Dusp1 deletion unveils its central role in the regulation of redox homeostasis and inflammation in the mouse cochlea
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ABSTRACT:
PROVIDER: PRJNA734936 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14718200.fastq.gz | Fastqsanger.gz | |||
| SRR14718201.fastq.gz | Fastqsanger.gz | |||
| SRR14718202.fastq.gz | Fastqsanger.gz | |||
| SRR14718203.fastq.gz | Fastqsanger.gz | |||
| SRR14718204.fastq.gz | Fastqsanger.gz |
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Project description:Stress-activated protein kinases (SAPK) have been associated with sensorineural hearing loss (SNHL) of multiple etiologies. The activity of these kinases is tightly regulated by the dual-specificity phosphatase 1 (DUSP1), thus, DUSP1 loss of function leads to the sustained activation of SAPK. In the hearing organ, DUSP1 is an indispensable component of the stress response machinery, and its deficit accelerates SNHL progression, triggers the inflammatory response and promotes hair cell (HC) and spiral neurons (SGN) death. Here, we have studied the link between inflammation and redox imbalance in the cochlea by further characterizing the transcriptome of the Dusp1-/- mouse. RNAseq and subsequent GSEA indicated that Dusp1-/- mice present a distinct gene expression pattern of key cellular programs, including altered expression of genes of the inflammatory response and glutathione metabolism. To dissociate both components, Dusp1-/- mice were treated with the antioxidant N-acetylcysteine (NAC). Treatment with NAC delayed the onset of SNHL and reduced cochlear damage. Less HC were TUNEL+ and SGN showed less p-H2AX foci. NAC treatment not only improved redox balance but also reduced cytokine production and macrophage recruitment in Dusp1-/ -mice. In conclusion, our data point to DUSP1 as an essential node to control the cross-regulation of oxidative stress and inflammation.
2021-06-29 | GSE176114 | GEO
Project description:Stress-activated protein kinases (SAPK) are associated with sensorineural hearing loss (SNHL) of multiple etiologies. Their activity is tightly regulated by dual-specificity phosphatase 1 (DUSP1), whose loss of function leads to sustained SAPK activation. Dusp1 gene knockout in mice accelerates SNHL progression and triggers inflammation, redox imbalance and hair cell (HC) death. To better understand the link between inflammation and redox imbalance, we analyzed the cochlear transcriptome in Dusp1-/- mice. RNA sequencing analysis (GSE176114) indicated that Dusp1-/- cochleae can be defined by a distinct profile of key cellular expression programs, including genes of the inflammatory response and glutathione (GSH) metabolism. To dissociate the two components, we treated Dusp1-/- mice with N-acetylcysteine, and hearing was followed-up longitudinally by auditory brainstem response recordings. A combination of immunofluorescence, Western blotting, enzymatic activity, GSH levels measurements and RT-qPCR techniques were used. N-acetylcysteine treatment delayed the onset of SNHL and mitigated cochlear damage, with fewer TUNEL+ HC and lower numbers of spiral ganglion neurons with p-H2AX foci. N-acetylcysteine not only improved the redox balance in Dusp1-/- mice but also inhibited cytokine production and reduced macrophage recruitment. Our data point to a critical role for DUSP1 in controlling the cross-talk between oxidative stress and inflammation.
| S-EPMC8467085 | biostudies-literature
Project description:Activation of the Mitogen activated protein kinase (MAPK) cascade following Toll-like receptor (TLR) stimulation enables innate immune cells to rapidly activate cytokine gene expression. A balanced response to signals of infectious danger requires that cellular activation is transient. Here, we identify the MAPK phosphatase Dual specificity phosphatase-1 (DUSP1) as an essential endogenous regulator of the inflammatory response to LPS. DUSP1-deficient (DUSP1-/-) bone marrow derived macrophages showed selectively prolonged activation of p38 MAPK and increased cytokine production. Intraperitoneal challenge of DUSP1-/- mice with LPS caused increased lethality and overshooting production of IL-6 and TNF?. Transcriptional profiling revealed that DUSP1 controls a significant fraction of LPS-induced genes, that includes IL-6 and IL-10 as well as the chemokines CCL3, CCL4 and CXCL2. In contrast, the expression of the important mediators of endotoxin lethality, IFN? and IL-12, was not significantly altered by the absence of DUSP1. These data together demonstrate a specific regulatory role of DUSP1 in controlling a subset of LPS-induced genes that determines the outcome of endotoxin shock. Keywords: in vivo analysis of splenic mRNA expression
2005-12-15 | GSE3565 | GEO
Project description:Our work describes the application of mass spectrometry-based label-free quantitative proteomics for the identification of differentially expressed proteins between different-aged cochlea. We report proteins exclusively present as well as up- and downregulated in the cochlear sensory epithelium at significant developmental stages. Additionally, we report proteins exclusively present on P3 that were recently identified in the cochlea for the first time. We use bioinformatics to provide insight on biological functions and potential primary and secondary partners of the differentially expressed proteins. This study provides the first differentially expressed proteome in the mammalian cochlea at significant developmental stages; before hearing, during the onset of hearing, and when hearing is fully developed. We believe that these results will provide insights into the function of proteins that change during development and identify potential protein biomarkers related to hearing impairments.
2018-08-29 | PXD001973 | Pride
Project description:Adolescent cocaine abuse increases the risk for developing addiction in later life, but the underlying molecular mechanism remains poorly understood. Here, we establish adolescent cocaine-exposed (ACE) male mouse models. A subthreshold dose of cocaine (sdC) treatment, insufficient to produce conditioned place preference (CPP) in adolescent mice, induces CPP in ACE mice during adulthood, along with more activated CaMKII-positive neurons, higher dual specificity protein kinase phosphatase-1 (Dusp1) mRNA, lower DUSP1 activity, and lower DUSP1 expression in CaMKII-positive neurons in the medial prefrontal cortex (mPFC). Overexpressing DUSP1 in CaMKII-positive neurons suppresses neuron activity and blocks sdC-induced CPP in ACE mice during adulthood. On the contrary, depleting DUSP1 in CaMKII-positive neurons activates more neurons and further enhances sdC-induced behavior in ACE mice during adulthood. Also, ERK1/2 might be a downstream signal of DUSP1 in the process. Our findings reveal a role of mPFC DUSP1 in ACE-induced higher sensitivity to the drug in adult mice. DUSP1 might be a potential pharmacological target to predict or treat the susceptibility to addictive drugs caused by adolescent substance use.
2023-05-20 | GSE231074 | GEO
Project description:DUSP1 is involved in different cellular pathways including cancer cell proliferation, angiogenesis, invasion and resistance to chemotherapy. To understand more about the cellular responses regulated by DUSP1 in NSCLC cells, we interfered DUSP1 expression in the NSCLC cell line H460 and studied the changes in gene expression differentially regulated by this phosphatase. Keywords: Expression profiling by array in cells with genetic modification The human non small lung cancer cell line H460 used in this study was from ATCC (American Type Culture Collection). The cell line was maintained in RPMI (Gibco, Invitrogen) supplemented with 10% bovine serum and transfected by Lipofectamine Plus Reagent from Life Technologies as directed by the manufacturer. The DUSP1 pSuperRetro-derived vectors were constructed as described (Chattoppadhyay et al., 2006). Clones expressing siRNA for DUSP1 were selected for their ability to grow in the presence of puromycin and kept for selection. Stable transfection was confirmed by Western blotting. RNA was extracted and quality control was checked before hybridization on Affymetrix microarrays.
2010-12-09 | E-GEOD-19592 | biostudies-arrayexpress
Project description:DUSP1 is involved in different cellular pathways including cancer cell proliferation, angiogenesis, invasion and resistance to chemotherapy. To understand more about the cellular responses regulated by DUSP1 in NSCLC cells, we interfered DUSP1 expression in the NSCLC cell line H460 and studied the changes in gene expression differentially regulated by this phosphatase. Keywords: Expression profiling by array in cells with genetic modification
2010-12-09 | GSE19592 | GEO
Project description:Cutaneous squamous cell carcinoma (cSCC) is the second most prevalent cancer. In most of the cases, surgical removal of the tumor is a curative treatment but 3-5% of the tumors will progress or produce metastasis having a poor prognosis. Here we demonstrated the tumor suppressive role of DUSP1, a dual phosphatase that negatively regulates ERK activity. We demonstrated that DUSP1 constrains ERK signaling during inflammation and wound healing to sustain homeostasis by transiently decreasing its levels, but its permanent downregulation promotes progression to squamous cell carcinoma. Using mouse and human models we demonstrated that DUSP1 loss enhances ERK signaling, and tumor growth. RNAseq analysis revealed that DUSP1 null tumors are enriched in cancer stem cell gene signatures, but surprisingly, are also depleted from CD4, CD8, macrophages and DC cells, and DUSP1 null cancer cells express lower levels of chemo and cytokines, been immune excluded. Our data suggest that DUSP1 acts restricting cancer cell proliferation and promoting immune recruitment, presenting promising diagnostic and therapeutic potential.
2024-09-30 | GSE260920 | GEO
Project description:Activation of the Mitogen activated protein kinase (MAPK) cascade following Toll-like receptor (TLR) stimulation enables innate immune cells to rapidly activate cytokine gene expression. A balanced response to signals of infectious danger requires that cellular activation is transient. Here, we identify the MAPK phosphatase Dual specificity phosphatase-1 (DUSP1) as an essential endogenous regulator of the inflammatory response to LPS. DUSP1-deficient (DUSP1-/-) bone marrow derived macrophages showed selectively prolonged activation of p38 MAPK and increased cytokine production. Intraperitoneal challenge of DUSP1-/- mice with LPS caused increased lethality and overshooting production of IL-6 and TNF. Transcriptional profiling revealed that DUSP1 controls a significant fraction of LPS-induced genes, that includes IL-6 and IL-10 as well as the chemokines CCL3, CCL4 and CXCL2. In contrast, the expression of the important mediators of endotoxin lethality, IFN? and IL-12, was not significantly altered by the absence of DUSP1. These data together demonstrate a specific regulatory role of DUSP1 in controlling a subset of LPS-induced genes that determines the outcome of endotoxin shock. Experiment Overall Design: Mice were injected intraperitoneally with E. coli LPS (10µg/g bodyweight) and sacrificed 6h later. Total spleen RNA (5 µg) was prepared, labeled and hybridized to Affymetrix MOE430A 2.0 GeneChips according to the manufacturer's instructions. Three biological replicates per condition were analysed. CEL Files were processed for global normalization and generation of expression values using the rma algorithm in the R affy package (www.bioconductor.org).
2007-11-01 | E-GEOD-3565 | biostudies-arrayexpress
Project description:Salivary gland squamous cell carcinomas (SG-SCCs) are a rare type of head and neck cancers which are linked to poor prognosis. Due to their low frequencies, the molecular mechanisms responsible for their aggressiveness are poorly understood. In this work we studied the function of the phosphatase DUSP1, a negative regulator of MAPK activity, in controlling the progression of SG-SCCs. We generated DUSP1 KO clones in A253 human cells. These clones showed a reduced ability to grow in 2D, self-renew in ECM matrices and grow tumors in immunodeficient mice. This was caused by an overactivation of the stress and apoptosis kinase JNK1/2 in DUSP1-KO clones. Interestingly, RNAseq analysis revealed that the expression of SOX2, a well know self-renewal gene was decreased at the mRNA and protein level. Unexpectedly, CRISPR-KO of SOX2 did not recapitulate DUSP1-KO phenotype, and SOX2-null cells had an enhanced ability to self-renew and grow tumors in mice. Gene expression analysis demonstrated that SOX2-null cells have a decreased squamous differentiation profile -losing TP63 expression- and an increased migratory phenotype, with an enhanced epithelial to mesenchymal transition signature. In summary, our data indicates that DUSP1 and SOX2 have opposite functions in SG-SCC, being DUSP1 necessary for tumor growth and SOX2 dispensable, and with a tumor suppressor function. Our data will suggest that the expression SOX2 and DUSP1 could be a useful biomarker to predict the progression of patients with SG-SCCs.
2024-05-01 | GSE253468 | GEO