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

Cell cycle events are regulated by sequential activation and inactivation of Cdk kinases. Mitotic exit is accomplished by the inactivation of mitotic Cdk kinase, which is mainly achieved by degradation of cyclins. The ubiquitin-proteasome system is involved in this process, requiring APC/C (anaphase-promoting complex/cyclosome) as a ubiquitin ligase. In Xenopus and clam oocytes, the ubiquitin-conjugating enzymes that function with APC/C have been identified as two proteins, UBC4 and UBCx/E2-C. Previously we reported that the fission yeast ubiquitin-conjugating enzyme UbcP4/Ubc11, a homologue of UBCx/E2-C, is required for mitotic transition. Here we show that the other fission yeast ubiquitin-conjugating enzyme, UbcP1/Ubc4, which is homologous to UBC4, is also required for mitotic transition in the same manner as UbcP4/Ubc11. Both ubiquitin-conjugating enzymes are essential for cell division and directly required for the degradation of mitotic cyclin Cdc13. They function nonredundantly in the ubiquitination of CDC13 because a defect in ubcP1/ubc4+ cannot be suppressed by high expression of UbcP4/Ubc11 and a defect in ubcP4/ubc11+ cannot be suppressed by high expression of UbcP1/Ubc4. In vivo analysis of the ubiquitinated state of Cdc13 shows that the ubiquitin chains on Cdc13 were short in ubcP1/ubc4 mutant cells while ubiquitinated Cdc13 was totally reduced in ubcP4/ubc11 mutant cells. Taken together, these results indicate that the two ubiquitin-conjugating enzymes play distinct and essential roles in the degradation of mitotic cyclin Cdc13, with the UbcP4/Ubc11-pathway initiating ubiquitination of Cdc13 and the UbcP1/Ubc4-pathway elongating the short ubiquitin chains on Cdc13.
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PMID:Two ubiquitin-conjugating enzymes, UbcP1/Ubc4 and UbcP4/Ubc11, have distinct functions for ubiquitination of mitotic cyclin. 1272 8

Cks proteins are small evolutionarily conserved proteins that interact genetically and physically with cyclin-dependent kinases. However, in spite of a large body of genetic, biochemical and structural research, no compelling unifying model of their functions has emerged. Here we show, by investigating the essential role of Cks1 in Saccharomyces cerevisiae, that the protein is primarily involved in promoting mitosis by modulating the transcriptional activation of the APC/C protein-ubiquitin ligase activator Cdc20. Cks1 is required for both the periodic dissociation of Cdc28 kinase from the CDC20 promoter and the periodic association of the proteasome with the promoter. We propose that the essential role of Cks1 is to recruit the proteasome to, and/or dissociate the Cdc28 kinase from, the CDC20 promoter, thus facilitating transcription by remodelling transcriptional complexes or chromatin associated with the CDC20 gene.
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PMID:Cks1-dependent proteasome recruitment and activation of CDC20 transcription in budding yeast. 1282 7

The discs large (hDlg) tumor suppressor is intimately involved in the control of cell contact, polarity, and proliferation by interacting with several components of the epithelial junctional complex and with the APC tumor suppressor protein. In epithelial cells, hDlg protein stability is regulated through the ubiquitin-proteasome pathway: hDlg is actively degraded in isolated cells, whereas it accumulates upon cell-cell contact. During neoplastic transformation of epithelial cells, loss of the differentiated morphology and progression toward a metastatic phenotype correlate with down-regulation of hDlg levels and loss of contact-dependent stabilization. Here we show that upon hyperphosphorylation, hDlg interacts with the beta-TrCP ubiquitin ligase receptor through a DSGLPS motif within its Src homology 3 domain. As a consequence, overexpression of beta-TrCP enhances ubiquitination of Dlg protein and decreases its stability, whereas a dominant negative beta-TrCP mutant inhibits this process. Furthermore, a mutant Dlg protein that is unable to bind beta-TrCP displays a higher protein stability and is insensitive to beta-TrCP. Using RNA interference, we also demonstrate that endogenous beta-TrCP regulates hDlg protein levels in epithelial cells. Finally, we show that beta-TrCP selectively induces the degradation of the membrane-cytoplasmic pool, without affecting the nuclear pool of hDlg.
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PMID:Regulation of the discs large tumor suppressor by a phosphorylation-dependent interaction with the beta-TrCP ubiquitin ligase receptor. 1290 44

Recent studies of the Smad family proteins, which are the key signal transducers of the TGF-beta family ligands, have revealed the ability of Smads to interact with various components of the 26S proteasome system. Such interactions are now known to contribute to the regulation of Smad protein levels before and after Smad activation. Most importantly, such interactions are also shown to be an integral part of the signaling functions of Smads. Through a physical interaction with different ubiquitin E3 ligases (HECT family, SCF and APC complex), the TGF-beta/activin responsive Smad3 exhibits the novel ability to regulate the ubiquitination of several key regulators, such as the oncoprotein SnoN and the multi-domain docking protein HEF1. The proteasomal degradation of these two proteins links TGF-beta signaling to multiple signaling pathways involving SnoN and HEF1. Through the interaction with proteasome beta subunit HsN3 and the substrate marker protein ornithine decarboxylase antizyme (AZ), the BMP responsive Smad1 regulates the proteasomal targeting events that contribute to the degradation of Smad1 and its interacting proteins, one of which is SNIP1, a repressor of the transcriptional co-activator CBP/p300. Thus, the novel physical link between Smads and components in the 26S proteasome system allow the intracellular events triggered by the TGF-beta family ligands to connect with those induced by many other extracellular regulators, thereby forming an extremely complex signaling network to regulate a wide range of biological activities.
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PMID:The 26S proteasome system in the signaling pathways of TGF-beta superfamily. 1295 30

Colorectal cancer (CRC) is the second leading cause of cancer death in the USA. Accumulation of beta-catenin protein is nearly ubiquitous in colon adenomas and cancers, presumably due to mutations in the APC or beta-catenin genes that inhibit proteasome-dependent degradation of beta-catenin protein. Substantial clinical, epidemiological, and animal evidence indicate that sulindac and other non-steroidal anti-inflammatory drugs (NSAIDs) prevent the development of CRC. The mechanisms by which sulindac exerts its potent growth inhibitory effects against colon tumor cells are incompletely understood, but down-regulation of beta-catenin has been suggested as one potential mechanism. The goal of this study was to determine the mechanism of beta-catenin protein down-regulation by sulindac metabolites. Treatment of human colon cancer cell lines with apoptotic concentrations of sulindac metabolites (sulindac sulfide, sulindac sulfone) induced a dose- and time-dependent inhibition of beta-catenin protein expression. Inhibition of proteasome activity with MG-132 partially blocked the ability of sulindac sulfide and sulindac sulfone to inhibit beta-catenin protein expression. Pretreatment with the caspase inhibitor z-VAD-fmk blocked morphological signs of apoptosis as well as caspase cleavage, and also partially prevented beta-catenin degradation by sulindac metabolites. These effects occurred in cells with bi-allelic APC mutation (SW480), with wild-type APC but mono-allelic beta-catenin mutation (HCT116) and in cells that lack expression of either COX-1 or -2 (HCT15). These results indicate that loss of beta-catenin protein induced by sulindac metabolites is COX independent and at least partially due to reactivation of beta-catenin proteasome degradation and partially a result of caspase activation during the process of apoptosis.
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PMID:Sulindac metabolites induce caspase- and proteasome-dependent degradation of beta-catenin protein in human colon cancer cells. 1455 7

Faithful segregation of homologous chromosomes during the first meiotic division is essential for further embryo development. The question at issue is whether the same mechanisms ensuring correct separation of sister chromatids in mitosis are at work during the first meiotic division. In mitosis, sister chromatids are linked by a cohesin complex holding them together until their disjunction at anaphase. Their disjunction is mediated by Separase, which cleaves the cohesin. The activation of Separase requires prior degradation of its associated inhibitor, called securin. Securin is a target of the APC/C (Anaphase Promoting Complex/Cyclosome), a cell cycle-regulated ubiquitin ligase that ubiquitinates securin at the metaphase-to-anaphase transition and thereby targets it for degradation by the 26S proteasome. After securin degradation, Separase cleaves the cohesins and triggers chromatid separation, a prerequisite for anaphase. In yeast and worms, the segregation of homologous chromosomes in meiosis I depends on the APC/C and Separase activity. Yet, it is unclear if Separase is required for the first meiotic division in vertebrates because APC/C activity is thought to be dispensable in frog oocytes. We therefore investigated if Separase activity is required for correct chromosome segregation in meiosis I in mouse oocytes.
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PMID:The meiosis I-to-meiosis II transition in mouse oocytes requires separase activity. 1456 5

The expression of human thymidine kinase 1 (hTK1) is highly dependent on the growth states and cell cycle stages in mammalian cells. The amount of hTK1 is significantly increased in the cells during progression to the S and M phases, and becomes barely detectable in the early G(1) phase by a proteolytic control during mitotic exit. This tight regulation is important for providing the correct pool of dTTP for DNA synthesis at the right time in the cell cycle. Here, we investigated the mechanism responsible for mitotic degradation of hTK1. We show that hTK1 is degraded via a ubiquitin-proteasome pathway in mammalian cells and that anaphase-promoting complex/cyclosome (APC/C) activator Cdh1 is not only a necessary but also a rate-limiting factor for mitotic degradation of hTK1. Furthermore, a KEN box sequence located in the C-terminal region of hTK1 is required for its mitotic degradation and interaction capability with Cdh1. By in vitro ubiquitinylation assays, we demonstrated that hTK1 is targeted for degradation by the APC/C-Cdh1 ubiquitin ligase dependent on this KEN box motif. Taken together, we concluded that activation of the APC/C-Cdh1 complex during mitotic exit controls timing of hTK1 destruction, thus effectively minimizing dTTP formation from the salvage pathway in the early G(1) phase of the cell cycle in mammalian cells.
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PMID:Mitotic degradation of human thymidine kinase 1 is dependent on the anaphase-promoting complex/cyclosome-CDH1-mediated pathway. 1470 26

The Anaphase Promoting Complex/Cyclosome (APC/C) is an E3 ubiquitin ligase that covalently attaches ubiquitins onto proteins to target them for proteolysis by the 26S proteasome. During mitosis, the APC/C is instrumental in allowing the cell to enter and exit from mitosis. The APC/C accomplishes this by using different specificity factors to recognize, interact with, and ubiquitylate key proteins that block cell cycle progression. The specificity factors, Cdc20p and Cdh1p, are not always associated with the APC/C and indeed they have the ability to interact with substrates in isolation. The molecular events that take place in order for Cdc20p and Cdh1p to couple substrates and APC/C are currently being resolved. Meanwhile, evidence has emerged suggesting that at least one of the specificity factors, Cdc20p, might be capable of functioning independently of the APC/C.
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PMID:Cdc20 in S-phase: the Banquo at replication's banquet. 1472 78

Several reports including those from this laboratory have demonstrated that bone marrow cells (BMC) downregulate in vitro both mixed leukocyte reaction and cytotoxic T lymphocyte reactions. We consequently hypothesized that a general property of immature cells of hematopoietic organs is their ability to suppress immune reactivity. As one of these suppressive activities, the lack of costimulatory molecules was proposed as a mechanism by which immature antigen presenting cells of the bone marrow might be involved. In the present report, we used two culture environments, each of which would regulate a different maturation pattern of human bone marrow-derived enriched dendritic antigen presenting cells (DC or APC) to determine the respective effects on in vitro immune regulatory function. Human BMC depleted of CD3+ cells were cultured with either: interleukin-4 (IL-4) and granulocyte macrophage-colony stimulating factor (GM-CSF), to maintain DC-enriched populations in an immature state (iAPC); or an interferon-gamma (IFNgamma), tumor necrosis factor alpha (TNF-alpha), GM-CSF, LPS, and IL-6 cocktail to promote the maturation of DC-enriched APC (mAPC). These iAPC and mAPC were, respectively, phenotypically characterized and also tested in vitro for the following: (1) both direct and indirect-antigen presentation functions; (2) immune regulatory functions on the response of autologous and allogeneic peripheral blood lymphocytes (PBL); and (3) Western blot analysis determining the levels of both major histocompatibility complex (MHC) class I related cytoplasmic transporter molecules associated with antigen processing (TAP1) and as well as proteasome activator molecules (PA28alpha). The iAPC population expressed fewer dendritic cell markers (CD83 and DCsign), and costimulator molecules (CD86 and CD40) than the mAPC, such that there was an approximate threefold increase in expression of CD83, 2.5-fold increase in DCsign, and a threefold increase in CD40 and CD86 on mAPC than on iAPC (p=0.005 for CD83; p=0.001 for DCsign; p=0.001 for CD86; and p=0.001 for CD40). In lymphoproliferative assays, indirect and direct alloantigen presentation by iAPC was weaker than by mAPC (p=0.05 and 0.04). In addition, iAPC were able to downregulate allogeneic CTL responses. Also, after pulsing with Epstein-Barr virus (EBV) protein antigens, the iAPC were less efficient in their presentation to autologous EBV-specific T-cell lines, and caused an inhibition of EBV-CTL generation. The expression of TAP1 and PA28alpha was reduced in iAPC in comparison to mAPC. These findings support the notion that a maturation state of BMC-derived APC correlates with their capacity to present antigen. The observed in vitro deficiency of this function by immature bone marrow cells may therefore contribute to the immune downregulatory capacity seen in the BMC compartment.
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PMID:Antigen presentation and immune regulatory capacity of immature and mature-enriched antigen presenting (dendritic) cells derived from human bone marrow. 1496 64

Proteasome inhibitors, like MG132, can exert cell growth inhibitory and apoptotic effects in different tumor types. The apoptotic mechanism of these compounds involves the activation of the effector caspases. beta-catenin, also an oncogene, represents one of the substrates of these proteases, but the consequences of its cleavage are poorly understood. We investigated its function during apoptosis induced by MG132 in three hepatocellular carcinoma (HCC) cell lines, endowed (HepG2 and HuH-6) or not (HA22T/VGH) with activating mutations of beta-catenin. Induction of apoptosis was associated with cell growth inhibition, accumulation of the cells at the G(2)/M phases of the cell cycle, as well as with fragmentation of beta-catenin (but not of alpha- or gamma-catenin) in all the cell lines. The cleavage of beta-catenin was inhibited by the caspase inhibitors Z-VAD-fmk and Z-DEVD-fmk. Fragmented beta-catenin was found in the nuclei of the treated cells. Analyses through the reporter plasmid pTOPflash showed that MG132 significantly reduces Tcf transcriptional activity in the cells. This was associated with a decrease in the mRNA expression of survivin and c-myc, which are target genes of the APC/beta-catenin/Tcf signaling. Nevertheless, Z-VAD-fmk or Z-DEVD-fmk did not reverse the MG132 effects on Tcf transcriptional activity, suggesting that the compound may affect this activity also by other mechanisms. Overall, the present study supports the therapeutic potential of the proteasome inhibitors in HCC.
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PMID:Induction of apoptosis by the proteasome inhibitor MG132 in human HCC cells: Possible correlation with specific caspase-dependent cleavage of beta-catenin and inhibition of beta-catenin-mediated transactivation. 1506 80


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