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TNF-a-induced MEK/ERK-dependent regulation of Cartilage Matrix Genes

ABSTRACT: TNF-a is increased in the synovial fluid of patients with rheumatoid arthritis and osteoarthritis. TNF-a activates MEK/ERK in chondrocytes; however the overall functional relevance of MEK/ERK to TNF-a-regulated gene expression in chondrocytes is unknown. Chondrocytes were treated with TNF-a with or without the MEK1/2 inhibitor U0126 for 24 h. Microarray analysis was used to identify genes regulated by TNF-a in a MEK1/2-dependent fashion. Keywords: compound, signalling response

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE14402 | GEO | 2009/01/14

SECONDARY ACCESSION(S): PRJNA111789

REPOSITORIES: GEO

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Transcription profiling of rat chondrocytes were treated with TNF-a with or without the MEK1/2 inhibitor U0126 for 24 h to investigate TNF-a-induced MEK/ERK-dependent regulation of Cartilage Matrix Genes

Project description:TNF-a is increased in the synovial fluid of patients with rheumatoid arthritis and osteoarthritis. TNF-a activates MEK/ERK in chondrocytes; however the overall functional relevance of MEK/ERK to TNF-a-regulated gene expression in chondrocytes is unknown. Chondrocytes were treated with TNF-a with or without the MEK1/2 inhibitor U0126 for 24 h. Microarray analysis was used to identify genes regulated by TNF-a in a MEK1/2-dependent fashion. Experiment Overall Design: Primary chondrocytes from the femoral condyles of neonatal rats were treated with DMSO (control sample), TNF-a, U0126 (selective MEK1/2 inhibitor) or TNF-a and U0126. Two biological replicates were collected for each treatment. Total RNA was collected and analyzed by Affymetrix Microarray.

2009-01-17 | E-GEOD-14402 | biostudies-arrayexpress

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PDGF-induced genes regulated by the PI3K and MEK/ERK signaling pathways

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Critical requirement of ERK/MAPK signaling in respiratory tract development

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Critical requirement of ERK/MAPK signaling in respiratory tract development

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Transcription profiling of mouse chondrocytes treated with MEK/ERK pathway inhibitors

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2009-05-11 | E-GEOD-15069 | biostudies-arrayexpress

A subset of metastatic pancreatic ductal adenocarcinomas depends quantitatively on oncogenic Kras/Mek/Erk-induced hyperactive mTOR signalling

Project description:Objective Oncogenic Kras-activated robust Mek/Erk signals phosphorylate to the tuberous sclerosis complex (Tsc) and deactivates mammalian target of rapamycin (mTOR) suppression in pancreatic ductal adenocarcinoma (PDAC); however, Mek and mTOR inhibitors alone have demonstrated minimal clinical antitumor activity. Design We generated transgenic mouse models in which mTOR was hyperactivated either through the Kras/Mek/Erk cascade, by loss of Pten or through Tsc1 haploinsufficiency. Primary cancer cells were isolated from mouse tumours. Oncogenic signalling was assessed in vitro and in vivo, with and without single or multiple targeted molecule inhibition. Transcriptional profiling was used to identify biomarkers predictive of the underlying pathway alterations and of therapeutic response. Results from the preclinical models were confirmed on human material. Results Reduction of Tsc1 function facilitated activation of Kras/Mek/Erk-mediated mTOR signalling, which promoted the development of metastatic PDACs. Single inhibition of mTOR or Mek elicited strong feedback activation of Erk or Akt, respectively. Only dual inhibition of Mek and PI3K reduced mTOR activity and effectively induced cancer cell apoptosis. Analysis of downstream targets demonstrated that oncogenic activity of the Mek/Erk/Tsc/mTOR axis relied on Aldh1a3 function. Moreover, in clinical PDAC samples, ALDH1A3 specifically labelled an aggressive subtype. Conclusions These results advance our understanding of Mek/Erk-driven mTOR activation and its downstream targets in PDAC, and provide a mechanistic rationale for effective therapeutic matching for Aldh1a3-positive PDACs.

2015-10-05 | GSE48643 | GEO

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