ERK5 sustains autocrine mitogenic balance for cell fate specification in human pluripotent stem cells [MEK4DD RNA-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE234056 | GEO | 2024/03/01
REPOSITORIES: GEO
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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.
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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.
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Project description:Background: Gq-coupled G protein-coupled receptors (GPCR) mediate the actions of a variety of messengers that are key regulators of cardiovascular function. Enhanced Gaq-mediated signaling plays an important role in cardiac hypertrophy and in the transition to heart failure. We have recently described that Gaq acts as an adaptor protein that facilitates PKCz-mediated activation of ERK5 in epithelial cells. Since the ERK5 cascade is known to be involved in cardiac hypertrophy, we have investigated the potential relevance of this pathway in Gq-dependent signaling in cardiac cells. Methodology/Principal Findings: We have explored the mechanisms involved in Gq-coupled GPCR-mediated stimulation of the ERK5 pathway and its functional consequences in cardiac hypertrophy using both cultured cardiac cells and an animal model of angiotensin- dependent induction of cardiac hypertrophy in wild-type and PKCz knockout mice. We find that PKC? is required for the activation of the ERK5 pathway by Gq-coupled GPCR in cardiomyocytes and in cardiac fibroblasts. Stimulation of ERK5 by angiotensin II is blocked upon pharmacological inhibition or siRNA-mediated silencing of PKCz in primary cultures of cardiac cells and in cardiomyocytes isolated from PKCz-deficient mice. Moreover, these mice do not develop cardiac hypertrophy upon chronic challenge with angiotensin II, as assessed by morphological, biomarker, electrocardiographic and global gene expression pattern analysis. Conclusion/Significance: Our data put forward that PKC? is essential for Gq- dependent ERK5 activation in cardiac cells and indicate a key cardiac physiological role for this recently described Gaq/PKCz/MEK5 signaling axis. Littermate wild-type and PKCz -/- male mice (32 weeks of age) were subjected to continuous infusion of angiotensin II (or PBS as a control) for 14 days, a well established model for the induction of cardiac hypertrohy
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