation of Emi1 to ubiquitin by purified SCF(beta-TrCP). Cdk1-cyclin B, another major mitotic protein kinase, has no influence on this process by itself but stimulates the action of Plk1 at low, physiological concentrations. Plk1 phosphorylates serine residues in the DSGxxS sequence of Emi1, as suggested by the reduced phosphorylation of a derivative in which the two serines were mutated to nonphosphorylatable amino acids. Transfection with an small interfering RNA duplex directed against Plk1 caused the accumulation of Emi1 in mitotically arrested HeLa cells. It is suggested that phosphorylation of Emi1 by Plk1 is involved in its degradation in mitosis.
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PMID:Role of Polo-like kinase in the degradation of early mitotic inhibitor 1, a regulator of the anaphase promoting complex/cyclosome. 1514 69

The mitotic checkpoint prevents cells with unaligned chromosomes from prematurely exiting mitosis by inhibiting the anaphase-promoting complex/cyclosome (APC/C) from targeting key proteins for ubiquitin-mediated proteolysis. Great efforts have been made recently to identify and characterize the factors involved in this checkpoint pathway. These studies will ultimately lead to a better understanding of cell cycle defects and chromosome instability. We report here a protocol for purification of an inhibitor of the APC/C from HeLa cells, called mitotic checkpoint complex (MCC). Our procedure is based on biochemical purification and characterization of the APC/C inhibitory activity from extracts of HeLa cells.
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PMID:Purification of the mitotic checkpoint complex, an inhibitor of the APC/C from HeLa cells. 1522 May 31

p55Cdc proteins participate in activation and timing of ubiquitin ligation by APC/C. Labeling of the substrates with ubiquitin leads to degradation of the cell cycle proteins through the proteasome in mitosis. Consistent with the phase in which the protein functions p55Cdc mRNA is expressed during the cell cycle starting in S phase with a maximum in G2/M. We analyzed the human p55Cdc promoter responsible for this expression pattern and found with SIRF (Cell-Cycle Site-Regulating p55Cdc/Fizzy-Transcription) a novel element which downregulates transcription in a cell cycle-dependent manner. Activation of gene transcription is independent of the SIRF element and NF-Y. The nucleotide sequence of SIRF is essentially identical in human, rat, and mouse p55Cdc whereas other parts of the promoter are not conserved. SIRF requires its natural promoter context for its regulatory function. With a length of 44 nucleotides this element is unusually long and may require a large protein complex for its regulation.
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PMID:SIRF--a novel regulator element controlling transcription from the p55Cdc/Fizzy promoter during the cell cycle. 1524 Jan 41

The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase in the ubiquitin-mediated proteolysis pathway (UMP). To understand how the APC/C was targeted to its substrates, we performed a detailed analysis of one of the APC/C components, Cdc23p. In live cells, Cdc23-GFP localized to punctate nuclear spots surrounded by homogenous nuclear signal throughout the cell cycle. These punctate spots colocalized with two outer kinetochore proteins, Slk19p and Okp1p, but not with the spindle pole body protein, Spc42p. In late anaphase, the Cdc23-GFP was also visualized along the length of the mitotic spindle. We hypothesized that spindle checkpoint activation may affect the APC/C nuclear spot localization. Localization of Cdc23-GFP was disrupted upon nocodazole treatment in the kinetochore mutant okp1-5 and in the cdc20-1 mutant. Cdc23-GFP nuclear spot localization was not affected in the ndc10-1 mutant, which is defective in spindle checkpoint function. Additional studies using a mad2Delta strain revealed a microtubule dependency of Cdc23-GFP spot localization, whether or not the checkpoint response was activated. On the basis of these data, we conclude that Cdc23p localization was dependent on microtubules and was affected by specific types of kinetochore disruption.
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PMID:Changes in the localization of the Saccharomyces cerevisiae anaphase-promoting complex upon microtubule depolymerization and spindle checkpoint activation. 1528 Feb 25

Regulated protein degradation has emerged as a key recurring theme in multiple aspects of cell-cycle regulation. Importantly, the irreversible nature of proteolysis makes it an invaluable complement to the intrinsically reversible regulation through phosphorylation and other post-translational modifications. Consequently, ubiquitin-protein ligases, the protagonists of regulated protein destruction, have gained prominence that compares to that of the cyclin-dependent kinases (Cdks) in driving the eukaryotic cell-cycle clock. This review will focus on the two main players, the related ubiquitin-protein ligases APC/C and SCF, and how they control cell-cycle progression. I will also try to delineate the regulation and interplay of these destruction mechanisms, which are intricately connected to the kinase network as well as to extrinsic signals. Moreover, cell-cycle ubiquitin-protein ligases are themselves subject to proteolytic control in cis as well as in trans. Finally, a careful comparison of the functions and regulation of APC/C and SCF shows that, in certain aspects, their logic of action is fundamentally different.
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PMID:APC/C and SCF: controlling each other and the cell cycle. 1538 93

The anaphase-promoting complex or cyclosome (APC/C) is a multi-subunit ubiquitin ligase that regulates the eukaryotic cell cycle. APC/C belongs to the RING finger class of ubiquitin ligases that function by interacting with a ubiquitin-conjugating enzyme (Ubc), thus inciting the Ubc to transfer ubiquitin onto a target protein. Extensive studies with APC/C in other organisms have identified several possible Ubcs that might function as partners for APC/C. This report presents phenotypic and biochemical evidence showing that, in Caenorhabditis elegans, UBC-2 interacts specifically with the APC/C. This conclusion is based on three lines of evidence: first, the RNAi phenotype of ubc-2 is indistinguishable from RNAi phenotypes of APC/C subunits; second, RNAi of ubc-2 but not other Ubcs enhances the phenotype of hypomorphic APC/C mutants; third, purified UBC-2 and APC-11, the RING finger subunit of the APC/C, show robust ubiquitination activity in in vitro assays. APC-11 interaction is specific for UBC-2 as ubiquitination is not seen when APC-11 is combined other C. elegans Ubcs. As expected from the Ubc that functions with the APC/C, ubc-2(RNAi) produces metaphase blocks in both mitotic germ cells and in meiotic divisions of post-fertilization oocytes. In addition, ubc-2(RNAi) results in two germline phenotypes that appear to be unrelated to the APC/C: an expanded transition zone indicative of a pre-pachytene meiotic arrest and endo-reduplicated oocytes indicative of a problem in ovulation or oocyte-soma interactions.
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PMID:Caenorhabditis elegans UBC-2 functions with the anaphase-promoting complex but also has other activities. 1546 91

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.
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PMID:The anaphase-promoting complex (APC): the sum of its parts? 1549 98

Research in the past 15 years has shown that the mammalian cell cycle is controlled by the action of cyclin-dependent kinases (CDKs). A crucial substrate of the CDKs in G1-phase is the retinoblastoma tumor suppressor (pRB), which restrains proliferation largely by repressing the activity of the E2F transcription factors. More recent work has shown that the cell cycle is also a tale of two classes of ubiquitin ligases, referred to as SCF and APC/C ligases. CDKs, E2F and ubiquitin ligases reciprocally regulate each other, resulting in complex feedback loops. Perturbation of this network of molecular machines is associated with proliferative diseases, including cancer.
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PMID:Cell cycle, proteolysis and cancer. 1553 Jul 72

Neuronal plasticity relies on tightly regulated control of protein levels at synapses. One mechanism to control protein abundance is the ubiquitin-proteasome degradation system. Recent studies have implicated ubiquitin-mediated protein degradation in synaptic development, function, and plasticity, but little is known about the regulatory mechanisms controlling ubiquitylation in neurons. In contrast, ubiquitylation has long been studied as a central regulator of the eukaryotic cell cycle. A critical mediator of cell-cycle transitions, the anaphase-promoting complex/cyclosome (APC/C), is an E3 ubiquitin ligase. Although the APC/C has been detected in several differentiated cell types, a functional role for the complex in postmitotic cells has been elusive. We describe a novel postmitotic role for the APC/C at Drosophila neuromuscular synapses: independent regulation of synaptic growth and synaptic transmission. In neurons, the APC/C controls synaptic size via a downstream effector Liprin-alpha; in muscles, the APC/C regulates synaptic transmission, controlling the concentration of a postsynaptic glutamate receptor.
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PMID:Independent regulation of synaptic size and activity by the anaphase-promoting complex. 1555 Feb 51


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