P38α activation-mediated IFNAR1 downregulation by tumor derived factors induced neutrophil-attracting chemokines production
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ABSTRACT:
PROVIDER: PRJNA552538 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9640942.fastq.gz | Fastqsanger.gz | |||
| SRR9640943.fastq.gz | Fastqsanger.gz | |||
| SRR9640944.fastq.gz | Fastqsanger.gz | |||
| SRR9640945.fastq.gz | Fastqsanger.gz |
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Project description:Tumor derived factors induced type I interferon receptor (IFNAR1) downregulation both in vivo and in vitro. IFNAR1 was shown to be phosphorylated, ubiquitinated and downregulated in response to soluble or vesicular tumor derived factors in a p38-dependent manner. Upon administration of B16F10 tumor derived factors, lungs of Ifnar1S526A knock-in mice (termed "SA"), where mutation in a phospho-acceptor site within the IFNAR1 phospho-degron renders IFNAR1 insensitive to p38-driven phosphorylation, ubiquitination and degradation, retained IFNAR1 and sustained the expression of the IFN stimulated genes. Futuremore, careful examination and validation of gene expression profiles revealed an increased expression of several chemokines known to attract neutrophils (including Cxcl1, Cxcl3 and Cxcl5) in the lungs of WT mice treated with tumor derived factors. This increase was notably less pronounced in the SA mice, suggesting that IFNAR1 downregulation by tumor derived factors induced neutrophil-attracting chemokines production.
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Project description:p38α MAP kinase plays an important tumor suppressor role, which is mediated by both its negative effect on cell proliferation and its pro-apoptotic activity. Surprisingly, most tumor suppressor mechanisms coordinated by p38α have been reported to occur at the post- translational level. This contrasts with the important role of p38α in the regulation of transcription and the profound changes in gene expression that normally occur during tumorigenesis. We have analyzed whole genome expression profiles of Ras-transformed wild- type and p38α-deficient cells and have identified 202 genes that are potentially regulated by p38α in transformed cells. Expression analysis has confirmed the regulation of these genes by p38α in tumors, and functional validation has identified several of them as likely mediators of the tumor suppressor effect of p38α on Ras-induced transformation. Interestingly, about 10% of the genes that are negatively regulated by p38α in transformed cells contribute to EGF receptor signalling. Our results suggest that inhibition of EGF receptor signalling by transcriptional targets of p38α is an important function of this signalling pathway in the context of tumor suppression. We have investigated how transcriptional regulation contributes to the tumor suppressor effect of p38α, by comparing whole-genome expression profiles of wild-type (WT) and p38α- deficient (p38α-/-) mouse embryo fibroblasts (MEFs) expressing oncogenic H-RasG12V
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Project description:The P38α modulates proliferation, survival and differentiation of different kinds of celll. Here, we demonstrate that loss of P38α accelerates recovery from anemia in mice by promoting survival of erythroblasts. To identify gene expression changes in P38α+/- versus P38α-/- erythroblasts, we sorted erythroblasts from P38α+/- and P38α-/- mice during recovery from anemia and performed microarray analysis.
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Project description:There is considerable evidence that inhibition of p38α mitogen-activated protein kinase diminishes cardiac damage during myocardial ischemia. During myocardial ischemia p38α interacts with TAB1, a scaffold protein, which promotes p38α autoactivation; active p38α (pp38α) then trans-phosphorylates TAB1. Previously, we solved the X-ray structure of the p38α-TAB1(384-412) complex. Here we further characterize the interaction by resolving the structure of the pp38α-TAB1(1-438) complex in the active state. Based on this information we created a global knock-in mouse with substitution of four residues on TAB1 (V390A, Y392A, V408G, M409A) we show are required for docking onto p38α. Whereas ablating p38α or TAB1 results in early embryonal lethality, the TAB1 KI mice are viable, develop normally and have no appreciable alteration in their lymphocyte repertoire or myocardial transcriptional profile. Nonetheless, following in vivo regional myocardial ischemia, infarction volume is significantly reduced and the trans- phosphorylation of TAB1 is disabled. Unexpectedly, the activation of myocardial p38α during ischemia is only mildly attenuated in TAB1 KI hearts, an effect most likely due to the removal of the steric hindrance to MAP2K3 binding. We conclude that it is the phosphorylation of TAB1 by pp38α during ischemia that is associated with cardiac damage. The data reveal that it is possible to selectively inhibit signalling downstream of p38α to attenuate ischemic injury. Our findings validate the p38α-TAB1 complex as a therapeutic target that may circumvent the toxicity associated with ATP-competitive inhibitors of p38α.
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Project description:Here, we describe the identification and characterization of p38α as a novel regulator of DUX4 expression in FSHD myotubes. By using multiple highly characterized, potent and specific inhibitors of p38α/β, we show a robust reduction of DUX4 expression, activity and cell death across FSHD1 and FSHD2 patient-derived lines. RNA-seq profiling reveals that a small number of genes are differentially expressed upon p38α/β inhibition, the vast majority of which are DUX4 target genes. Our results reveal a novel and apparently critical role for p38α in the aberrant activation of DUX4 in FSHD and support the potential of p38α/β inhibitors as effective therapeutics to treat FSHD at its root cause.
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Project description:Purpose: The goals of this study is to compare transcriptome profiles of microglia from different mouse genotypes using RNA-seq analysis. HIV-associated neurocognitive disorders (HAND) occur in about 50% of infected individuals. Transgenic mice expressing the soluble HIV-1 envelope glycoprotein gp120 in astroglia (HIVgp120tg) display key neuropathological features of NeuroHIV patients (Toggas et al., 1994; Maung et al., 2014; Ojeda-Juarez et al., 2020). Here we show that microglial p38α MAPK plays a crucial role in neuronal injury triggered in vivo by the viral envelope glycoprotein. Cre-expression driven by the CX3CR1 promotor in HIVgp120tg mice carrying floxed alleles of p38a MAPK results in deletion of p38α in microglia and complete protection against neuronal injury and loss. RNA-seq analysis of microglia indicates that p38α deficiency leads to upregulation of neuroprotective and downregulation of neurotoxic factors. The expression patterns of genes associated with neurotransmission differ between brains protected from neuronal injury in the presence of transgenic gp120 and non-transgenic controls, suggesting a non-toxic modulation of neurons by the viral protein and microglial p38α deficiency.
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