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MEK5 is Activated by Shear Stress, Activates ERK5 And Induces KLF4 To Modulate TNF Responses in Human Dermal Microvascular Endothelial Cells

ABSTRACT: MEK5 is activated by shear stress in large vessel endothelial cells (ECs) and contributes to the suppression of pro-inflammatory changes in the arterial wall. We used microarray analyses of total RNA from MEK5/CA-transduced HDMECs compared to LacZ control-transduced HDMECs to identify distinct classes of several regulated genes, including KLF4, eNOS, and ICAM. We conclude that MEK5 activation by shear stress may modulate inflammatory responses in the microvasculature, and these actions are partly mediated by KLF4.

ORGANISM(S): Homo sapiens

PROVIDER: GSE25145 | GEO | 2010/12/31

SECONDARY ACCESSION(S): PRJNA134487

REPOSITORIES: GEO

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MEK5 is Activated by Shear Stress, Activates ERK5 And Induces KLF4 To Modulate TNF Responses in Human Dermal Microvascular Endothelial Cells

Project description:MEK5 is activated by shear stress in large vessel endothelial cells (ECs) and contributes to the suppression of pro-inflammatory changes in the arterial wall. We used microarray analyses of total RNA from MEK5/CA-transduced HDMECs compared to LacZ control-transduced HDMECs to identify distinct classes of several regulated genes, including KLF4, eNOS, and ICAM. We conclude that MEK5 activation by shear stress may modulate inflammatory responses in the microvasculature, and these actions are partly mediated by KLF4. Total RNA was isolated from 8 separate paired (derived from same primary isolate) MEK5/CA and LacZ transduced HDMEC lines

2010-12-31 | E-GEOD-25145 | biostudies-arrayexpress

The MEK5-ERK5 Kinase Axis Controls Lipid Metabolism in Small Cell Lung Cancer

Project description:Small cell lung cancer (SCLC), accounts for about 15 percent of all lung cancers, is a neuroendocrine type of carcinoma and is incredibly aggressive, with a dire diagnosis of 5% survival at 5 years. FDA-approved therapies for this disease are almost exclusively limited to chemotherapy and radiotherapy, to which resistance arises within months. Despite global sequencing efforts, few activating mutations have been discovered in SCLC tumors, and targetable alterations account for very small subsets of patients. Due to this lack of a strong oncogenic driver for conventional targeted therapy, SCLC has the potential to benefit from non-oncogene-addiction-based therapeutic approaches. We therefore focused on finding novel non-mutated pathways which could be targetable in SCLC. Restricting our search to kinases, a highly-targetable group of enzymes, we elucidated the active kinome of SCLC and upon identifying MEK5 as a SCLC-specific active kinase, further investigated the role of the MEK5-ERK5 kinase axis in this tumor type. We found that reduction in this axis in both human and murine SCLC cells causes increased susceptibility to apoptosis, and decreased subcutaneous tumor growth in vivo. Transcriptomic analysis of MEK5 and ERK5-knockdown cells showed downregulation of lipid metabolism pathways and SREBP target genes. Based on targeted lipidomics analyses of these same cells, which showed downregulated cholesterol ester species, we focused on the mevalonate arm of the SREBP pathway.

2021-10-17 | GSE121538 | GEO

A kinome-wide high-content siRNA screen identifies MEK5-ERK5 signaling as critical for breast cancer cell EMT and metastasis

Project description:We have employed a high-content microscopy screen in combination with a kinome and phosphatome-wide siRNA library to identify signaling pathways underlying an EMT of murine mammary epithelial cells and breast cancer cells. This screen identified the MEK5-ERK5 axis as a critical player in TGFb-mediated EMT. Suppression of MEK5-ERK5 signaling completely prevented the morphological and molecular changes occurring during a TGFb-induced EMT and, conversely, forced highly metastatic breast cancer cells into a differentiated epithelial state. Inhibition of MEK5-ERK5 signaling also repressed breast cancer cell migration and invasion and substantially reduced lung metastasis without affecting primary tumor growth. The results suggest that the MEK5-ERK5 signaling axis plays an important role in the induction and maintenance of breast cancer cell migration and invasion and thus represents an exploitable target for the pharmacological inhibition of cancer cell metastasis.

2018-05-17 | GSE100403 | GEO

MEK5-mediated gene expression changes in DU145 human prostate cancer cells

Project description:Mitogen/extracellular signal-regulated kinase kinase-5 (MEK5) belongs to the family of MAP kinases. It is activated by the upstream kinases MEKK2 and MEKK3. MEK5, in turn, phosphorylates and activates extracellular signal-regulated kinase 5 (ERK5) at Thr218/Tyr220. MEK5/ERK5 pathway plays a pivotal role in tumor initiation and progression, including prostate cancer. MEK5 protein is overexpressed in prostate cancer cells compared with normal cells and MEK5 levels are correlated with prostate cancer metastasis. Global gene expression was determined in DU145 cells stably expressing a scrambled (control) shRNA or MEK5 shRNA using the Agilent Mouse Whole Genome microarrays. Gene ontology and pathway analysis of differentially expressed genes using Ingenuity Pathway Analysis and gene set enrichment analysis (GSEA) revealed MEK5 knockdown attenuates a number or critical signaling pathways required for prostate tumor growth and progression.

2023-08-16 | GSE156399 | GEO

MEK5-mediated gene expression changes in PC3 human prostate cancer cells

Project description:Mitogen/extracellular signal-regulated kinase kinase-5 (MEK5) belongs to the family of MAP kinases. It is activated by the upstream kinases MEKK2 and MEKK3. MEK5, in turn, phosphorylates and activates extracellular signal-regulated kinase 5 (ERK5) at Thr218/Tyr220. MEK5/ERK5 pathway plays a pivotal role in tumor initiation and progression, including prostate cancer. MEK5 protein is overexpressed in prostate cancer cells compared with normal cells and MEK5 levels are correlated with prostate cancer metastasis. Global gene expression was determined in PC3 cells stably expressing a scrambled (control) shRNA or MEK5 shRNA using the Agilent Mouse Whole Genome microarrays. Gene ontology and pathway analysis of differentially expressed genes using Ingenuity Pathway Analysis and gene set enrichment analysis (GSEA) revealed MEK5 knockdown attenuates a number or critical signaling pathways required for prostate tumor growth and progression.

2023-08-16 | GSE156401 | GEO

MEKK3-MEK5-ERK5 signaling promotes mitochondrial degradation.

Project description: Not available

| S-EPMC7576125 | biostudies-literature

The MEK5/ERK5 Pathway in Health and Disease.

Project description: Not available

| S-EPMC8303459 | biostudies-literature

The MEK5-ERK5 Kinase Axis Controls Lipid Metabolism in Small Cell Lung Cancer

Project description:The MEK5-ERK5 Kinase Axis Controls Lipid Metabolism in Small Cell Lung Cancer

| PRJNA497599 | ENA

MEK5/ERK5 activation regulates colon cancer stem-like cell properties.

Project description: Not available

| S-EPMC6370793 | biostudies-literature

KLF4 Recruits SWI/SNF to Increase Chromatin Accessibility and Reprogram the Endothelial Enhancer Landscape under Laminar Shear Stress

Project description:Physiologic laminar shear stress (LSS) induces an endothelial gene expression profile that is vasculo-protective. In this report, we delineate how LSS mediates changes in the epigenetic landscape to promote this beneficial response. We show that under LSS, KLF4 interacts with the SWI/SNF nucleosome remodeling complex to increase accessibility at enhancer sites that promote expression of homeostatic endothelial genes. By combining molecular and computational approaches we discovered enhancers that loop to promoters of known and novel KLF4- and LSS-responsive genes that stabilize endothelial cells and suppress inflammation, such as BMPR2 and DUSP5. By linking enhancers to genes that they regulate under physiologic LSS, our work establishes a foundation for interpreting how non-coding DNA variants in these regions might disrupt protective gene expression to influence vascular disease. AP-MS studies: For KLF gain-of-function, pulmonary artery endothelial cells (PAEC) were transduced with adenoviral vectors encoding a constitutively active mutant of MEK5 (caMEK5), or GFP as control. 90h post-transduction cells were lysed and AP was performed using antibodies targeting either KLF (sc166238, Santa Cruz Biotechnology) or FLAG (F7425, Millipore Sigma). Datafiles correspond to: GK: GFP-tranduced controls using anti-KLF antibodies for AP. GF: GFP-tranduced controls using anti-FLAG antibodies for AP. KK: caMEK5-transduced cells with anti-KLF antibodies for AP. KF: caMEK5-tranduced cells with anti-FLAG antibodies for AP.

2020-07-24 | MSV000085825 | MassIVE

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