Critical requirement of ERK/MAPK signaling in respiratory tract development
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE51643 | GEO | 2014/09/02
SECONDARY ACCESSION(S): PRJNA224160
REPOSITORIES: GEO
Similar Datasets
Project description:The mammalian genome contains two ERK/MAP kinase kinase genes, Mek1 and Mek2, which encode dual-specificity kinases responsible for ERK/MAP kinase activation. To define the function of ERK/MAPK signaling pathway in lung development, we performed tissue-specific deletions of Mek1 function in a Mek2 null background. Inactivation of both Mek genes in mesenchyme resulted in several phenotypes including giant omphalocele, skeletal defects, pulmonary hypoplasia, abnormal trachea patterning, and death at birth. Microarray analysis with RNA extracted from lungs of E15.5 Dermo1+/Cre, Mek1+/flox;Mek2-/-;Dermo1+/Cre and Mek1flox/flox;Mek2-/-;Dermo1+/Cre embryos was performed to evaluate the molecular impact of the loss of all Mek alleles in mesenchyme on lung development. . Total RNA was isolated from lungs of E15.5 Dermo1+/Cre embryos (control), from E15.5 Mek1+/flox;Mek2- /-;Dermo1+/Cre embryos (experimental) and from E15.5 Mek1flox/flox;Mek2-/-;Dermo1+/Cre embryos (experimental). Four specimens were analyzed per genotype.
2014-09-02 | E-GEOD-51643 | biostudies-arrayexpress
Project description:Though mitogen activated protein kinase kinases (MKK or MEK) 1 and 2 are widely assumed to be functionally redundant some reports indicate they possess distinct biologic activities. To test the hypothesis that MEK1 and MEK2 signaling pathways are interchangeable we used two complementary approaches to determine the necessity and sufficiency of individual MEK1 and MEK2 signaling pathways for human melanoma SK-MEL-28 cell proliferation. To test the necessity we targeted MEK1 and/or MEK2 using specific siRNAs. An effect on proliferation was observed only when both MEK1 and MEK2 were knocked down indicating that neither of the individual MEK isoforms is necessary for SK-MEL-28 cell proliferation. To test the sufficiency we inhibited multiple MEK and MKK signaling pathways in SK-MEL-28 cells with anthrax lethal toxin (LeTx) a MEK/MKK-specific protease and rescued individual MEK signaling pathways by expressing a cleavage-resistant form of MEK (MEKcr). In this fashion ERK activation was retained only in MEK2cr-expressing cells but not in MEK1cr-expressing cells following LeTx treatment. Microarray analysis revealed groups of non-overlapping downstream transcriptional targets of MEK1 and MEK2 and indicated a substantial rescue effect of MEK2cr on proliferation pathways. Furthermore LeTx efficiently inhibited the cell proliferation and anchorage-independent growth of SK-MEL-28 cells expressing MKK1cr but not MEK2cr. These results not only indicate that in this cellular context MEK2 signaling pathway alone is sufficient for ERK activation melanoma cell proliferation and anchorage-independent growth but MEK1 is not but also demonstrate that MEK1 and MEK2 signaling pathways are not redundant and interchangeable for melanoma cell proliferation. We conclude that while MEK2 alone is sufficient for SK-MEL-28 cell proliferation MEK1 can conditionally compensate for loss of MEK2. SK-MEL-28 melanoma cells +/- cleavage resistant MKK1/MKK2
2011-06-24 | E-GEOD-23930 | biostudies-arrayexpress
Project description:Though mitogen activated protein kinase kinases (MKK or MEK) 1 and 2 are widely assumed to be functionally redundant some reports indicate they possess distinct biologic activities. To test the hypothesis that MEK1 and MEK2 signaling pathways are interchangeable we used two complementary approaches to determine the necessity and sufficiency of individual MEK1 and MEK2 signaling pathways for human melanoma SK-MEL-28 cell proliferation. To test the necessity we targeted MEK1 and/or MEK2 using specific siRNAs. An effect on proliferation was observed only when both MEK1 and MEK2 were knocked down indicating that neither of the individual MEK isoforms is necessary for SK-MEL-28 cell proliferation. To test the sufficiency we inhibited multiple MEK and MKK signaling pathways in SK-MEL-28 cells with anthrax lethal toxin (LeTx) a MEK/MKK-specific protease and rescued individual MEK signaling pathways by expressing a cleavage-resistant form of MEK (MEKcr). In this fashion ERK activation was retained only in MEK2cr-expressing cells but not in MEK1cr-expressing cells following LeTx treatment. Microarray analysis revealed groups of non-overlapping downstream transcriptional targets of MEK1 and MEK2 and indicated a substantial rescue effect of MEK2cr on proliferation pathways. Furthermore LeTx efficiently inhibited the cell proliferation and anchorage-independent growth of SK-MEL-28 cells expressing MKK1cr but not MEK2cr. These results not only indicate that in this cellular context MEK2 signaling pathway alone is sufficient for ERK activation melanoma cell proliferation and anchorage-independent growth but MEK1 is not but also demonstrate that MEK1 and MEK2 signaling pathways are not redundant and interchangeable for melanoma cell proliferation. We conclude that while MEK2 alone is sufficient for SK-MEL-28 cell proliferation MEK1 can conditionally compensate for loss of MEK2.
2011-06-24 | GSE23930 | GEO
Project description:Histiocytic neoplasms are clonal disorders of the monocyte/macrophage lineage defined by mutations activating MAP kinase signaling, including BRAFV600E mutations in ~50% of patients, which confer robust responses to BRAF inhibition. More recently, the MEK inhibitor cobimetinib was FDA-approved for BRAFV600-wild-type histiocytosis patients. Here following genomic analysis of 500 pediatric and adult patients with diverse histiocytoses, the most common alteration following BRAFV600E was MEK1E102_I103 in-frame deletion. MEK1E102_I103del and related RAF-independent MEK mutants were associated with an aggressive multi-system clinical phenotype with worse progression-free survival with MEK inhibition as compared to patients with other classes of MEK1/2 mutations. Given that cancer-associated MEK1/2 mutations have not been modeled in vivo and the clinical importance of MEK1 mutations in histiocytoses, we generated MEK1E102_I103del conditional knock-in mice. Using three distinct hematopoietic Cre drivers, these mice developed a 100% penetrant, lethal disorder by 6 weeks of age with expansion of classical and non-classical monocytes, macrophages, and Cd11b+ conventional dendritic cells which infiltrated hematopoietic organs, liver, and skin. MEK1-mutant mice were sensitive to single-agent treatment with the oral ERK inhibitor ulixertinib. We consequently treated five MEK1E102_I103del-mutant patients with ulixertinib on prospective IRB-approved Single Patient Use Expanded Access protocols, four of whom had disease refractory to MEK inhibition. Four of five patients experienced objective clinical and/or radiological responses to ulixertinib. These data reveal the impact of oncogenic MEK kinase mutations in vivo, identify patients with likelihood of resistance to MEK inhibition, and nominate ERK inhibition as a therapeutic approach to overcome resistance to MEK inhibition in histiocytoses.
2024-09-03 | GSE268618 | GEO
Project description:Cartilage originates from mesenchymal cell condensations that differentiate into chondrocytes of transient growth plate cartilage or permanent cartilage of the articular joint surface and trachea. MicroRNAs fine-tune the activation of entire signaling networks and thereby modulate complex cellular responses, but so far only limited data are available on miRNAs that regulate cartilage development. Here we characterize an miRNA which promotes the biosynthesis of a key component in the RAF/MEK/ERK pathway in cartilage. Specifically, by transcriptome profiling we identified miR-322 to be upregulated during chondrocyte differentiation. Among the various miR-322 target genes in the RAF/MEK/ERK pathway, only Mek1 was identified as a regulated target in chondrocytes. Surprisingly, an increased concentration of miR-322 stabilizes Mek1-mRNA to arise protein levels and dampen ERK1/2 phosphorylation, while cartilage-specific inactivation in mice linked the loss of miR-322 to decreased MEK1 levels and increased RAF/MEK/ERK pathway activation. Such mice died perinatally due to tracheal growth restriction and respiratory failure. Hence, a single miRNA can stimulate the production of an inhibitory component of a central signaling pathway to impair cartilage development.
2017-10-03 | GSE98036 | GEO
Project description:Radial progenitors deficient in both Mek1 and Mek2 fail to transition to the gliogenic mode in late embryogenesis, and astrocyte and oligodendroglial precursors fail to appear. In exploring mechanisms, we found the Ets transcription family member Etv5/Erm is strongly regulated by MEK. Our microarray assay showed that Erm is specifically downregulated in Mek mutant brain.
2012-09-06 | GSE40675 | GEO
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
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. Keywords: compound, signalling response
2009-01-14 | GSE14402 | GEO
Project description:Radial progenitors deficient in both Mek1 and Mek2 fail to transition to the gliogenic mode in late embryogenesis, and astrocyte and oligodendroglial precursors fail to appear. In exploring mechanisms, we found the Ets transcription family member Etv5/Erm is strongly regulated by MEK. Our microarray assay showed that Erm is specifically downregulated in Mek mutant brain. RNA was extracted from dorsal corticies of E18.5 WT or Mek1,2\NesCre conditional mutant embryos. There were totally 4 samples: 2 WT and 2 mutants. 200 ng of total RNA was prepared for microarray hybridization according to the GeneChip® Whole Transcript (WT) Sense Target Labeling Assay user manual.
2012-09-06 | E-GEOD-40675 | biostudies-arrayexpress
Project description:Scaffold proteins regulate intracellular MAP kinase signaling by providing critical spatial and temporal specificity. We have shown previously that the scaffold protein MEK1 partner (MP1) is localized to late endosomes by the adaptor protein p14. Using conditional gene disruption of p14 in livers of mice we analysed protein and transcript signatures in tissue samples. Further biological network analysis predicted that the differentially expressed transcripts and proteins are involved in cell cycle progression and regulation of cellular proliferation. Although some of the here identified signatures were previously linked to phospho-ERK activity, most of them were novel targets of late endosomal p14/MP1/MEK/ERK signaling module. Finally, the proliferation defect was confirmed in a chemically induced liver regeneration model in p14 liver knock-out mice. Conditional liver p14 KO mice were generated by mating p14 f/f mice with mice expressing Cre recombinase under control of Alb promoter and alpha-fetoprotein enhancer. The obtained p14 floxed/floxed;AlfpCre(p14 liver KO) mice were used in experiments as KO mice. To prevent the influence of AlfpCre transgene we used p14 +/+;AlfpCre mice as a control. All mice were derived in a C57BL/6 background and were six weeks old. Expression profiles of KO mouse samples were compared to expression profiles of corresponding control mice and differentially expressed genes were identified.
2011-02-01 | E-GEOD-24461 | biostudies-arrayexpress