Normal mouse skin lacking Hras
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE60769 | GEO | 2015/03/01
SECONDARY ACCESSION(S): PRJNA259516
REPOSITORIES: GEO
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Project description:Oncogenic activating mutations in Ras genes are among the most common drivers of human disease. Treating mouse skin with the chemical carcinogen DMBA induces a characteristic mutation in Hras at codon 61. To understand how skin responds to a constitutive lack of Hras, we generated a cohort of Hras knockout mice. A backcross was generated using male Mus spretus and female FVB/N Hras-/- mice; female F1 hybrids were mated with male FVB/N Hras -/- or Hras -/+ mice to generate a backcross population. This series contains mice that were Hras -/-. Mice were aged to 8 weeks and a tail skin sample was snap frozen.
2015-03-01 | E-GEOD-60769 | biostudies-arrayexpress
Project description:Human tumours show a high level of clonal heterogeneity that contributes to malignant progression and metastasis, but the processes that influence the timing of metastatic dissemination of subclones are unknown. Here, we have used whole exome sequencing of 98 matched benign, malignant, and metastatic skin tumours from genetically heterogeneous mice to demonstrate that most metastases disseminate synchronously from the primary tumour, but then evolve separately, acquiring an additional set of mutations during growth at distant sites. Shared mutations between primary carcinomas and their matched metastases have the distinct A>T signature of the initiating carcinogen Dimethylbanzanthracene (DMBA), but non-shared mutations are primarily G>T or C>T substitutions, associated with oxidative stress. We found recurrent point mutations in several hundred genes, including several in the Ras (Hras, Kras, and Pik3ca) pathway. We propose that carcinogen-driven mouse tumour models can aid our understanding of the forces that shape clonal and genetic evolution of human cancers.
2015-10-11 | GSE63967 | GEO
Project description:In many mouse models of skin cancer, only a few tumors typically form although many cells competent for tumorigenesis receive the same oncogenic mutations. These observations suggest a selection process for defining tumor initiating cells. Here we use quantitative mRNA- and miR-Seq to determine the impact of HRasG12V on the transcriptome of keratinocytes. We discover that microRNA-203 is downregulated by HRasG12V. Using a knockout mouse model, we demonstrate that loss of microRNA-203 promotes selection and expansion of tumor-initiating cells. Conversely, restoration of microRNA-203 with an inducible model potently inhibits proliferation of these cells. We comprehensively identify microRNA-203 targets required for HRas-initiated tumorigenesis. These targets include important effectors of the Ras pathway and essential genes required for cell division. Together, this study establishes a role for the loss of microRNA-203 in promoting selection and expansion of HRas mutated cells and identifies a mechanism through which microRNA-203 antagonizes HRas-mediated tumorigenesis.
2015-07-23 | GSE66055 | GEO
Project description:In many mouse models of skin cancer, only a few tumors typically form although many cells competent for tumorigenesis receive the same oncogenic mutations. These observations suggest a selection process for defining tumor initiating cells. Here we use quantitative mRNA- and miR-Seq to determine the impact of HRasG12V on the transcriptome of keratinocytes. We discover that microRNA-203 is downregulated by HRasG12V. Using a knockout mouse model, we demonstrate that loss of microRNA-203 promotes selection and expansion of tumor-initiating cells. Conversely, restoration of microRNA-203 with an inducible model potently inhibits proliferation of these cells. We comprehensively identify microRNA-203 targets required for HRas-initiated tumorigenesis. These targets include important effectors of the Ras pathway and essential genes required for cell division. Together, this study establishes a role for the loss of microRNA-203 in promoting selection and expansion of HRas mutated cells and identifies a mechanism through which microRNA-203 antagonizes HRas-mediated tumorigenesis.
2015-07-23 | GSE66054 | GEO
Project description:In many mouse models of skin cancer, only a few tumors typically form although many cells competent for tumorigenesis receive the same oncogenic mutations. These observations suggest a selection process for defining tumor initiating cells. Here we use quantitative mRNA- and miR-Seq to determine the impact of HRasG12V on the transcriptome of keratinocytes. We discover that microRNA-203 is downregulated by HRasG12V. Using a knockout mouse model, we demonstrate that loss of microRNA-203 promotes selection and expansion of tumor-initiating cells. Conversely, restoration of microRNA-203 with an inducible model potently inhibits proliferation of these cells. We comprehensively identify microRNA-203 targets required for HRas-initiated tumorigenesis. These targets include important effectors of the Ras pathway and essential genes required for cell division. Together, this study establishes a role for the loss of microRNA-203 in promoting selection and expansion of HRas mutated cells and identifies a mechanism through which microRNA-203 antagonizes HRas-mediated tumorigenesis. Identifying mRNA and microRNA networks regulated by oncogenic HRasG12V in primary keratinocytes through the use of 3Seq and small-RNA-Sequencing. Additionally we utilize ribosome-profiling, 3Seq, Microarray and Ago2-HITS-CLIP approaches to identify novel miR-203 target genes.
2015-07-23 | E-GEOD-66054 | biostudies-arrayexpress
Project description:In many mouse models of skin cancer, only a few tumors typically form although many cells competent for tumorigenesis receive the same oncogenic mutations. These observations suggest a selection process for defining tumor initiating cells. Here we use quantitative mRNA- and miR-Seq to determine the impact of HRasG12V on the transcriptome of keratinocytes. We discover that microRNA-203 is downregulated by HRasG12V. Using a knockout mouse model, we demonstrate that loss of microRNA-203 promotes selection and expansion of tumor-initiating cells. Conversely, restoration of microRNA-203 with an inducible model potently inhibits proliferation of these cells. We comprehensively identify microRNA-203 targets required for HRas-initiated tumorigenesis. These targets include important effectors of the Ras pathway and essential genes required for cell division. Together, this study establishes a role for the loss of microRNA-203 in promoting selection and expansion of HRas mutated cells and identifies a mechanism through which microRNA-203 antagonizes HRas-mediated tumorigenesis. Identifying mRNA and microRNA networks regulated by oncogenic HRasG12V in primary keratinocytes through the use of 3Seq and small-RNA-Sequencing. Additionally we utilize ribosome-profiling, 3Seq, Microarray and Ago2-HITS-CLIP approaches to identify novel miR-203 target genes.
2015-07-23 | E-GEOD-66055 | biostudies-arrayexpress
Project description:Modern omics technologies allow us obtaining global information on different types of biological networks. However, integrating these different types of analyzes into a coherent framework for a comprehensive biological interpretation remains challenging. Here, we present a conceptual framework that integrates protein interaction, phosphoproteomics and transcriptomics data. Applying this method to analyze HRAS signaling from different subcellular compartments shows that spatially-defined networks contribute specific functions to HRAS signaling. Changes in HRAS protein interactions at different sites lead to different kinase activation patterns that differentially regulate gene transcription. HRAS mediated signaling is the strongest from the plasma membrane, but it regulates the largest number of genes from the endoplasmic reticulum. The integrated networks provide a topologically and functionally resolved view of HRAS signaling. They reveal new HRAS functions including the control of cell migration from the endoplasmic reticulum and p53 dependent cell survival when signaling from the Golgi apparatus.
2019-03-08 | PXD012506 | Pride
Project description:Costello syndrome (CS) is a congenital disorder caused by heterozygous activating germline HRAS mutations in the canonical Ras/mitogen-activated protein kinase (Ras/MAPK) pathway. CS is one of the RASopathies, a large group of syndromes due to mutations within various components of the Ras/MAPK pathway. An important part of the phenotype that greatly impacts quality of life is hypotonia. To gain a better understanding of the mechanisms underlying hypotonia in CS, a mouse model with an activating HrasG12V allele was utilized. We identified a skeletal myopathy that was due in part to an inhibition of embryonic myogenesis and myofiber formation, resulting in a reduction of myofiber size and number that led to reduced muscle mass and strength. In addition to hyperactivation of the Ras/MAPK and PI3K/AKT pathways, there was a significant reduction of p38 signaling, as well as global transcriptional alterations consistent with the myopathic phenotype. Inhibition of Ras/MAPK pathway signaling using a MEK inhibitor rescued the HrasG12V myopathy phenotype both in vitro and in vivo, demonstrating that increased MAPK signaling is the main cause of the muscle phenotype in CS.
2021-11-16 | GSE187493 | GEO
Project description:Modern omics technologies allow us obtaining global information on different types of biological networks. However, integrating these different types of analyzes into a coherent framework for a comprehensive biological interpretation remains challenging. Here, we present a conceptual framework that integrates protein interaction, phosphoproteomics and transcriptomics data. Applying this method to analyze HRAS signaling from different subcellular compartments shows that spatially-defined networks contribute specific functions to HRAS signaling. Changes in HRAS protein interactions at different sites lead to different kinase activation patterns that differentially regulate gene transcription. HRAS mediated signaling is the strongest from the plasma membrane, but it regulates the largest number of genes from the endoplasmic reticulum. The integrated networks provide a topologically and functionally resolved view of HRAS signaling. They reveal new HRAS functions including the control of cell migration from the endoplasmic reticulum and p53 dependent cell survival when signaling from the Golgi apparatus.
2019-03-08 | PXD012505 | Pride
Project description:In the present study, we applied a quantitative MS-based strategy to characterize the proteome and phosphoproteome in HRAS- or IDH1-driven glioma cells. We describe the driving roles of the MEK and PI3K signaling pathways in RAS-NHA cells, and uncover oncogenic signaling in other pathways. We highlight the interplay between the signaling cascades and show that inhibition of MEK and PI3K reverses phosphorylation signaling patterns driven by oncogenic RAS overexpression. Applying a histone hybrid chemical labeling method and high-resolution MS, we identified significant histone methylation, acetylation, and butyrylation changes in IDH1mut-NHA cells. Our results suggest a global transcriptional repressive state, consistent with the down-regulation of the proteome, transcriptome, and the DNA hyper-methylated state in IDH1mut-NHA cells. We provide a unique resource of altered proteins, phosphosites, and histone PTMs in RAS and IDH1 mutant astrocytoma cell lines, providing insight into oncogenesis in glioma beyond the transcriptomic level.
2016-12-23 | PXD004945 | Pride