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)

The anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase functions with the E2 ubiquitin-conjugating enzyme UbcH10 in the orderly progression through mitosis by marking key mitotic regulators for destruction by the 26-S proteasome. UbcH10 is overexpressed in many human cancer types and is associated with tumor progression. However, whether UbcH10 overexpression causes tumor formation is unknown. To address this central question and to define the molecular and cellular consequences of UbcH10 overexpression, we generated a series of transgenic mice in which UbcH10 was overexpressed in graded fashion. In this study, we show that UbcH10 overexpression leads to precocious degradation of cyclin B by the APC/C, supernumerary centrioles, lagging chromosomes, and aneuploidy. Importantly, we find that UbcH10 transgenic mice are prone to carcinogen-induced lung tumors and a broad spectrum of spontaneous tumors. Our results identify UbcH10 as a prominent protooncogene that causes whole chromosome instability and tumor formation over a wide gradient of overexpression levels.
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PMID:Overexpression of the E2 ubiquitin-conjugating enzyme UbcH10 causes chromosome missegregation and tumor formation. 2006 91

The APC/C (anaphase-promoting complex/cyclosome) is an E3 ubiquitin ligase that targets specific substrates for degradation by the 26S proteasome. APC/C activity depends on two cofactors, namely Cdc20 (cell division cycle 20) and Cdh1, which select the appropriate targets for ubiquitination. It is well established that APC/C is a target of the SAC (spindle assembly checkpoint) during mitosis and has critical roles in controlling the protein levels of major regulators of mitosis and DNA replication. In addition, recent studies have suggested new cell-cycle-independent functions of APC/C in non-mitotic cells and specifically in neuronal structure and function. Given the relevant functions of APC/C in cell proliferation and neuronal physiology, modulating APC/C activity may have beneficial effects in the clinic.
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PMID:The anaphase-promoting complex/cyclosome (APC/C): cell-cycle-dependent and -independent functions. 2007 37

F-box proteins are the substrate recognition subunits of SCF (Skp1, Cul1, F-box protein) ubiquitin ligase complexes. Skp2 is a nuclear F-box protein that targets the CDK inhibitor p27 for ubiquitin- and proteasome-dependent degradation. In G(0) and during the G(1) phase of the cell cycle, Skp2 is degraded via the APC/C(Cdh1) ubiquitin ligase to allow stabilization of p27 and inhibition of CDKs, facilitating the maintenance of the G(0)/G(1) state. APC/C(Cdh1) binds Skp2 through an N-terminal domain (amino acids 46-94 in human Skp2). It has been shown that phosphorylation of Ser64 and Ser72 in this domain dissociates Skp2 from APC/C. More recently, it has instead been proposed that phosphorylation of Skp2 on Ser72 by Akt/PKB allows Skp2 binding to Skp1, promoting the assembly of an active SCF(Skp2) ubiquitin ligase, and Skp2 relocalization/retention into the cytoplasm, promoting cell migration via an unknown mechanism. According to these reports, a Skp2 mutant in which Ser72 is substituted with Ala is unable to promote cell proliferation and loses its oncogenic potential. Given the contrasting reports, we revisited these results and conclude that phosphorylation of Skp2 on Ser72 does not control Skp2 binding to Skp1 and Cul1, has no influence on SCF(Skp2) ubiquitin ligase activity, and does not affect the subcellular localization of Skp2.
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PMID:Phosphorylation of Ser72 is dispensable for Skp2 assembly into an active SCF ubiquitin ligase and its subcellular localization. 2016 Apr 77

The mitotic (or spindle assembly) checkpoint system ensures accurate segregation of chromosomes by delaying anaphase until all chromosomes are correctly attached to the mitotic spindle. This system acts by inhibiting the activity of the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase to target securin for degradation. APC/C is inhibited by a mitotic checkpoint complex (MCC) composed of BubR1, Bub3, Mad2, and Cdc20. The molecular mechanisms of the inactivation of the mitotic checkpoint, including the release of APC/C from inhibition, remain obscure. It has been reported that polyubiquitylation by the APC/C is required for the inactivation of the mitotic checkpoint [Reddy SK, Rape M, Margansky WA, Kirschner MW (2007) Nature, 446:921-924]. We confirmed the involvement of polyubiquitylation, but found that another process, which requires ATP cleavage at the beta-gamma position (as opposed to alpha-beta bond scission involved in ubiquitylation), is essential for the release of APC/C from checkpoint inhibition. ATP (beta-gamma) cleavage is required both for the dissociation of MCC components from APC/C and for the disassembly of free MCC, whereas polyubiquitylation is involved only in the former process. We find that the requirement for ATP (beta-gamma) cleavage is not due to the involvement of the 26S proteasome and that the phenomena observed are not due to sustained activity of protein kinase Cdk1/cyclin B, caused by inhibition of the degradation of cyclin B. Thus, some other energy-consuming process is needed for the inactivation of the mitotic checkpoint.
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PMID:ATP is required for the release of the anaphase-promoting complex/cyclosome from inhibition by the mitotic checkpoint. 2021 61

Within the mammalian ovary, oocytes remain arrested at G2 for several years. Then a peri-ovulatory hormonal cue triggers meiotic resumption by releasing an inhibitory phosphorylation on the kinase Cdk1. G2 arrest, however, also requires control in the concentrations of the Cdk1-binding partner cyclin B1, a process achieved by anaphase-promoting complex (APC(Cdh1)) activity, which ubiquitylates and so targets cyclin B1 for degradation. Thus, APC(Cdh1) activity prevents precocious meiotic entry by promoting cyclin B1 degradation. However, it remains unresolved how cyclin B1 levels are suppressed sufficiently to maintain arrest but not so low that they make oocytes hormonally insensitive. Here, we examined spatial control of this process by determining the intracellular location of the proteins involved and using nuclear-targeted cyclin B1. We found that raising nuclear cyclin B1 concentrations, an event normally observed in the minutes before nuclear envelope breakdown, was a very effective method of inducing the G2/M transition. Oocytes expressed only the alpha-isoform of Cdh1, which was predominantly nuclear, as were Cdc27 and Psmd11, core components of the APC and the 26S proteasome, respectively. Furthermore, APC(Cdh1) activity appeared higher in the nucleus, as nuclear-targeted cyclin B1 was degraded at twice the rate of wild-type cyclin B1. We propose a simple spatial model of G2 arrest in which nuclear APC(Cdh1)-proteasomal activity guards against any cyclin B1 accumulation mediated by nuclear import.
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PMID:Spatial regulation of APCCdh1-induced cyclin B1 degradation maintains G2 arrest in mouse oocytes. 2022 64

Cdr2 is a tumor antigen expressed in a high percentage of breast and ovarian tumors and is the target of a naturally occurring tumor immune response in patients with paraneoplastic cerebellar degeneration, but little is known of its regulation or function in cancer cells. Here we find that cdr2 is cell cycle regulated in tumor cells with protein levels peaking in mitosis. As cells exit mitosis, cdr2 is ubiquitinated by the anaphase promoting complex/cyclosome (APC/C) and rapidly degraded by the proteasome. Previously we showed that cdr2 binds to the oncogene c-myc, and here we extend this observation to show that cdr2 and c-myc interact to synergistically regulate c-myc-dependent transcription during passage through mitosis. Loss of cdr2 leads to functional consequences for dividing cells, as they show aberrant mitotic spindle formation and impaired proliferation. Conversely, cdr2 overexpression is able to drive cell proliferation in tumors. Together, these data indicate that the onconeural antigen cdr2 acts during mitosis in cycling cells, at least in part through interactions with c-myc, to regulate a cascade of actions that may present new targeting opportunities in gynecologic cancer.
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PMID:The onconeural antigen cdr2 is a novel APC/C target that acts in mitosis to regulate c-myc target genes in mammalian tumor cells. 2038 33

Recent studies have shown a critical function for the ubiquitin-proteasome system (UPS) in regulating the signalling network for DNA damage responses and DNA repair. To search for new UPS targets in the DNA damage signalling pathway, we have carried out a non-biased assay to identify fast-turnover proteins induced by various types of genotoxic stress. This endeavour led to the identification of Rad17 as a protein exhibiting a distinctive pattern of upregulation followed by subsequent degradation after exposure to UV radiation in human primary cells. Our characterization showed that UV-induced Rad17 oscillation is mediated by Cdh1/APC, a ubiquitin-protein ligase. Studies using a degradation-resistant Rad17 mutant demonstrated that Rad17 stabilization prevents the termination of checkpoint signalling, which in turn attenuates the cellular re-entry into cell-cycle progression. The findings provide an insight into how the proteolysis of Rad17 by Cdh1/APC regulates the termination of checkpoint signalling and the recovery from genotoxic stress.
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PMID:Proteolysis of Rad17 by Cdh1/APC regulates checkpoint termination and recovery from genotoxic stress. 2042 96

The balance between cell cycle progression and apoptosis is important for both surveillance against genomic defects and responses to drugs that arrest the cell cycle. In this report, we show that the level of the human anti-apoptotic protein Mcl-1 is regulated during the cell cycle and peaks at mitosis. Mcl-1 is phosphorylated at two sites in mitosis, Ser64 and Thr92. Phosphorylation of Thr92 by cyclin-dependent kinase 1 (CDK1)-cyclin B1 initiates degradation of Mcl-1 in cells arrested in mitosis by microtubule poisons. Mcl-1 destruction during mitotic arrest requires proteasome activity and is dependent on Cdc20/Fizzy, which mediates recognition of mitotic substrates by the anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase. Stabilisation of Mcl-1 during mitotic arrest by mutation of either Thr92 or a D-box destruction motif inhibits the induction of apoptosis by microtubule poisons. Thus, phosphorylation of Mcl-1 by CDK1-cyclin B1 and its APC/C(Cdc20)-mediated destruction initiates apoptosis if a cell fails to resolve mitosis. Regulation of apoptosis, therefore, is linked intrinsically to progression through mitosis and is governed by a temporal mechanism that distinguishes between normal mitosis and prolonged mitotic arrest.
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PMID:Phosphorylation of Mcl-1 by CDK1-cyclin B1 initiates its Cdc20-dependent destruction during mitotic arrest. 2064 46

We have recently demonstrated that TRB3, a novel stress-inducible protein, is an unstable protein regulated by the ubiquitin-proteasome system. The expression level of TRB3 protein is down-regulated by anaphase-promoting complex/cyclosome-cell division cycle division 20 homolog 1 (APC/C(Cdh1)) through its D-box motif. Here we demonstrate that TRB3 regulates the stability of cell division cycle 25 A (Cdc25A), an essential activator of cyclin dependent kinases (CDKs). The expression level of Cdc25A protein is suppressed by over-expression of TRB3, while knockdown of TRB3 enhances the endogenous Cdc25A expression level. On the other hand, Cdc25A degradation induced by DNA damage is significantly rescued by TRB3. When serine residues in the DSG motif, which is the critical sequences for the degradation of Cdc25A induced by DNA damage, is mutated to alanine (Cdc25A(DSG2X)), both stimulatory and protective effects of TRB3 on the Cdc25A degradation is disappeared. TRB3 protein interacts with both wild Cdc25A and mutant Cdc25A(DSG2X). Expression level of the endogenous TRB3 protein is down-regulated in a genotoxic condition. These results suggest TRB3 is a regulator for adjusting the expression level of Cdc25A both in a normal and a genotoxic conditions.
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PMID:Dual mode of regulation of cell division cycle 25 A protein by TRB3. 2060 98

Our previous study demonstrates that Bcr-Abl fusion oncogene frequently found in chronic myeloid leukemia (CML) cells can up-regulate Skp2 expression via transcriptional activation. However, Bcr-Abl also modulates Skp2 protein stability in these cells. Treatment of Bcr-Abl kinase inhibitor imatinib led to G1 growth arrest accompanied with reduced Skp2 expression. Interestingly, reduction of Skp2 protein occurred prior to down-regulation of Skp2 mRNA suggesting a post-translational control. The half-life of Skp2 protein was significantly attenuated in imatinib-treated cells. These effects are not cell line specific because similar results were also found in CML cells obtained from patients. Knockdown of Bcr-Abl similarly caused Skp2 protein instability. The decrease of Skp2 was induced by increased protein degradation through the ubiquitin/proteasome pathway. Imatinib treatment or Bcr-Abl knockdown reduced Emi1, an endogenous inhibitor of the E3 ligase APC/Cdh1 which mediated Skp2 degradation. We found that Emi1 stability was regulated by phosphorylation and mutation of tyrosine 142 reduced the stability. Our data suggested Bcr-Abl-induced Emi1 phosphorylation might be mediated by Src kinase. Firstly, Src inhibitor SU6656 inhibited Emi1 tyrosine phosphorylation in K562 cells. Secondly, transfection of v-Src rescued the reduction of Emi1 by imatinib. Thirdly, mutation of tyrosine 142 to phenylalanine (Y142F) abolished the phosphorylation of Emi1 by recombinant Src kinase. In addition, ectopic expression of wild type but not Y142F mutant Emi1 counteracted imatinib-caused growth arrest. Collectively, our results suggest that Bcr-Abl increases Emi1 phosphorylation and stability to prevent Skp2 protein degradation via APC/Cdh1-induced ubiquitination and to enhance proliferation of CML cells.
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PMID:Bcr-Abl-induced tyrosine phosphorylation of Emi1 to stabilize Skp2 protein via inhibition of ubiquitination in chronic myeloid leukemia cells. 2071 63


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