APC-Rab35
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB70885 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:BACKGROUND: p53 is an important tumor suppressor with a known role in the later stages of colorectal cancer, but its relevance to the early stages of neoplastic initiation remains somewhat unclear. Although p53-dependent regulation of Wnt signalling activity is known to occur, the importance of these regulatory mechanisms during the early stages of intestinal neoplasia has not been demonstrated. METHODS: We have conditionally deleted the Adenomatous Polyposis coli gene (Apc) from the adult murine intestine in wild type and p53 deficient environments and subsequently compared the phenotype and transcriptome profiles in both genotypes. RESULTS: Expression of p53 was shown to be elevated following the conditional deletion of Apc in the adult small intestine. Furthermore, p53 status was shown to impact on the transcription profile observed following Apc loss. A number of key Wnt pathway components and targets were altered in the p53 deficient environment. However, the aberrant phenotype observed following loss of Apc (rapid nuclear localisation of beta-catenin, increased levels of DNA damage, nuclear atypia, perturbed cell death, proliferation, differentiation and migration) was not significantly altered by the absence of p53. CONCLUSION: p53 related feedback mechanisms regulating Wnt signalling activity are present in the intestine, and become activated following loss of Apc. However, the physiological Wnt pathway regulation by p53 appears to be overwhelmed by Apc loss and consequently the activity of these regulatory mechanisms is not sufficient to modulate the immediate phenotypes seen following Apc loss. Thus we are able to provide an explanation to the apparent contradiction that, despite having a Wnt regulatory capacity, p53 loss is not associated with early lesion development. Samples were collected from genetically modified mice. Gene recombination was induced using IP administration of beta-napthoflavone.
2015-06-25 | E-GEOD-70262 | biostudies-arrayexpress
Project description:Vil-CreERT2 was used to drive loss of APC (Adenomatous polyposis coli) in the murine intestinal epithelium. 4 days post induction, mice were sampled and 1cm of tissue from the proximal intestine was collected into RNA later. This was compared to control (wild-type) intestine. This analysis allows investigation of transcriptional changes following APC loss (and therefore activation of the WNT signalling pathway).
2019-12-31 | GSE112226 | GEO
Project description:Nearly all colorectal cancers have dysregulated Wnt signalling, predominantly through the mutation of the Apc (Adenomatous Polyposis Coli) gene. Therefore it is of vital importance to elucidate the key Wnt target genes in intestinal cells in vivo. We have used a novel inducible cre-lox based murine system (designated ApcFlox) to investigate the consequences of perturbation of Wnt signalling following inactivation of Apc in vivo within 100% of the intestinal epithelium. We have employed microarray analysis at 3 time points within our ApcFlox system (Day 3 prior to the onset of phenotype, day 4 the establishment of the phenotype and day 5 gross phenotype of altered proliferation, differentiation and migration) and from adenomas arising in the ApcMin/+ background allowing us characterise Wnt/beta-catenin target genes based on their expression profiles during different stages of intestinal tumourigenesis. Furthermore, we have employed microarray analysis using livers from our ApcFlox system and have demonstrated that there is very little overlap in the Wnt target genes induced by Apc loss in the liver and the intestine. More importantly, we have been able to determine a novel set of putative Wnt/beta-catenin target genes which are upregulated at both early and late stages of tumourigenesis in the intestine and may represent novel therapeutic targets in colon cancer. Samples were collected from Genetcially modified mice of the genotypes indicated on the sample records. Where appropriate, gene recombination was induced using IP administration of beta-napthoflavone. Cohorts of samples were used to compare the affects of APC loss in the small intestine at three time points (and compared to matched control samples in which the gene was not recombined). Furthermore, these samples were compared to colonic polyps (and normal colon) taken from the Apcmin Mouse.
2015-01-31 | E-GEOD-65461 | biostudies-arrayexpress
Project description:Nearly all colorectal cancers have dysregulated Wnt signalling, predominantly through the mutation of the Apc (Adenomatous Polyposis Coli) gene. Therefore it is of vital importance to elucidate the key Wnt target genes in intestinal cells in vivo. We have used a novel inducible cre-lox based murine system (designated ApcFlox) to investigate the consequences of perturbation of Wnt signalling following inactivation of Apc in vivo within 100% of the intestinal epithelium. We have employed microarray analysis at 3 time points within our ApcFlox system (Day 3 prior to the onset of phenotype, day 4 the establishment of the phenotype and day 5 gross phenotype of altered proliferation, differentiation and migration) and from adenomas arising in the ApcMin/+ background allowing us characterise Wnt/beta-catenin target genes based on their expression profiles during different stages of intestinal tumourigenesis. Furthermore, we have employed microarray analysis using livers from our ApcFlox system and have demonstrated that there is very little overlap in the Wnt target genes induced by Apc loss in the liver and the intestine. More importantly, we have been able to determine a novel set of putative Wnt/beta-catenin target genes which are upregulated at both early and late stages of tumourigenesis in the intestine and may represent novel therapeutic targets in colon cancer.
2015-01-31 | GSE65461 | GEO
Project description:BACKGROUND: p53 is an important tumor suppressor with a known role in the later stages of colorectal cancer, but its relevance to the early stages of neoplastic initiation remains somewhat unclear. Although p53-dependent regulation of Wnt signalling activity is known to occur, the importance of these regulatory mechanisms during the early stages of intestinal neoplasia has not been demonstrated. METHODS: We have conditionally deleted the Adenomatous Polyposis coli gene (Apc) from the adult murine intestine in wild type and p53 deficient environments and subsequently compared the phenotype and transcriptome profiles in both genotypes. RESULTS: Expression of p53 was shown to be elevated following the conditional deletion of Apc in the adult small intestine. Furthermore, p53 status was shown to impact on the transcription profile observed following Apc loss. A number of key Wnt pathway components and targets were altered in the p53 deficient environment. However, the aberrant phenotype observed following loss of Apc (rapid nuclear localisation of beta-catenin, increased levels of DNA damage, nuclear atypia, perturbed cell death, proliferation, differentiation and migration) was not significantly altered by the absence of p53. CONCLUSION: p53 related feedback mechanisms regulating Wnt signalling activity are present in the intestine, and become activated following loss of Apc. However, the physiological Wnt pathway regulation by p53 appears to be overwhelmed by Apc loss and consequently the activity of these regulatory mechanisms is not sufficient to modulate the immediate phenotypes seen following Apc loss. Thus we are able to provide an explanation to the apparent contradiction that, despite having a Wnt regulatory capacity, p53 loss is not associated with early lesion development.
2015-06-25 | GSE70262 | GEO
Project description:Dysregulated Wnt signalling is seen in approximately 30% of hepatocellular cancers, thus finding pathways downstream of activation of Wnt signalling is key. Using cre lox technology we have deleted the the adenomatous polyposis coli tumour suppressor protein (Apc) within the adult mouse liver and observed a rapid increase in nuclear beta-catenin and C-Myc. This is associated with an induction of proliferation leading to hepatomegally within 4 days of gene deletion. To investigate the downstream pathways responsible for these phenotypes we analysed the impact of inactivating Apc in the context of deficiency of the potentially key effectors beta-catenin and c-Myc. beta-catenin loss rescues both the proliferation and hepatomegally phenotypes following Apc loss. However c-Myc deletion, which rescues the phenotypes of Apc loss in the intestine, had no effect on the phenotypes of Apc loss. The consequences of deregulation the Wnt pathway within the liver are therefore strikingly different to those observed within the intestine, with the vast majority of Wnt targets beta-catenin dependent but c-Myc independent in the liver.
2015-01-31 | GSE65476 | GEO
Project description:Dysregulated Wnt signalling is seen in approximately 30% of hepatocellular cancers, thus finding pathways downstream of activation of Wnt signalling is key. Using cre lox technology we have deleted the the adenomatous polyposis coli tumour suppressor protein (Apc) within the adult mouse liver and observed a rapid increase in nuclear beta-catenin and C-Myc. This is associated with an induction of proliferation leading to hepatomegally within 4 days of gene deletion. To investigate the downstream pathways responsible for these phenotypes we analysed the impact of inactivating Apc in the context of deficiency of the potentially key effectors beta-catenin and c-Myc. beta-catenin loss rescues both the proliferation and hepatomegally phenotypes following Apc loss. However c-Myc deletion, which rescues the phenotypes of Apc loss in the intestine, had no effect on the phenotypes of Apc loss. The consequences of deregulation the Wnt pathway within the liver are therefore strikingly different to those observed within the intestine, with the vast majority of Wnt targets beta-catenin dependent but c-Myc independent in the liver. Samples were collected from Genetcially modified mice of the genotypes indicated in the characteristics field. Gene recombination was induced using IP administration of beta-napthoflavone. Cohorts of samples were used to compare the affects of APC loss, cMYC loss and combined APC and cMYC loss in the liver (and compared to matched control samples in which the genes were not recombined).
2015-01-31 | E-GEOD-65476 | biostudies-arrayexpress
Project description:Epithelial polarity is controlled by a polarity machinery including the Rho GTPase CDC42 and Scribble/PAR. By using intestinal stem cell (ISC)-specific deletion of CDC42 in Olfm4-IRES-eGFPCreERT2;CDC42flox/flox mice, we found that ISC-initiated CDC42 loss caused a drastic hyper-proliferation of transit amplifying (TA) cells and disrupted epithelial polarity. CDC42-null crypts displayed expanded TA cell and diminished ISC populations, accompanied by elevated hippo signaling via YAP/TAZ - Ereg and mTOR activation, independent from canonical Wnt signaling. YAP/TAZ conditional knockout restored the balance of ISC/TA cell populations and crypt proliferation but did not rescue the polarity in CDC42-null small intestine. mTOR or EGFR inhibitor treatment of CDC42 KO mice exhibited similar rescuing effects without affecting YAP/TAZ signaling. Inducible ablation of Scribble in intestinal epithelial cells mimics that of CDC42 KO defects including crypt hyperplasia and hippo signaling activation. Mammalian epithelial polarity regulates ISC and TA cell fate and proliferation via a hippo-Ereg-mTOR cascade.
2021-10-23 | GSE166736 | GEO
Project description:Tissue morphogenesis relies on proper differentiation of morphogenetic domains, adopting specific cell behaviours. Yet, how signalling pathways interact to determine and coordinate these domains remains poorly understood. Dorsal closure (DC) of the Drosophila embryo represents a powerful model to study epithelial cell sheet sealing. In this process, JNK (JUN N-terminal Kinase) signalling controls leading edge (LE) differentiation generating local forces and cell shape changes essential for DC. The LE represents a key morphogenetic domain in which, in addition to JNK, a number of signalling pathways converges and interacts (anterior/posterior -AP- determination; segmentation genes, such as Wnt/Wingless; TGFβ/Decapentaplegic). To better characterize properties of the LE morphogenetic domain, we used microarrays to identify genes whose expression is regulated by the JNK pathway during dorsal closure of the Drosophila embryo.
2010-07-07 | GSE21805 | GEO
Project description:Based on the ability of FGF and/or WNT signaling to control posterior fate and intestinal lineage commitment, several groups have reported that treating mouse or human Pluripotent Stem Cell (PSC) derived definitive endoderm (DE) with small molecules or ligands that activate WNT signaling, or a combination of WNT and FGF signaling can induce an intestinal fate in human DE. In this current study, we leverage hESC derived human intestinal organoids (HIOs) to test the hypothesis that the duration of exposure to high levels of FGF and WNT signaling controls regional intestinal identity, with shorter durations generating intestine similar to the proximal duodenum, and longer durations distalizing HIOs to become similar to jejunum/ileum. Our results demonstrate that exposing human definitive endoderm (DE) cultures to short or long incubations of media that activate WNT and FGF siganling results in gene and protein expression profiles that are consistent with tissue that has been patterned into proximal (duodenum) or distal (ileum) small intestine, respectively.
2016-07-04 | E-MTAB-4168 | biostudies-arrayexpress