Role of nuclear p38 in the transcriptional response to oxidative stress in Drosophila (ChIP-Seq)
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ABSTRACT:
ORGANISM(S): Drosophila melanogaster
PROVIDER: GSE220758 | GEO | 2024/08/09
REPOSITORIES: GEO
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Project description:p38 mitogen-activated protein kinases play fundamental roles in the regulation of the cellular response to environmental stress. p38 is known to regulate translation, mRNA processing and stability, and transcription. The transcriptional response mediated by phosphorylated p38 (P-p38) to extracellular stimuli, such as growth factors, cytokines and different environmental agents, has been thoroughly analysed in a variety of tissues and organisms. However, the genomic localisation of P-p38 is poorly understood. Here, we analysed the chromatin binding of activated P-p38 and the transcriptional response triggered by reactive oxygen species (ROS) in Drosophila S2 cells. We found that P-p38 is already bound to chromatin in basal conditions and relocates in the genome after exposure to high levels of ROS. The distribution pattern of P-p38 suggests that it is involved in the activation and repression of transcription in S2 cells, mainly regulating house-keeping functions.
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Project description:Cells have the ability to respond and adapt to environmental changes through the activation of stress-activated protein kinases (SAPKs). Although it has been shown that p38 SAPK signalling participates in the regulation of gene transcription, there is not a comprehensive genome-wide transcription study reported to date describing neither the role of the p38 SAPK on the immediate response to stress and its kinetics nor a comparative vision of the genes that respond to different stimuli that activate the p38 SAPK. Here, we report a whole genome microarray analyses on wild type mouse embryonic fibroblasts (MEFs) treated with different p38 SAPK activators, namely the physiological cytokine TNF alpha, the protein synthesis inhibitor antibiotic anisomycin and osmostress. In addition, we have analysed the contribution of p38 alpha the major isoform of p38 present in MEF cells, in the overall transcription in response to those stimuli by both, the inhibition of p38 SAPK by using a chemical inhibitor (SB203580) and the use of p38 alpha knock out MEFs. Furthermore, we have analysed the kinetics of the gene expression response to osmostress by the p38 SAPK. Two samples have been analysed; wild type Mouse embryonic fibroblast (WT-MEFs) and MAPK p38alfa knock out MEFs (KO-MEFs) respectively treated with 11 and 4 different treatments. Each experiment was performed in duplicate and referenced to a pool of two non-treated WT MEFs.
2010-09-29 | E-GEOD-18320 | biostudies-arrayexpress
Project description:Cells have the ability to respond and adapt to environmental changes through the activation of stress-activated protein kinases (SAPKs). Although it has been shown that p38 SAPK signalling participates in the regulation of gene transcription, there is not a comprehensive genome-wide transcription study reported to date describing neither the role of the p38 SAPK on the immediate response to stress and its kinetics nor a comparative vision of the genes that respond to different stimuli that activate the p38 SAPK. Here, we report a whole genome microarray analyses on wild type mouse embryonic fibroblasts (MEFs) treated with different p38 SAPK activators, namely the physiological cytokine TNF alpha, the protein synthesis inhibitor antibiotic anisomycin and osmostress. In addition, we have analysed the contribution of p38 alpha the major isoform of p38 present in MEF cells, in the overall transcription in response to those stimuli by both, the inhibition of p38 SAPK by using a chemical inhibitor (SB203580) and the use of p38 alpha knock out MEFs. Furthermore, we have analysed the kinetics of the gene expression response to osmostress by the p38 SAPK.
2010-09-29 | GSE18320 | GEO
Project description:Mitogen-activated protein kinases (MAPKs) regulate cardiomyocyte growth and apoptosis in response to extracellular stimulation, but the downstream effectors that mediate their pathophysiological effects remain poorly understood. We determined the targets and role of p38 MAPK in the heart in vivo by using local adenovirus-mediated gene transfer of constitutively active upstream kinase mitogen-activated protein kinase kinase 3b (MKK3bE) and wild-type p38α in rats. DNA microarray analysis of animals with cardiac-specific overexpression of p38 MAPK revealed that 264 genes were upregulated more than 2-fold including multiple genes controlling cell division, cell signaling, inflammation, adhesion and transcription. Several previously unknown p38 target genes were found. Using gel mobility shift assays we identified several cardiac transcription factors that were directly activated by p38 MAPK. Finally, we determined the functional significance of the altered cardiac gene expression profile by histological analysis and echocardiographic measurements, which indicated that p38 MAPK overexpression induced gene expression results in cell proliferation, myocardial inflammation and fibrosis. In conclusion, we defined the novel target genes and transcription factors as well as the functional effects of p38 MAPK in the heart. Expression profiling of p38 MAPK overexpression identified cell cycle regulatory and inflammatory genes critical for pathological processes in the adult heart. Keywords: Gene transfer
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Project description:p38 and JNK are activated in response to acute stress and inflammatory signals. Through modification of a plethora of substrates, these kinases profoundly re-shape cellular physiology for the optimal response to a harmful environment and/or an inflammatory state. Here, we utilized phospho-proteomics to identify several hundred substrates for both kinases. Our results indicate that the scale of signaling from p38 and JNK are of a similar magnitude. Among the many new targets, we highlight the regulation of the transcriptional regulators GIGYF1 and 2 by p38-dependent MK2 phosphorylation and 14-3-3 binding. We also show that the Golgi apparatus contains numerous substrates, and is a major target for regulation by p38 and JNK. When activated, these kinases mediate structural rearrangement of the Golgi apparatus which positively affects protein flux through the secretory system. Our work expands on our knowledge about p38 and JNK signaling with important biological ramifications.
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Project description:Cisplatin kills proliferating cells via DNA damage but also has profound effects on post-mitotic cells in tumors, kidneys, and neurons. However, the effects of cisplatin on post-mitotic cells are still poorly understood. Among model systems, C. elegans adults are unique in having completely post-mitotic somatic tissues. The p38 MAPK pathway controls ROS detoxification via SKN-1/NRF and immune responses via ATF-7/ATF2. We show that p38 MAPK pathway mutants are sensitive to cisplatin, but while cisplatin exposure increases ROS levels, skn-1 mutants are resistant. Cisplatin exposure leads to phosphorylation of PMK-1/MAPK and ATF-7 and the IRE-1/TRF-1 signaling module functions upstream of the p38 MAPK pathway to activate signaling. We identify the response proteins whose increased abundance depends on IRE-1/p38 MAPK activity as well as cisplatin exposure. Four of these proteins are necessary for protection from cisplatin toxicity, which is characterized by necrotic death. We conclude that the p38 MAPK pathway-driven proteins are crucial for adult cisplatin resilience.
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Project description:Environmental particle inhalation and persistent herpesvirus infection are omnipresent and associated with chronic lung diseases. Previously, we showed that pulmonary exposure to soot-like carbonaceous nanoparticles (CNP) or fibre-shaped engineered double-walled carbon nanotubes (DWCNT) induced an increase of lytic virus protein expression in latently murine gammaherpesvirus 68 (MHV-68) infected mouse lungs, with a similar pattern as acute infection suggesting virus reactivation. However, the molecular mechanisms underlying herpesvirus reactivation as well as herpesvirus reactivation associated disease exacerbation caused by particle exposure remain unclear. Here, we investigated the effects of environmental relevant repeated particle exposure and herpesvirus reactivation mechanistically, and therapeutically. In the MHV-68 mouse model, we identified elevated lung inflammation and emphysema-like injury after repetitive CNP exposure. We further uncovered that CNP reactivated latent herpesvirus mainly in CD11b+ macrophages. Mechanistically, ERK1/2, JNK and p38 MAPK were rapidly activated after CNP and DWCNT exposure in persistently MHV-68 infected bone marrow-derived macrophages, followed by upregulation of viral gene expression and increased viral titer but without generating a pro-inflammatory transcriptional signature. Pharmacological inhibition of p38 activation abrogated CNP but not DWCNT triggered virus reactivation. In vivo, p38 inhibitor pretreatment of latently infected mice also attenuated CNP exposure induced MHV-68 reactivation. Our findings suggest that particle pollution is an environmental challenge to trigger herpesvirus reactivation and related chronic lung disease by activating latent herpesvirus via p38 MAPK dependent signalling. Pharmacological p38 inhibition might serve as a protective target to alleviate particle exposure related chronic lung disease exacerbations.
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