Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A key player in mitotic progression is a cell-cycle-regulated ubiquitin-protein ligase complex known as the anaphase-promoting complex or cyclosome (APC/C). The APC/C is part of the machinery that promotes the metaphase-anaphase transition by mediating the ubiquitin-dependent destruction of anaphase inhibitors and initiates exit from mitosis by degrading mitotic cyclins. This review describes the known components and substrates of the mitotic ubiquitination machinery and discusses how a new subfamily of proteins that contain the WD40 repeat (the Fizzy/Cdc20p family) might activate the APC/C to allow temporal differences in substrate ubiquitination during progression through mitosis.
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PMID:Proteolytic ratchets that control progression through mitosis. 969 48

Programmed proteolysis of proteins such as mitotic cyclins and Cut2/Pds1p requires a 9-residue conserved motif known as the destruction box (D-box). Strong expression of protein fragments containing destruction boxes, such as the first 70 residues of Cdc13 (N70), inhibits the growth of Schizosaccharomyces pombe at metaphase. This inhibition can be overcome either by removal of all lysine residues from N70 using site-directed mutagenesis (K0-N70) or by raising the concentration of intracellular ubiquitin. Consistent with the idea that competition for ubiquitin accounts for some of its inhibitory effects, wild-type N70 not only stabilized D-box proteins, but also Rum1 and Cdc18, which are degraded by a different pathway. The K0-N70 construct was neither polyubiquitinated nor degraded in vitro, but it blocked the growth of strains of yeast in which anaphase-promoting complex/cyclosome (APC/C) function was compromised by mutation, and specifically inhibited proteolysis of APC/C substrates in vivo. Both K0-N70 and 20-residue D-box peptides blocked polyubiquitination of other D-box-containing substrates in a cell-free ubiquitination assay system. These data suggest the existence of a D-box receptor protein that recognizes D-boxes prior to ubiquitination.
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PMID:The role of the destruction box and its neighbouring lysine residues in cyclin B for anaphase ubiquitin-dependent proteolysis in fission yeast: defining the D-box receptor. 975 67

Dendritic cells (DCs) effectively process exogenous and endogenous Ag and present peptide in the context of both class I and class II molecules. We have demonstrated that peripheral blood DCs efficiently degrade synthetic class I peptides at their cell surface within minutes as determined by analyzing DC supernatants by HPLC. Fragments were verified as bona fide cleavage products by direct sequencing using collision-induced dissociation tandem mass spectrometry. The predominant degradative activities were 1) not secreted but associated with activity at the plasma membrane, 2) ecto-orientated, 3) not induced by peptide-specific interactions, and 4) not associated with nonspecific uptake. Sequence analysis indicated that both N- and C-terminal as well as endoproteolytic events were occurring at the cell surface. The primary exoproteolytic event was identified as CD13 or CD13-like activity through inhibition studies and could be inhibited by ubiquitin and metal-chelating agents. Endoproteolytic events could be inhibited in the presence of DTT, but the precise nature of this enzyme is still undetermined. Compared with the starting monocyte population, DCs cultured in the presence of granulocyte-macrophage CSF/IL-4 exhibited the highest degradative rate (4.3 nmol/min), followed by cultured monocytes (2.9 nmol/min) and freshly isolated monocytes (1.0 nmol/min). In addition to increased enzymatic activity, a change in substrate specificity was noted. Results are discussed with respect to APC loading, and alternatives are offered for circumventing such degradation.
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PMID:Rapid extracellular degradation of synthetic class I peptides by human dendritic cells. 978 Jan 72

Present in organisms ranging from yeast to man, homologues of the Drosophila Polo kinase control multiple stages of cell division. At the onset of mitosis, Polo-like kinases (Plks) function in centrosome maturation and bipolar spindle formation, and they contribute to the activation of cyclin-dependent kinase (Cdk)1-cyclin B. Subsequently, they are required for the inactivation of Cdk1 and exit from mitosis. In the absence of Plk function, mitotic cyclins fail to be destroyed, indicating that Plks are important regulators of the anaphase-promoting complex/cyclosome (APC/C), a key component of the ubiquitin-dependent proteolytic degradation pathway. Finally, recent evidence implicates Plks in the temporal and spatial coordination of cytokinesis.
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PMID:Polo-like kinases: positive regulators of cell division from start to finish. 991 75

We have identified two highly conserved RING finger proteins, ROC1 and ROC2, that are homologous to APC11, a subunit of the anaphase-promoting complex. ROC1 and ROC2 commonly interact with all cullins while APC11 specifically interacts with APC2, a cullin-related APC subunit. YeastROC1 encodes an essential gene whose reduced expression resulted in multiple, elongated buds and accumulation of Sic1p and Cln2p. ROC1 and APC11 immunocomplexes can catalyze isopeptide ligations to form polyubiquitin chains in an E1- and E2-dependent manner. ROC1 mutations completely abolished their ligase activity without noticeable changes in associated proteins. Ubiquitination of phosphorylated I kappa B alpha can be catalyzed by the ROC1 immunocomplex in vitro. Hence, combinations of ROC/APC11 and cullin proteins proteins potentially constitute a wide variety of ubiquitin ligases.
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PMID:ROC1, a homolog of APC11, represents a family of cullin partners with an associated ubiquitin ligase activity. 1023 Apr 7

In eukaryotes, the activation of mitotic cyclin-dependent kinases (CDKs) induces mitosis, and their inactivation causes cells to leave mitosis. In budding yeast, two redundant mechanisms induce the inactivation of mitotic CDKs. In one mechanism, a specialized ubiquitin-dependent proteolytic system (called the APC-dependent proteolysis machinery) degrades the mitotic (Clb) cyclin subunit. In the other, the kinase-inhibitor Sic1 binds to mitotic CDKs and inhibits their kinase activity. The highly conserved protein phosphatase Cdc14 promotes both Clb degradation and Sic1 accumulation. Cdc14 promotes SIC1 transcription and the stabilization of Sic1 protein by dephosphorylating Sicl and its transcription factor Swi5. Cdc14 activates the degradation of Clb cyclins by dephosphorylating the APC-specificity factor Cdh1. So how is Cdc14 regulated? Here we show that Cdc14 is sequestered in the nucleolus for most of the cell cycle. During nuclear division, Cdc14 is released from the nucleolus, allowing it to reach its targets. A highly conserved signalling cascade, critical for the exit from mitosis, is required for this movement of Cdc14 during anaphase. Furthermore, we have identified a negative regulator of Cdc14, Cfi1, that anchors Cdc14 in the nucleolus.
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PMID:Cfi1 prevents premature exit from mitosis by anchoring Cdc14 phosphatase in the nucleolus. 1023 56

The ubiquitin-dependent proteolysis of mitotic cyclin B, which is catalyzed by the anaphase-promoting complex/cyclosome (APC/C) and ubiquitin-conjugating enzyme H10 (UbcH10), begins around the time of the metaphase-anaphase transition and continues through G1 phase of the next cell cycle. We have used cell-free systems from mammalian somatic cells collected at different cell cycle stages (G0, G1, S, G2, and M) to investigate the regulated degradation of four targets of the mitotic destruction machinery: cyclins A and B, geminin H (an inhibitor of S phase identified in Xenopus), and Cut2p (an inhibitor of anaphase onset identified in fission yeast). All four are degraded by G1 extracts but not by extracts of S phase cells. Maintenance of destruction during G1 requires the activity of a PP2A-like phosphatase. Destruction of each target is dependent on the presence of an N-terminal destruction box motif, is accelerated by additional wild-type UbcH10 and is blocked by dominant negative UbcH10. Destruction of each is terminated by a dominant activity that appears in nuclei near the start of S phase. Previous work indicates that the APC/C-dependent destruction of anaphase inhibitors is activated after chromosome alignment at the metaphase plate. In support of this, we show that addition of dominant negative UbcH10 to G1 extracts blocks destruction of the yeast anaphase inhibitor Cut2p in vitro, and injection of dominant negative UbcH10 blocks anaphase onset in vivo. Finally, we report that injection of dominant negative Ubc3/Cdc34, whose role in G1-S control is well established and has been implicated in kinetochore function during mitosis in yeast, dramatically interferes with congression of chromosomes to the metaphase plate. These results demonstrate that the regulated ubiquitination and destruction of critical mitotic proteins is highly conserved from yeast to humans.
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PMID:Cell cycle-regulated proteolysis of mitotic target proteins. 1056 81

The SCF complex (Skp1-Cullin-1-F-box) and the APC/cyclosome (anaphase-promoting complex) are two ubiquitin ligases that play a crucial role in eukaryotic cell cycle control. In fission yeast F-box/WD-repeat proteins Pop1 and Pop2, components of SCF are required for cell-cycle-dependent degradation of the cyclin-dependent kinase (CDK) inhibitor Rum1 and the S-phase regulator Cdc18. Accumulation of these proteins in pop1 and pop2 mutants leads to re-replication and defects in sexual differentiation. Despite structural and functional similarities, Pop1 and Pop2 are not redundant homologues. Instead, these two proteins form heterodimers as well as homodimers, such that three distinct complexes, namely SCFPop1/Pop1, SCFPop1/Pop2 and SCFPop2/Pop2, appear to exist in the cell. The APC/cyclosome is responsible for inactivation of CDK/cyclins through the degradation of B-type cyclins. We have identified two novel components or regulators of this complex, called Apc10 and Ste9, which are evolutionarily highly conserved. Apc10 (and Ste9), together with Rum1, are required for the establishment of and progression through the G1 phase in fission yeast. We propose that dual downregulation of CDK, one via the APC/cyclosome and the other via the CDK inhibitor, is a universal mechanism that is used to arrest the cell cycle at G1.
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PMID:Two distinct ubiquitin-proteolysis pathways in the fission yeast cell cycle. 1058 40

Cullin 1/CDC53 represents a multigene family and has been linked to the ubiquitin-mediated proteolysis of several different proteins. We recently identified two closely related RING finger proteins, ROC1 and ROC2, that share considerable sequence similarity to an APC subunit, APC11, and demonstrated ROC1 as an essential subunit of CUL1 and CDC53 ubiquitin ligases. We report here that the expression of ROC1, ROC2 and APC11 genes are induced by mitogens and remain constant during the cell cycle. Unlike other subunits of SCF and APC E3 ligases, ectopically expressed ROC family proteins are degraded by a proteasome-inhibitor sensitive pathway and are stabilized by associating with cullins. Mutations at the conserved Phe79 and His80 residues in the RING finger of ROC1 diminish its binding with cullins, resulting in a loss of cullin protection and ubiquitin ligase activity. These results suggest a potential mechanism for regulating the activity of ROC-cullin ligases through complex assembly and ROC/APC11 subunit ubiquitination.
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PMID:Association with cullin partners protects ROC proteins from proteasome-dependent degradation. 1059 84

The ubiquitin system drives the cell division cycle by the timely destruction of numerous regulatory proteins. Remarkably, the two main activities that catalyze substrate ubiquitination in the cell cycle, the Skp1-Cdc53/cullin-F-box protein (SCF) complexes and the anaphase-promoting complex/cyclosome (APC/C), define a new superfamily of E3 ubiquitin ligases, all based on related cullin and RING-H2 finger protein subunits. The circuits that interconnect the SCF, APC/C and cyclin-dependent kinase activities form a master oscillator that coordinates the replication and segregation of the genome.
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PMID:Proteolysis and the cell cycle: with this RING I do thee destroy. 1067 94


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