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)

Regulated separation of sister chromatids is the key event of mitosis. Sister chromatids remain cohered from the moment of DNA duplication until anaphase. Two known factors account for cohesion: DNA catenations and cohesin complexes. Premature loss of centromeric cohesion is prevented by the spindle checkpoint. Here we show that sororin, a protein implicated in promoting cohesion through effects on cohesin complexes, is involved in maintenance of cohesion in response to the spindle checkpoint. Sororin-depleted cells reach prometaphase with cohered sister chromatids and are able to form metaphase plates. However, loss of cohesion in anaphase is asynchronous and cells are unresponsive to the spindle checkpoint, accumulating with separated sisters scattered throughout the cytoplasm. These phenotypes are similar to those seen after Shugoshin depletion, suggesting that sororin and Shugoshin might act in concert. Furthermore, sororin-depleted and Shugoshin-depleted cells lose cohesion independently of the APC/C. Therefore, sororin and Shugoshin protect centromeric cohesion in response to the spindle checkpoint, but prevent the removal of cohesion by a mechanism independent of the APC/C.
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PMID:Regulation of centromeric cohesion by sororin independently of the APC/C. 1736 Nov 2

The molecular hallmarks of inflammation-mediated lung carcinogenesis have not been fully clarified, mainly due to the scarcity of appropriate animal models. We have used a silica-induced multistep lung carcinogenesis model driven by chronic inflammation to study the evolution of molecular markers and genetic alterations. We analyzed markers of DNA damage response (DDR), proliferative stress, and telomeric stress: gamma-H2AX, p16, p53, and TERT. Lung cancer-related epigenetic and genetic alterations, including promoter hypermethylation status of p16(CDKN2A), APC, CDH13, Rassf1, and Nore1A, as well as mutations of Tp53, epidermal growth factor receptor, K-ras, N-ras, and c-H-ras, have been also studied. Our results showed DDR pathway activation in preneoplastic lesions, in association with inducible nitric oxide synthase and p53 induction. p16 was also induced in early tumorigenic progression and was inactivated in bronchiolar dysplasias and tumors. Remarkably, lack of mutations of Ras and epidermal growth factor receptor, and a very low frequency of Tp53 mutations suggest that they are not required for tumorigenesis in this model. In contrast, epigenetic alterations in p16(CDKN2A), CDH13, and APC, but not in Rassf1 and Nore1A, were clearly observed. These data suggest the existence of a specific molecular signature of inflammation-driven lung carcinogenesis that shares some, but not all, of the molecular landmarks of chemically induced lung cancer.
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PMID:Molecular analysis of a multistep lung cancer model induced by chronic inflammation reveals epigenetic regulation of p16 and activation of the DNA damage response pathway. 1797 4

In both yeast and mammals, uncapped telomeres activate the DNA damage response (DDR) and undergo end-to-end fusion. Previous work has shown that the Drosophila HOAP protein, encoded by the caravaggio (cav) gene, is required to prevent telomeric fusions. Here we show that HOAP-depleted telomeres activate both the DDR and the spindle assembly checkpoint (SAC). The cell cycle arrest elicited by the DDR was alleviated by mutations in mei-41 (encoding ATR), mus304 (ATRIP), grp (Chk1) and rad50 but not by mutations in tefu (ATM). The SAC was partially overridden by mutations in zw10 (also known as mit(1)15) and bubR1, and also by mutations in mei-41, mus304, rad50, grp and tefu. As expected from SAC activation, the SAC proteins Zw10, Zwilch, BubR1 and Cenp-meta (Cenp-E) accumulated at the kinetochores of cav mutant cells. Notably, BubR1 also accumulated at cav mutant telomeres in a mei-41-, mus304-, rad50-, grp- and tefu-dependent manner. Our results collectively suggest that recruitment of BubR1 by dysfunctional telomeres inhibits Cdc20-APC function, preventing the metaphase-to-anaphase transition.
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PMID:Unprotected Drosophila melanogaster telomeres activate the spindle assembly checkpoint. 1824 67

Shugoshin 1 (Sgo1) protects centromeric sister-chromatid cohesion in early mitosis and, thus, prevents premature sister-chromatid separation. The protein level of Sgo1 is regulated during the cell cycle; it peaks in mitosis and is down-regulated in G1/S. Here we show that Sgo1 is degraded during the exit from mitosis, and its degradation depends on the anaphase-promoting complex/cyclosome (APC/C). Overexpression of Cdh1 reduces the protein levels of ectopically expressed Sgo1 in human cells. Sgo1 is ubiquitinated by APC/C bound to Cdh1 (APC/C(Cdh1)) in vitro. We have further identified two functional degradation motifs in Sgo1; that is, a KEN (Lys-Glu-Asn) box and a destruction box (D box). Although removal of either motif is not sufficient to stabilize Sgo1, Sgo1 with both KEN box and D box deleted is stable in cells. Surprisingly, mitosis progresses normally in the presence of non-degradable Sgo1, indicating that degradation of Sgo1 is not required for sister-chromatid separation or mitotic exit. Finally, we show that the spindle checkpoint kinase Bub1 contributes to the maintenance of Sgo1 steady-state protein levels in an APC/C-independent mechanism.
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PMID:Multiple anaphase-promoting complex/cyclosome degrons mediate the degradation of human Sgo1. 1901 61

We report on the construction of maize minichromosomes using shuttle vectors harboring native centromeric segments, origins of replication, selectable marker genes, and telomeric repeats. These vectors were introduced into scutellar cells of maize immature embryos by microprojectile bombardment. Several independent transformation events were identified containing minichromosomes in addition to the normal diploid complement of 20 maize chromosomes. Immunostaining indicated that the minichromosomes recruited centromeric protein C, which is a specific component of the centromere/kinetochore complex. Minichromosomes were estimated to be 15-30 Mb in size based on cytological measurements. Fluorescent in situ hybridization (FISH) showed that minichromosomes contain the centromeric, telomeric, and exogenous unique marker sequences interspersed with maize retrotransposons. Minichromosomes were detected for at least a year in actively dividing callus cultures, providing evidence for their stability through numerous cell cycles. Plants were regenerated and minichromosomes were detected in root tips, providing confirmation of their normal replication and transmission during mitosis and through organogenesis. Assembly of maize artificial chromosomes may provide a tool to study centromere function and a foundation for developing new high capacity vectors for plant functional genomics and breeding.
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PMID:Artificial chromosome formation in maize (Zea mays L.). 1901 67

The mitotic spindle assembly checkpoint (SAC) is an essential control system of the eukaryotic cell cycle. This surveillance mechanism monitors the kinetochore, the multi-component complex that assembles on the centromeric DNA and attaches chromosomes to the microtubules of the spindle. The recruitment of mitotic checkpoint proteins to kinetochores that are not correctly attached to microtubules initiates a signalling cascade that results in the CDC20-dependent inhibition of the anaphase-promoting complex/cyclosome (APC/C). Mutations in the genes encoding for diverse SAC proteins have been identified in human tumour cells and associated with chromosome segregation and cancer progression. This work describes the current understanding on the organisation, function and structure of SAC components and shows this knowledge assists the identification of those that may constitute suitable targets for the clinical treatment of cancer.
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PMID:Assessment of the mitotic spindle assembly checkpoint (SAC) as the target of anticancer therapies. 1927 54

Accurate segregation of chromosome, initiated by abrupt and irreversible dissolution of sister-chromatid cohesion at anaphase, is crucial for the faithful inheritance of parental genomes during eukaryotic cell division. The dissolution of sister-chromatid cohesion is catalyzed by separase after the destruction of securin by the anaphase-promoting complex/cyclosome (APC/C). However, separase was localized to the mitotic centrosome, raising the question as how separase hydrolyzes sister-chromatid cohesion of centromere at the anaphase onset. Here we show that separase is associated with mitotic chromosomes and this association is regulated by Aurora B kinase. Using a panel of separase antibodies, we found that separase protein was accumulated in mitosis and degraded at the end of telophase. To study the spatiotemporal distribution of separase in mitosis, we carried out immunofluorescence microscopic analyses. Surprisingly, separase was found to be associated with mitotic chromosomes from prophase to metaphase and dissociated from the chromosomes in anaphase right after sister chromatids separation. Staining of isolated mitotic chromosomes from Nocodazole-arrested cells revealed that separase is concentrated at the centromeric cohesion. To examine if any mitotic kinases are responsible for chromosomal localization of separase in mitosis, we carried out RNAi-mediated knockdown and found that association of separase with mitotic chromosomes was a function of Aurora B. Consistent with the phenotype seen in the Aurora B-repressed cells, inhibition of Aurora B kinase by hersperadin prevents the association of separase with chromosomes. Our results suggest that Aurora B kinase activity helps coordinate the association of separase with chromosome and the initiation of sister-chromatid separation.
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PMID:Recruitment of separase to mitotic chromosomes is regulated by Aurora B. 1934 97

Centromeres provide a region of chromatin upon which kinetochores are assembled in mitosis. Centromeric protein C (CENP-C) is a core component of this centromeric chromatin that, when depleted, prevents the proper formation of both centromeres and kinetochores. CENP-C localizes to centromeres throughout the cell cycle via its C-terminal part, whereas its N-terminal part appears necessary for recruitment of some but not all components of the Mis12 complex of the kinetochore. We now find that all kinetochore proteins belonging to the KMN (KNL1/Spc105, the Mis12 complex, and the Ndc80 complex) network bind to the N-terminal part of Drosophila CENP-C. Moreover, we show that the Mis12 complex component Nnf1 interacts directly with CENP-C in vitro. To test whether CENP-C's N-terminal part was sufficient to recruit KMN proteins, we targeted it to the centrosome by fusing it to a domain of Plk4 kinase. The Mis12 and Ndc80 complexes and Spc105 protein were then all recruited to centrosomes at the expense of centromeres, leading to mitotic abnormalities typical of cells with defective kinetochores. Thus, the N-terminal part of Drosophila CENP-C is sufficient to recruit core kinetochore components and acts as the principal linkage between centromere and kinetochore during mitosis.
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PMID:CENP-C is a structural platform for kinetochore assembly. 2148 64

Formation of the synaptonemal complex (SC), or synapsis, between homologs in meiosis is essential for crossing over and chromosome segregation [1-4]. How SC assembly initiates is poorly understood but may have a critical role in ensuring synapsis between homologs and regulating double-strand break (DSB) and crossover formation. We investigated the genetic requirements for synapsis in Drosophila and found that there are three temporally and genetically distinct stages of synapsis initiation. In "early zygotene" oocytes, synapsis is only observed at the centromeres. We also found that nonhomologous centromeres are clustered during this process. In "mid-zygotene" oocytes, SC initiates at several euchromatic sites. The centromeric and first euchromatic SC initiation sites depend on the cohesion protein ORD. In "late zygotene" oocytes, SC initiates at many more sites that depend on the Kleisin-like protein C(2)M. Surprisingly, late zygotene synapsis initiation events are independent of the earlier mid-zygotene events, whereas both mid and late synapsis initiation events depend on the cohesin subunits SMC1 and SMC3. We propose that the enrichment of cohesion proteins at specific sites promotes homolog interactions and the initiation of euchromatic SC assembly independent of DSBs. Furthermore, the early euchromatic SC initiation events at mid-zygotene may be required for DSBs to be repaired as crossovers.
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PMID:A pathway for synapsis initiation during zygotene in Drosophila oocytes. 2211 59

Accurate chromosome segregation during mitosis is critical for maintaining genomic stability. The kinetochore--a large protein assembly on centromeric chromatin--functions as the docking site for spindle microtubules and a signaling hub for the spindle checkpoint. At metaphase, spindle microtubules from opposing spindle poles capture each pair of sister kinetochores, exert pulling forces, and create tension across sister kinetochores. The spindle checkpoint detects improper kinetochore-microtubule attachments and translates these defects into biochemical activities that inhibit the anaphase-promoting complex or cyclosome (APC/C) throughout the cell to delay anaphase onset. A deficient spindle checkpoint leads to premature sister-chromatid separation and aneuploidy. Here, we review recent progress on the generation, propagation, transmission, and silencing of the spindle checkpoint signals from kinetochores to APC/C.
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PMID:Tracking spindle checkpoint signals from kinetochores to APC/C. 2359 56


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