Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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An oncogenic Kras expression signature identified by cross-species

ABSTRACT: Mouse lung cancers were generated using the KrasLA model, in which a latent mutated Kras2 allele (resulting in the amino acid substitution G12D) is sporadically activated through spontaneous homologous recombination. These mice develop lung adenomas with full penetrance; over time, the tumors acquire morphologic characteristics reminiscent of those of human adenocarcinoma, such as nuclear atypia and a high mitotic index. KrasLA2 mice on a 129svJae background were crossed with wild type C57B/6J mice to obtain F1 progeny. The initial report of this mouse model described two alleles, KrasLA1 and KrasLA2. All expression profiles in this study were generated using the KrasLA2 mice. We call the model KrasLA throughout for simplicity. Mice bearing the KrasLA latent allele were allowed to develop to 5-6 month of age and sacrificed by cervical dislocation. Lungs were removed and placed in RNAlaterTM solution (Ambion). Individual tumors large enough to be easily dissected (3mm-8mm) were removed and cut into 2 pieces. One piece was placed in formalin to be used for histological analysis while the other piece was stored at -80 for RNA/DNA extraction. Gene expression profiling was perfomed on lung tumors derived from KrasLA mouse (n = 31) and normal mouse lung samples (n = 19).

ORGANISM(S): Mus musculus

SUBMITTER: Dedeepya Vaka

PROVIDER: E-GEOD-49200 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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An oncogenic KRAS2 expression signature identified by cross-species gene-expression analysis.

Sweet-Cordero Alejandro A Mukherjee Sayan S Subramanian Aravind A You Han H Roix Jeffrey J JJ Ladd-Acosta Christine C Mesirov Jill J Golub Todd R TR Jacks Tyler T

Nature genetics 20041219 1

Using advanced gene targeting methods, generating mouse models of cancer that accurately reproduce the genetic alterations present in human tumors is now relatively straightforward. The challenge is to determine to what extent such models faithfully mimic human disease with respect to the underlying molecular mechanisms that accompany tumor progression. Here we describe a method for comparing mouse models of cancer with human tumors using gene-expression profiling. We applied this method to the ...[more]

PMID: 15608639

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Project description:To identify a novel target for the treatment of heart failure, we examined gene expression in the failing heart. Among the genes analyzed, 12/15 lipoxygenase (12/15-LOX) was markedly up-regulated in heart failure. To determine whether increased expression of 12/15-LOX causes heart failure, we established transgenic mice that overexpressed 12/15-LOX in cardiomyocytes. Echocardiography showed that 12/15-LOX transgenic mice developed systolic dysfunction. Cardiac fibrosis increased in 12/15-LOX transgenic mice with advancing age, and was associated with the infiltration of macrophages. Consistent with these observations, cardiac expression of monocyte chemoattractant protein-1 (Mcp-1) was up-regulated in 12/15-LOX transgenic mice compared with wild-type mice. Treatment with 12-hydroxy-eicosatetraenotic acid, a major metabolite of 12/15-LOX, increased MCP-1 expression in cardiac fibroblasts and endothelial cells, but not in cardiomyocytes. Inhibition of Mcp-1 reduced the infiltration of macrophages into the myocardium and prevented both systolic dysfunction and cardiac fibrosis in 12/15-LOX transgenic mice. Likewise, disruption of 12/15-LOX significantly reduced cardiac Mcp-1 expression and macrophage infiltration, thereby improving systolic dysfunction induced by chronic pressure overload. Our results suggest that cardiac 12/15-LOX is involved in the development of heart failure and that inhibition of 12/15-LOX could be a novel treatment for this condition. Heart failure is still one of the leading causes of death worldwide. Therefore, it is important to elucidate the underlying mechanisms of heart failure and develop more effective treatments for this condition. To clarify the molecular mechanisms of heart failure, we performed microarray analysis using cardiac tissue samples obtained from a hypertensive heart failure model (Dahl salt-sensitive rats). ~300 genes showed significant changes of expression in the failing hearts compared with control hearts. Among the genes analyzed, 12/15-lipoxygenase (12/15-LOX) was most markedly up-regulated in failing hearts compared with control hearts .

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An oncogenic Kras expression signature identified by cross-species

Publications

An oncogenic KRAS2 expression signature identified by cross-species gene-expression analysis.

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