46,930 research outputs found
Loss of APC induces polyploidy as a result of a combination of defects in mitosis and apoptosis
Full text linkMutations in the adenomatous polyposis coli (APC) tumor suppressor gene initiate a majority of colorectal cancers. Acquisition of chromosomal instability is an early event in these tumors. We provide evidence that the loss of APC leads to a partial loss of inter-kinetochore tension at metaphase and alters mitotic progression. Furthermore, we show that inhibition of APC in U2OS cells compromises the mitotic spindle checkpoint. This is accompanied by a decrease in the association of the checkpoint proteins Bub1 and BubR1 with kinetochores. Additionally, APC depletion reduced apoptosis. As expected from this combination of defects, tetraploidy and polyploidy are consequences of APC inhibition in vitro and in vivo. The removal of APC produced the same defects in HCT1 16 cells that have constitutively active P-catenin. These data show that the loss of APC immediately induces chromosomal instability as a result of a combination of mitotic and apoptotic defects. We suggest that these defects amplify each other to increase the incidence of tetra- and polyploidy in early stages of tumorigenesis
Càncer colorectal hereditari: Aplicacions diagnòstiques de l'estudi de la dosi dels gens APC, MLH1 i MSH2
Full text link[cat] Les síndromes de càncer colorectal (CCR) hereditari representen entre un 3% i un 5% de tots els casos de CCR i inclouen tots aquells individus amb un elevat grau d'agregació familiar. La més freqüent és la síndrome de Lynch, causada per la presència de mutacions en els gens reparadors del DNA, majoritàriament MLH1 i MSH2. La poliposi adenomatosa familiar (FAP) és la segona en incidència, es caracteritza per l'aparició de pòlips precursors a la neoplàsia colorectal i la seva causa principal és la presència de mutacions en el gen supressor tumoral APC. En els últims anys s'ha descobert que els grans reordenaments d'aquests gens són responsables de la malaltia en una part de les famílies que pateixen aquestes síndromes. A més, estudis d'expressió d'aquests gens en línia germinal han demostrat l'existència de desequilibris al·lèlics tant en famílies portadores de mutacions com en famílies on no es detecten mutacions en el DNA. L'objectiu d'aquesta tesi és l'estudi de la dosi en la dels gens MLH1, MSH2 i APC, implicats en la síndrome de Lynch i la FAP. D'aquesta forma, hem analitzat la dosi tant a nivell de DNA (grans reordenaments) com a nivell d'RNA (expressió específica d'al·lel), sempre treballant amb línia germinal de pacients. Els resultats aquí recollits permeten millorar l'estratègia de diagnòstic molecular de les famílies amb síndrome de Lynch i FAP que són ateses al nostre centre, al mateix temps que la comprensió del procés tumorogènic.[eng] Hereditary colorectal cancer (CRC) syndromes represent about 3% to 5% of all cases of CRC and include all those individuals with high familiar aggregation. The most frequent syndrome is Lynch syndrome, caused by the presence of mutations in the mismatch repair (MMR) genes, mostly MLH1 and MSH2. Familiar adenomatous polyposis (FAP) is the second in incidence, is characterized by precursor polyps and its mainly caused by mutations in the tumoral suppressor gene APC. Recently, it has been discovered that gross rearrangements of these genes are responsible of these two syndromes. Also, expression analyses of these genes in the germline have demonstrated the existence of allelic imbalances in both families carrying pathogenic mutations and families without detected mutations. Our aim was to study de dose of MLH1, MSH2 and APC genes in the germline of Lynch syndrome and polyposis families, respectively. To that end, we analyzed the dose at DNA level (gross rearrangements) and at RNA level (allele-specific expression) of these patients. The results summarized in this thesis permit improving the molecular diagnostic strategy in Lynch syndrome and FAP families, and also improve the knowledge of the tumorogenic process
Precocious activation of APC/C-Cdh1 at pre-anaphase causes genome instability
Full text linkFaithful chromosome segregation and thereby accurate gene transmission are crucial for all organisms. Until proper attachment of the mitotic spindle to the kinetochore is established, the ubiquitin ligase (E3) Cdc20-activated APC/C (anaphase promoting complex/cyclosome) is repressed by the spindle assembly checkpoint (SAC) and sister chromatin cohesion is protected. Mutants defective in SAC fail to arrest at metaphase even in the presence of damaged microtubules. Interestingly, a similar phenomenon occurs in yeast cells defective in Bub2, a negative factor of the mitotic exit network (MEN), which is required for telophase onset, although its precise molecular mechanism is unknown. Here, we show that chromosome missegregation occurs frequently in bub2∆ cells in the presence of damaged microtubules. The loss of Bub2 caused precocious activation of APC/C-Cdh1/Hct1 at pre-anaphase, leading to securin degradation and then separase-mediated cohesin cleavage. Overexpression of CDH1 and CDC14, encoding Cdc14 phosphatase, at pre-anaphase similarly caused chromosome missegregation. Thus, sequential activation of APC/C-Cdc20 and then APC/C-Cdh1 is critical for precise chromosome segregation and precocious activation of APC/C-Cdh1 at pre-anaphase causes genomic instability. Since degradation of human securin is also mediated by APC/C-Cdc20 and APC/C-Cdh1, this study predicts that precocious activation APC/C-Cdh1 in human cells similarly causes genomic instability, and thereby cell death or tumorigenesis
Meat and fish consumption, APC gene mutations and hMLH1 expression in colon and rectal cancer: a prospective cohort study (The Netherlands).
Full text linkOBJECTIVE: The aim of this study was to investigate the associations between meat and fish consumption and APC mutation status and hMLH1 expression in colon and rectal cancer. METHODS: The associations were investigated in the Netherlands Cohort Study, and included 434 colon and 154 rectal cancer patients on whom case-cohort analyses (subcohort n = 2948) were performed. RESULTS: Total meat consumption was not associated with the endpoints studied. Meat product (i.e. processed meat) consumption showed a positive association with colon tumours harbouring a truncating APC mutation, whereas beef consumption was associated with an increased risk of colon tumours without a truncating APC mutation (incidence rate ratio (RR) highest versus lowest quartile of intake 1.61, 95% confidence interval (CI) 0.96-2.71, p-trend = 0.04 and 1.58, 95% CI 1.10-2.25, p-trend = 0.01, respectively). Consumption of other meat (horsemeat, lamb, mutton, frankfurters and deep-fried meat rolls) was associated with an increased risk of rectal cancer without a truncating APC mutation (RR intake versus no intake 1.79, 95% CI 1.10-2.90). No associations were observed for meat consumption and tumours lacking hMLH1 expression. CONCLUSIONS: Our data indicate that several types of meat may contribute differently to the aetiology of colon and rectal cancer, depending on APC mutation status but not hMLH1 expression of the tumour
The <i>Adenomatous Polyposis Coli</i> protein contributes to normal compaction of mitotic chromatin
Full text linkThe tumour suppressor <i>Adenomatous Polyposis Coli</i> (APC) is required for proper mitosis; however, the exact role of APC in mitosis is not understood. Using demembranated sperm chromatin exposed to meiotic <i>Xenopus</i> egg extract and HeLa cells expressing fluorescently labelled histones, we established that APC contributes to chromatin compaction. Sperm chromatin in APC-depleted <i>Xenopus</i> egg extract frequently formed tight round or elongated structures. Such abnormally compacted chromatin predominantly formed spindles with low microtubule content. Furthermore, in mitotic HeLa cells expressing GFP- and mCherry-labelled H2B histones, depletion of APC caused a decrease in the donor fluorescence lifetime of neighbouring fluorophores, indicative of excessive chromatin compaction. Profiling the chromatin-associated proteome of sperm chromatin incubated with <i>Xenopus</i> egg extracts revealed temporal APC-dependent changes in the abundance of histones, closely mirrored by chromatin-associated Topoisomerase IIa, condensin I complex and Kif4. In the absence of APC these factors initially accumulated on chromatin, but then decreased faster than in controls. We also found and validated significant APC-dependent changes in chromatin modifiers Set-a and Rbbp7. Both were decreased on chromatin in APC-depleted extract; in addition, the kinetics of association of Set-a with chromatin was altered in the absence of APC
Genetic dissection of differential signaling threshold requirements for the Wnt/β-catenin pathway in vivo
Full text linkContributions of null and hypomorphic alleles of Apc in mice produce both developmental and pathophysiological phenotypes. To ascribe the resulting genotype-to-phenotype relationship unambiguously to the Wnt/beta-catenin pathway, we challenged the allele combinations by genetically restricting intracellular beta-catenin expression in the corresponding compound mutant mice. Subsequent evaluation of the extent of resulting Tcf4-reporter activity in mouse embryo fibroblasts enabled genetic measurement of Wnt/beta-catenin signaling in the form of an allelic series of mouse mutants. Different permissive Wnt signaling thresholds appear to be required for the embryonic development of head structures, adult intestinal polyposis, hepatocellular carcinomas, liver zonation, and the development of natural killer cells. Furthermore, we identify a homozygous Apc allele combination with Wnt/beta-catenin signaling capacity similar to that in the germline of the Apc(min) mice, where somatic Apc loss-of-heterozygosity triggers intestinal polyposis, to distinguish whether co-morbidities in Apc(min) mice arise independently of intestinal tumorigenesis. Together, the present genotype phenotype analysis suggests tissue-specific response levels for the Wnt/beta-catenin pathway that regulate both physiological and pathophysiological conditions
The adenomatous polyposis coli protein unambiguously localizes to microtubule plus-ends and is involved in establishing parallel arrays of microtubule bundles in highly polarised epithelial cells
Full text linkLoss of full-length adenomatous polyposis coli (APC) protein correlates with the development of colon cancers in familial and sporadic cases. In addition to its role in regulating ß-catenin levels in the Wnt signaling pathway, the APC protein is implicated in regulating cytoskeletal organization. APC stabilizes microtubules in vivo and in vitro, and this may play a role in cell migration (Näthke, I.S., C.L. Adams, P. Polakis, J.H. Sellin, and W.J. Nelson. 1996. J. Cell Biol. 134:165–179; Mimori-Kiyosue, Y., N. Shiina, and S. Tsukita. 2000. J. Cell Biol. 148:505–517; Zumbrunn, J., K. Inoshita, A.A. Hyman, and I.S. Näthke. 2001. Curr. Biol. 11:44–49) and in the attachment of microtubules to kinetochores during mitosis (Fodde, R., J. Kuipers, C. Rosenberg, R. Smits, M. Kielman, C. Gaspar, J.H. van Es, C. Breukel, J. Wiegant, R.H. Giles, and H. Clevers. 2001. Nat. Cell Biol. 3:433–438; Kaplan, K.B., A. Burds, J.R. Swedlow, S.S. Bekir, P.K. Sorger, and I.S. Näthke. 2001. Nat. Cell Biol. 3:429–432). The localization of endogenous APC protein is complex: actin- and microtubule-dependent pools of APC have been identified in cultured cells (Näthke et al., 1996; Mimori-Kiyosue et al., 2000; Reinacher-Schick, A., and B.M. Gumbiner. 2001. J. Cell Biol. 152:491–502; Rosin-Arbesfeld, R., G. Ihrke, and M. Bienz. 2001. EMBO J. 20:5929–5939). However, the localization of APC in tissues has not been identified at high resolution. Here, we show that in fully polarized epithelial cells from the inner ear, endogenous APC protein associates with the plus ends of microtubules located at the basal plasma membrane. Consistent with a role for APC in supporting the cytoskeletal organization of epithelial cells in vivo, the number of microtubules is significantly reduced in apico-basal arrays of microtubule bundles isolated from mice heterozygous for APC. © 2002 Mogensen et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). </p
rdmpage/apni-apc-coldp: v0.1
No full textAustralian Plant Names Index (APNI) and Australian Plant Census (APC) as a Catalogue of Life Data Package (ColDP
Apc mutation induces resistance of colonic cells to lipoperoxide-triggered apoptosis induced by faecal water from haem-fed rats
Full text linkRecent epidemiological studies suggest that high meat intake is associated with promotion of colon cancer linked to haem-iron intake. We previously reported that dietary haem, in the form of either haemoglobin or meat, promotes precancerous lesions in the colon of rats given a low-calcium diet. The mechanism of promotion by haem is not known, but is associated with increased lipid peroxidation in faecal water and strong cytotoxic activity of faecal water on a cancerous mouse colonic epithelial cell line. To better understand the involvement of faecal water components of haem-fed rats in colon cancer promotion, we explored the effect of faecal water on normal (Apc +/+) or premalignant cells (Apc Min/+). Further, we tested if this effect was correlated to lipoperoxidation and 4-hydroxynonenal (HNE). We show here for the first time that heterozygote Apc mutation represents a strong selective advantage, via resistance to apoptosis induction (caspase 3 pathway), for colonic cells exposed to a haem-iron induced lipoperoxidation. The fact that HNE treatment of the cells provoked the same effects as the faecal water of rats fed the haem-rich diet suggests that this compound triggers apoptosis in those cells. We propose that this mechanism could be involved in the promotion of colon carcinogenesis by haem in vivo
OldCats/APC-and-SNIP-analysis: publish
No full textAPC and SNIP analysis by using cwts and doaj dataset
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