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The TAB1-p38α complex aggravates myocardial injury and can be targeted by small molecules

ABSTRACT: The TAB1-p38α complex aggravates myocardial injury and can be targeted by small molecules

PROVIDER: PRJEB28171 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR2733180_1.fastq.gz	Fastqsanger.gz
	ERR2733180_2.fastq.gz	Fastqsanger.gz
	ERR2733181_1.fastq.gz	Fastqsanger.gz
	ERR2733181_2.fastq.gz	Fastqsanger.gz
	ERR2733182_1.fastq.gz	Fastqsanger.gz

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The TAB1-p38α complex aggravates myocardial injury and can be targeted by small molecules

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.

2018-08-27 | E-MTAB-6460 | biostudies-arrayexpress

The TAB1-p38α complex aggravates myocardial injury and can be targeted by small molecules.

Project description:Inhibiting MAPK14 (p38α) diminishes cardiac damage in myocardial ischemia. During myocardial ischemia, p38α interacts with TAB1, a scaffold protein, which promotes p38α autoactivation; active p38α (pp38α) then transphosphorylates TAB1. Previously, we solved the X-ray structure of the p38α-TAB1 (residues 384-412) complex. Here, we further characterize the interaction by solving the structure of the pp38α-TAB1 (residues 1-438) complex in the active state. Based on this information, we created a global knock-in (KI) mouse with substitution of 4 residues on TAB1 that we show are required for docking onto p38α. Whereas ablating p38α or TAB1 resulted in early embryonal lethality, the TAB1-KI mice were viable and had no appreciable alteration in their lymphocyte repertoire or myocardial transcriptional profile; nonetheless, following in vivo regional myocardial ischemia, infarction volume was significantly reduced and the transphosphorylation of TAB1 was disabled. Unexpectedly, the activation of myocardial p38α during ischemia was only mildly attenuated in TAB1-KI hearts. We also identified a group of fragments able to disrupt the interaction between p38α and TAB1. We conclude that the interaction between the 2 proteins can be targeted with small molecules. The data reveal that it is possible to selectively inhibit signaling downstream of p38α to attenuate ischemic injury.

| S-EPMC6141180 | biostudies-literature

Expression and functional validation of new p38α transcriptional targets in tumorigenesis

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

2011-11-23 | E-GEOD-26762 | biostudies-arrayexpress

Role of P38α in stress erythropoiesis

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.

2018-12-21 | GSE111751 | GEO

TRIM21 aggravates cardiac injury after myocardial infarction via promoting M1 macrophage polarization

Project description:TRIM21 aggravates cardiac injury after myocardial infarction via promoting M1 macrophage polarization

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STING aggravates ferroptosis-dependent myocardial ischemia-reperfusion injury by targeting GPX4 for autophagic degradation

Project description:STING aggravates ferroptosis-dependent myocardial ischemia-reperfusion injury by targeting GPX4 for autophagic degradation

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Expression and functional validation of new p38α transcriptional targets in tumorigenesis

2011-11-23 | GSE26762 | GEO

P38α Regulates Expression of DUX4 in Facioscapulohumeral Muscular Dystrophy

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.

2020-06-26 | GSE153301 | GEO

Plasma microRNA signatures for perioperative myocardial injury.

Project description:The pathophysiological mechanism(s) underlying PMI remain controversial. Small non-coding molecules that modulate gene expression may enhance the detection of myocardial injury and provide further mechanistic insight. We profiled plasma exosomal microRNA in patients who sustained PMI after elective non-cardiac surgery

2020-07-26 | GSE144777 | GEO

STING aggravates ferroptosis-dependent myocardial ischemia-reperfusion injury by targeting GPX4 for autophagic degradation

Project description:To investigate the potential signal pathways affected by the deletion of the Sting gene in mice during ischemia-reperfusion (IR), we extracted the myocardial tissues of mice 24 hours after ischemia-reperfusion. Subsequently, we conducted gene expression profiling analysis using the data obtained from RNA-seq of STING-CKO mice and their control counterparts.

2025-04-10 | GSE291453 | GEO

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