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)

APC/C complex has been known to regulate cell cycle progression via its ubiquitin E3 ligase activity that targets a number of cell cycle regulators. In a recent report, it is shown that APC/C interacts with transcription co-activators, CBP and p300, via its APC5 and APC7 subunits. The authors further demonstrate the functional significance of APC/C-CBP/p300 interaction in regulating both transcription and cell cycle progression. These findings have profound implications in unveiling additional functions and regulatory mechanisms of these two seemingly independent molecular modulators.
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PMID:Cross-talk between APC/C and CBP/p300. 1686 17

Ubiquitin-mediated proteolysis is one of the key mechanisms underlying cell cycle control. The removal of barriers posed by accumulation of negative regulators, as well as the clearance of proteins when they are no longer needed or deleterious, are carried out via the ubiquitin-proteasome system. Ubiquitin conjugating enzymes and protein-ubiquitin ligases collaborate to mark proteins destined for degradation by the proteasome by covalent attachment of multi-ubiquitin chains. Most regulated proteolysis during the cell cycle can be attributed to two families of protein-ubiquitin ligases. The anaphase promoting complex/cyclosome (APC/C) is activated during mitosis and G1 where it is responsible for eliminating proteins that impede mitotic progression and that would have deleterious consequences if allowed to accumulate during G1. SCF (Skp1/Culin/F-box protein) protein-ubiquitin ligases ubiquitylate proteins that are marked by phosphorylation at specific sequences known as phosphodegrons. Targeting of proteins for destruction by phosphorylation provides a mechanism for linking cell cycle regulation to internal and external signaling pathways via regulated protein kinase activities.
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PMID:The ubiquitin-proteasome pathway in cell cycle control. 1690 11

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

TGF-beta (transforming growth factor-beta) signals through serine/threonine kinase receptors and intracellular Smad transcription factors. An important regulatory step involves specific ubiquitination by Smurfs (Smad-ubiquitin regulatory factors), members of the HECT (homologous to E6-associated protein C-terminus) ubiquitin ligase family, which mediate the proteasomal degradation of Smads and/or receptors. Recently, we have defined a novel interaction between Smads and UCH37 (ubiquitin C-terminal hydrolase 37), a DUB (de-ubiquitinating enzyme) that could potentially counteract Smurf-mediated ubiquitination. We have demonstrated specific interactions between UCH37 and inhibitory Smad7, as well as weaker associations with Smad2 and Smad3. Importantly, Smad7 can act as an adaptor able to recruit UCH37 to the type I TGF-beta receptor. Consequently, UCH37 dramatically up-regulates TGF-beta-dependent gene expression by de-ubiquitinating and stabilizing the type I TGF-beta receptor. Our findings suggest that competing effects of ubiquitin ligases and DUBs in complex with Smad7 can serve to fine-tune responses to TGF-betas under various physiological and pathological conditions. Studies are currently under way using activity-based HA (haemagglutinin)-tagged ubiquitin probes to identify the full spectrum of DUBs that impact on Smad/TGF-beta signalling activity.
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PMID:Reversible ubiquitination regulates the Smad/TGF-beta signalling pathway. 1705 92

Cell cycle transitions are often accompanied by the degradation of regulatory molecules. Targeting proteins to the proteasome for degradation is accomplished by the covalent addition of ubiquitin chains. The specificity of this pathway is largely dictated by a set of enzymes called ubiquitin ligases (or E3s). The anaphase-promoting complex (or APC) is a ubiquitin ligase that has a particularly prominent role in regulating cell cycle progression. To date, the APC is the most complicated member of the RING/cullin family of multisubunit E3s. It includes at least 13 core subunits and three related adaptors. A combination of biochemical, genetic, and structural approaches are now shedding light on the enzymology of the APC. This review will focus on these data, drawing parallels with related ubiquitin ligases.
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PMID:Precise destruction: an emerging picture of the APC. 1711 80

Mitotic Aurora-A is an oncogene, which undergoes a cell-cycle-dependent regulation of both its synthesis and degradation. Overexpression of Aurora-A leads to aneuploidy and cellular transformation in cultured cells. It has been shown that the cell-cycle-dependent turnover of Aurora-A is mediated by Cdh1 (CDC20 homologue 1) through the anaphase-promoting complex/cyclosome (APC/C)-ubiquitin-proteasome pathway. We have described previously the identification of an Aurora-A kinase interacting protein, AURKAIP1 (formerly described as AIP), which is also involved in the destabilization of Aurora-A through the proteasome-dependent degradation pathway. In an attempt to investigate the mechanism of AURKAIP1-mediated Aurora-A degradation, we report here that AURKAIP1 targets Aurora-A for degradation in a proteasome-dependent but Ub (ubiquitin)-independent manner. AURKAIP1 inhibits polyubiquitination of Aurora-A. A non-interactive AURKAIP1 mutant that cannot destabilize Aurora-A restores ubiquitination of Aurora-A. An A-box mutant of Aurora-A, which cannot be targeted for proteasome-dependent degradation by Cdh1, can still be degraded by AURKAIP1. Inhibition of cellular ubiquitination either by expression of dominant negative Ub mutants or by studies in ts-20 (temperature sensitive-20) CHO (Chinese-hamster ovary) cell line lacking the E1 Ub activating enzyme at the restrictive temperature, cannot abolish AURKAIP1-mediated degradation of Aurora-A. AURKAIP1 specifically decreases the stability of Aurora-A in ts-20 CHO cells at the restrictive temperature, while cyclinB1 and p21 are not affected. This demonstrates that there exists an Ub-independent alternative pathway for Aurora-A degradation and AURKAIP1 promotes Aurora-A degradation through this Ub-independent yet proteasome-dependent pathway.
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PMID:Aurora-A kinase interacting protein 1 (AURKAIP1) promotes Aurora-A degradation through an alternative ubiquitin-independent pathway. 1712 67

The evolutionarily conserved PIF1 DNA helicase family is important for the maintenance of genome stability in the yeast, Saccharomyces cerevisiae. There are two PIF1 family helicases in S. cerevisiae, Pif1p and Rrm3p that both possess 5'-->3' DNA helicase activity but maintain unique functions in telomerase regulation and semi-conservative DNA replication. Database analysis shows that the PIF1 helicase family is represented by a single homologue in higher eukaryotes. To analyze the function of PIF1 homologues in mammals, we cloned the full length human PIF (hPIF) cDNA. Comparison of hPIF with its S. cerevisiae homologues showed that human PIF is equally similar to Pif1p and Rrm3p. Human PIF was expressed at low levels in a variety of tissues and immunofluorescence analysis showed that ectopic hPIF was localized to nuclear foci. hPIF was expressed in late S/G2 phase of the cell cycle and this cell cycle regulated abundance was conferred by both cell cycle regulated mRNA accumulation and ubiquitin-mediated degradation. Furthermore, hPIF is likely a target of the anaphase promoting complex/cyclosome as its abundance was decreased when an activator of the APC/C was overexpressed. Finally, antibodies against hPIF immunoprecipitated telomerase activity from human cell lines, and we have observed a physical interaction between hPIF and the catalytic subunit of telomerase, hTERT. Our data suggest that human PIF, like S. cerevisiae Pif1p, plays a role in telomerase regulation.
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PMID:Human PIF helicase is cell cycle regulated and associates with telomerase. 1717 55

The retinoblastoma protein (pRB) negatively regulates the progression from G1 to S phase of the cell cycle, in part, by repressing E2F-dependent transcription. pRB also possesses E2F-independent functions that contribute to cell-cycle control--for example, during pRB-mediated cell-cycle arrest pRB associates with Skp2, the F-box protein of the Skp1-Cullin-F-box protein (SCF) E3 ubiquitin ligase complex, and promotes the stability of the cyclin-dependent kinase-inhibitor p27(Kip1) through an unknown mechanism. Degradation of p27(Kip1) is mediated by ubiquitin-dependent targeting of p27(Kip1) by SCF -Skp2 (ref. 4). Here, we report a novel interaction between pRB and the anaphase-promoting complex/cyclosome (APC/C) that controls p27(Kip1) stability by targeting Skp2 for ubiquitin-mediated degradation. Cdh1, an activator of APC/C, not only interacts with pRB but is also required for a pRB-induced cell-cycle arrest. The results reveal an unexpected physical convergence between the pRB tumour-suppressor protein and E3 ligase complexes, and raise the possibility that pRB may direct APC/C to additional targets during pRB-mediated cell-cycle exit.
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PMID:Retinoblastoma protein and anaphase-promoting complex physically interact and functionally cooperate during cell-cycle exit. 1726 77

Lens development requires the precise coordination of cell division and differentiation. The mechanisms by which the differentiation program is initiated after cell cycle arrest remains not well understood. Cyclin-dependent kinase inhibitors (CKIs), such as p15 and p21, have been suggested to be critical components that inhibit G1 progression and therefore, their activation is necessary for quiescence and important for the onset of differentiation. Regulation of p15 and p21 is principally governed by transforming growth factor (TGF)-beta-signaling pathway. We have identified that Cdh1/APC, a critical ubiquitin protein ligase, plays an important role in regulating lens differentiation by facilitating TGF-beta-induced degradation of SnoN, a transcriptional corepressor that needs to be removed for transcriptional activation of p15 and p21. The depletion of Cdh1 by RNA interference attenuates the TGF-beta-mediated induction of p15 and p21 and significantly blocks lens differentiation. Expression of nondegradable SnoN also noticeably attenuates lens induction. Furthermore, we have shown that Cdh1 and SnoN form a complex at the onset of lens differentiation. In vivo histological analysis confirms our biochemical and genetic results. Thus, Cdh1/APC is crucial to the coordination of cell cycle progression and the initiation of lens differentiation through mediating TGF-beta-signaling-induced destruction of SnoN.
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PMID:The anaphase-promoting complex coordinates initiation of lens differentiation. 1721 16

Entry into mitosis is a highly regulated process, promoted by the activated Cyclin B1/Cdk1 complex. Activation of this complex is controlled, in part, by the protein kinase Aurora-A, which is a member of a multigenic serine/threonine kinase family. In normal cells, Aurora-A activity is regulated, at least in part, by degradation through the APC-ubiquitin-proteasome pathway. It has recently been proposed that, in Xenopus, Aurora-A degradation can be inhibited by phosphorylation. It would thus be expected that a phosphatase activity would release this blockade at the end of mitosis. Here, we have shown that the protein phosphatase PP2A and Aurora-A are colocalized at the cell poles during mitosis in human cells and interact within the same complex. Using the PP2A inhibitor okadaic acid and an RNAi approach, we have shown that this interaction is functional within the cell. PP2A/Aurora-A interaction is promoted by an S51D mutation in Aurora-A and inhibited by a phosphomimetic peptide centered around Aurora-A S51, thereby strongly suggesting that PP2A controls Aurora-A degradation by dephosphorylating serine 51 in the A box of the human enzyme.
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PMID:Functional interaction of Aurora-A and PP2A during mitosis. 1722 85


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