Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA120563 | ENA |
REPOSITORIES: ENA
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Project description:Deregulated developmental processes in the cerebellum cause medulloblastoma, the most common malignant tumor of the central nervous system. About 20-30% of cases are caused by mutations increasing the activity of the Sonic hedgehog (Shh) pathway, a critical mitogen in cerebellar development. The proto-oncogene Smoothened is a key transducer of the Shh pathway. Activating mutations in Smoothened that lead to constitutive activity of the Shh pathway have been identified in human medulloblastoma. To understand the molecular and cellular effects of Smoothened variants in normal development and medulloblastoma genesis, we generated the SmoA2 transgenic mouse model which expresses the transgene exclusively in granule neuron precursors. In this study, we demonstrate how two point mutations in a single molecule can produce starkly different phenotypes as seen in comparison to our previous model, ND2:SmoA1. The SmoA2 mice have severe aberrations in cerebellar development whereas the SmoA1 mice are largely normal during development. Medulloblastomas in the SmoA2 mice develop in the dysplastic cerebellar milieu. Intriguingly, despite disruptions in the stereotypic organization of the cerebellum, the SmoA2 mice do not exhibit any overt abnormalities in motor coordination. The differences in the global transcriptional profiles downstream of SmoA1 and SmoA2 further demonstrate the distinctiveness of the two oncogenic Smoothened mutations. The SmoA2 model serves as a unique spatiotemporal tool to investigate the functional significance of the reiterative cerebellar circuitry as well as to further understand Shh pathway mechanics in cerebellar development and oncogenesis. We previously generated a SmoA1 transgenic mouse medulloblastoma model, which expresses the SmoA1 transgene driven by the GNP-specific fragment of the promoter of ND2 transcription factor leading to constitutively active Shh signaling exclusively in the cerebellum. In this study, we characterize the ND2:SmoA2 transgenic mouse model with a similarly designed transgene expressing the SmoA2 mutation. To assess transcriptional changes downstream of SmoA1 and SmoA2, we evaluated global gene expression profiles of P5 SmoA1, SmoA2 and Wt age-matched cerebella. We chose this specific developmental stage because (1) the phenotypes of SmoA1 and SmoA2 are robust and distinct at P5; (2) at P5 GNPs undergo proliferation, migration and differentiation and therefore expression profiling could capture key differences in multiple processes.
2012-11-02 | E-GEOD-34593 | biostudies-arrayexpress
Project description:Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is silenced by promoter methylation in many types of tumors, yet ASC’s role in most cancers remains unknown. Here, we show that ASC is highly expressed in a model of medulloblastoma, the most common malignant pediatric brain cancer. Importantly, while ASC deficiency did not affect normal cerebellar development, ASC knock-out mice in the Smoothened (ND2:SmoA1) transgenic model of medulloblastoma exhibited a profound reduction in medulloblastoma incidence and delayed tumor onset. Premalignant lesions in cerebella of ASC-/-;ND2:SmoA1 mice displayed a striking decrease in number of ectopic progenitors. While proliferation rates decreased with ASC deletion, apoptosis and differentiation markers remained unchanged. Interestingly, ASC deficiency disrupted expression of genes in the TGF-ß pathway and increased the level of nuclear Smad3 in this medulloblastoma model. Together, these results demonstrate an unexpected requirement for ASC in Sonic hedgehog-driven medulloblastoma tumorigenesis, thus identifying ASC as a promising novel target for anti-tumor therapy. reference x sample
2014-05-23 | E-GEOD-48682 | biostudies-arrayexpress
Project description:Subtle variations in Pten dose determine cancer susceptibility: Gene expression profiling for MEF cells from a Ptenhy/+ mouse model. We have analyzed the survival and tumor spectrum in a population of Pten ‘hypermorphic’ mice (Ptenhy/+), which express approximately 80% of total Pten protein. Notably, the Ptenhy/+ developed a spectrum of tumors of variable latencies, with breast tumors occurring at the highest penetrance. Surprisingly, all breast tumors analyzed retain two intact copies of Pten, and maintain Pten protein levels above that observed in heterozygosity. Importantly, subtle down-regulation of Pten was found to alter the expression profile of genes involved in cell proliferation. Taken together, our findings support the notion that initiation of tumorigenesis can occur in the absence of genetic hits, thereby questioning the uniqueness of a saltatory model for cancer susceptibility. In order to understand whether subtle variations in Pten level may affect pathways involved in tumorigenesis, we analyzed the genome-wide expression profile of Ptenhy/+ mouse embryonic fibroblasts (MEFs).
2010-02-15 | GSE20316 | GEO
Project description:Subtle variations in Pten dose determine cancer susceptibility: Gene expression profiling for MEF cells from a Ptenhy/+ mouse model. We have analyzed the survival and tumor spectrum in a population of Pten âhypermorphicâ mice (Ptenhy/+), which express approximately 80% of total Pten protein. Notably, the Ptenhy/+ developed a spectrum of tumors of variable latencies, with breast tumors occurring at the highest penetrance. Surprisingly, all breast tumors analyzed retain two intact copies of Pten, and maintain Pten protein levels above that observed in heterozygosity. Importantly, subtle down-regulation of Pten was found to alter the expression profile of genes involved in cell proliferation. Taken together, our findings support the notion that initiation of tumorigenesis can occur in the absence of genetic hits, thereby questioning the uniqueness of a saltatory model for cancer susceptibility. In order to understand whether subtle variations in Pten level may affect pathways involved in tumorigenesis, we analyzed the genome-wide expression profile of Ptenhy/+ mouse embryonic fibroblasts (MEFs). In the Ptenhy/+ mouse model, mice are born with approximately 80% of total Pten protein and are viable and normally fertile. To decrease the expression level of Pten below homozygosity, we targeted intron 3 of Pten with a neomycin (Neo) cassette, under the control of the strong CMV promoter, thereby taking advantage of transcriptional interference. Next, we intercrossed Pten hy/+ mice with Pten+/- mice to generate cohorts of hypomorphic littermate mice with decreasing levels of Pten expression as follows: Ptenwt > Ptenhy/+ > Pten+/- >Ptenhy/- mice littermates. To preserve a constant 129/C57BL/6 mixed genetic background, we have crossed Pten hy/+ mice with Pten +/- for more than seven generations prior to analysis. As expected, Ptenhy/+ mouse embryonic fibroblasts (MEFs) display a level of Pten protein below Ptenwt and above Pten+/- .
2010-02-21 | E-GEOD-20316 | biostudies-arrayexpress
Project description:Study of mouse medulloblastoma in response to inhibitor of Smoothened. Keywords: gene modification
2008-03-01 | GSE7212 | GEO
Project description:Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a tumor suppressor that negatively regulates cell survival and proliferation by antagonizing phosphatidylinositol 3-kinase(PI3K)/protein kinase B(PKB/Akt) signaling. Loss of heterozygosity (LOH) of PTEN, reduced expression of PTEN and overexpression of phosphorylated Akt are frequently found in human gastric cancer, and their changes correlate with tumor progression and prognosis. Previous studies have shown that the deregulated miRNAs in human gastric cancer play important roles in gastric cancer cell proliferation, apoptosis and inflammation. However, miRNAs downstream PTEN/Akt signaling is poorly investigated. To clarify whether PTEN is involved in gastric tumorigenesis, we have generated a gastric epithelium specific PTEN knockout mouse which exhibited gastric tumor formation with enhanced cell proliferation.So the objectives of the microarray experiment were to, a) screen miRNAs which might be regulated by PTEN/Akt signaling by comparing the miRNA expression profiles between PTEN deficient and control gastric epithelia. 2) explore the microRNA mechanism involved in gastric cell proliferation and gastric tumorigenesis. miRNA profiling of mouse gastric epithelium,comparing Pten mutant mouse with controls. 4 samples. Experiments in 2 different time point, 20 days and 60 days after birth, 2 Biological replicates. Mutant tissue vs. controls from mixture of 3-4 mouse.
2013-09-02 | E-GEOD-27047 | biostudies-arrayexpress
Project description:Recent publications have described an important role for cross talk between PI-3 kinase and sonic hedgehog signaling pathways in the pathogenesis of medulloblastoma. Our primary objective was to determine if loss of Pten promotes medulloblastoma tumor formation. When mice expressing SmoA1 were crossed with mice heterozygous for Pten, SmoA1 +; Pten +/- mice exhibited decreased survival, an increased incidence, and a shorter time to onset of symptoms, compared to SmoA1 +; Pten +/+ mice. Tumors from SmoA1 +; Pten +/+ mice exhibited classic histology. In contrast, tumors from SmoA1 +; Pten +/- mice exhibited predominantly nodular/desmoplastic histology and evidence of neuronal differentiation. Analysis by gene expression microarray revealed a clear separation of gene signatures, with upregulation of genes such as Pik3cb, Mapk8, Frap1, and multiple genes involved in angiogenesis in SmoA1+; Pten +/- tumors. Downregulated genes included Pten, Trp53, and Rb1. Western blotting and immunohistochemical analysis revealed decreased expression of Pten and increased activation of Akt in the SmoA1+; Pten +/- tumors. Consistent with these findings, we detected strong expression of PCNA throughout the Pten +/+ tumors and focal areas of intense staining for PCNA in tumors from SmoA1 +/-; Pten +/- mice. Conversely, staining for Cleaved Caspase 3 revealed multiple punctuate foci in SmoA1 +; Pten +/+ tumors and almost no staining in SmoA1 +/-; Pten +/- tumors. These results suggest that increased signaling through PI-3 kinase pathways promotes MB tumorigenesis by driving proliferation and inhibiting apoptosis of granule neuron precursor cells in the developing cerebellum.
2009-11-21 | GSE19059 | GEO
Project description:PTEN, a widely investigated tumor suppressor, has at least two longer translational variants, PTEN and . However, the regulation and precise roles of endogenous PTEN/ in tumorigenesis remain greatly unknown. Here we show that USP9X and FBXW11 selectively regulate the stability of PTEN/ but not PTEN proteins by deubiqitination and ubiquitination respectively. USP9X promotes and FBXW11 suppresses tumorigenesis mediated by PTEN/. In contrast to the current paradigm for PTEN as a tumor suppressor, PTEN/ promote tumorigenesis of cancer cells in a phosphatase-independent manner. Mechanistically, PTEN/ localized in the nucleus regulate expressions of tumor-promoting genes such as NOTCH3 in the similar way as the H3K4 presenter WDR5. Further, PTEN/ but not PTEN directly interact with WDR5 to promote trimethylation of H3K4 and maintain a tumor-promoting signature. Taken together, our results indicate that PTEN/ are a double-edged sword for carcinogenesis, suggesting that reinterpretation of the importance of PTEN gene in carcinogenesis is warranted.
2019-11-14 | PXD013196 | Pride
Project description:Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is silenced by promoter methylation in many types of tumors, yet ASC's role in most cancers remains unknown. Here, we show that ASC is highly expressed in a model of medulloblastoma, the most common malignant pediatric brain cancer; ASC is also expressed in human medulloblastomas. Importantly, while ASC deficiency did not affect normal cerebellar development, ASC knockout mice on the Smoothened (ND2:SmoA1) transgenic model of medulloblastoma exhibited a profound reduction in medulloblastoma incidence and a delayed tumor onset. A similar decrease in tumorigenesis with ASC deficiency was also seen in the hGFAP-Cre:SmoM2 mouse model of medulloblastoma. Interestingly, hyperproliferation of the external granule layer (EGL) was comparable at P20 in both wild-type and ASC-deficient SmoA1 mice. However, while the apoptosis and differentiation markers remained unchanged at this age, proliferation makers were decreased, and the EGL was reduced in thickness and area by P60. This reduction in proliferation with ASC deficiency was also seen in isolated SmoA1 cerebellar granule precursor cells in vitro, indicating that the effect of ASC deletion on proliferation was cell autonomous. Interestingly, ASC-deficient SmoA1 cerebella exhibited disrupted expression of genes in the transforming growth factor-β pathway and increased level of nuclear Smad3. Taken together, these results demonstrate an unexpected role for ASC in Sonic hedgehog-driven medulloblastoma tumorigenesis, thus identifying ASC as a promising novel target for antitumor therapy.
2014-05-23 | GSE48682 | GEO
Project description:Deregulated developmental processes in the cerebellum cause medulloblastoma, the most common malignant tumor of the central nervous system. About 20-30% of cases are caused by mutations increasing the activity of the Sonic hedgehog (Shh) pathway, a critical mitogen in cerebellar development. The proto-oncogene Smoothened is a key transducer of the Shh pathway. Activating mutations in Smoothened that lead to constitutive activity of the Shh pathway have been identified in human medulloblastoma. To understand the molecular and cellular effects of Smoothened variants in normal development and medulloblastoma genesis, we generated the SmoA2 transgenic mouse model which expresses the transgene exclusively in granule neuron precursors. In this study, we demonstrate how two point mutations in a single molecule can produce starkly different phenotypes as seen in comparison to our previous model, ND2:SmoA1. The SmoA2 mice have severe aberrations in cerebellar development whereas the SmoA1 mice are largely normal during development. Medulloblastomas in the SmoA2 mice develop in the dysplastic cerebellar milieu. Intriguingly, despite disruptions in the stereotypic organization of the cerebellum, the SmoA2 mice do not exhibit any overt abnormalities in motor coordination. The differences in the global transcriptional profiles downstream of SmoA1 and SmoA2 further demonstrate the distinctiveness of the two oncogenic Smoothened mutations. The SmoA2 model serves as a unique spatiotemporal tool to investigate the functional significance of the reiterative cerebellar circuitry as well as to further understand Shh pathway mechanics in cerebellar development and oncogenesis.
2012-11-02 | GSE34593 | GEO