scholarly journals Deficit of mitogen-activated protein kinase phosphatase 1 (DUSP1) accelerates progressive hearing loss

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Adelaida M Celaya ◽  
Isabel Sánchez-Pérez ◽  
Jose M Bermúdez-Muñoz ◽  
Lourdes Rodríguez-de la Rosa ◽  
Laura Pintado-Berninches ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Cellular Response ◽  
Redox Status ◽  
Mitogen Activated Protein Kinase ◽  
Progressive Hearing Loss ◽  
Knock Out ◽  
Auditory Evoked Responses ◽  
Mitogen Activated Protein ◽  
Response To Stress ◽  
Stress Signals

Mitogen-activated protein kinases (MAPK) such as p38 and the c-Jun N-terminal kinases (JNKs) are activated during the cellular response to stress signals. Their activity is regulated by the MAPK-phosphatase 1 (DUSP1), a key component of the anti-inflammatory response. Stress kinases are well-described elements of the response to otic injury and the otoprotective potential of JNK inhibitors is being tested in clinical trials. By contrast, there are no studies exploring the role of DUSP1 in hearing and hearing loss. Here we show that Dusp1 expression is age-regulated in the mouse cochlea. Dusp1 gene knock-out caused premature progressive hearing loss, as confirmed by auditory evoked responses in Dusp1–/– mice. Hearing loss correlated with cell death in hair cells, degeneration of spiral neurons and increased macrophage infiltration. Dusp1–/– mouse cochleae showed imbalanced redox status and dysregulated expression of cytokines. These data suggest that DUSP1 is essential for cochlear homeostasis in the response to stress during ageing.

scholarly journals Author response: Deficit of mitogen-activated protein kinase phosphatase 1 (DUSP1) accelerates progressive hearing loss

2018 ◽  
Author(s):  
Adelaida M Celaya ◽  
Isabel Sánchez-Pérez ◽  
Jose M Bermúdez-Muñoz ◽  
Lourdes Rodríguez-de la Rosa ◽  
Laura Pintado-Berninches ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Author Response ◽  
Progressive Hearing Loss ◽  
Mitogen Activated Protein

scholarly journals Vaccinia-Related Kinase 2 Modulates the Stress Response to Hypoxia Mediated by TAK1

2007 ◽  
Vol 27 (20) ◽  
pp. 7273-7283 ◽  
Author(s):  
Sandra Blanco ◽  
Claudio Santos ◽  
Pedro A. Lazo
Keyword(s):  
Stress Response ◽  
Cellular Response ◽  
Mapk Signaling ◽  
Cellular Stress Response ◽  
Mitogen Activated Protein Kinase ◽  
Stable Complex ◽  
Intracellular Proteins ◽  
Mitogen Activated Protein ◽  
Jnk Activation ◽  
Protein Kinase Kinase

ABSTRACT Hypoxia represents a major stress that requires an immediate cellular response in which different signaling pathways participate. Hypoxia induces an increase in the activity of TAK1, an atypical mitogen-activated protein kinase kinase kinase (MAPKKK), which responds to oxidative stress by triggering cascades leading to the activation of c-Jun N-terminal kinase (JNK). JNK activation by hypoxia requires assembly with the JIP1 scaffold protein, which might also interact with other intracellular proteins that are less well known but that might modulate MAPK signaling. We report that TAK1 is able to form a stable complex with JIP1 and thus regulate the activation of JNK, which in turn determines the cellular stress response to hypoxia. This activation of TAK1-JIP1-JNK is suppressed by vaccinia-related kinase 2 (VRK2). VRK2A is able to interact with TAK1 by its C-terminal region, forming stable complexes. The kinase activity of VRK2 is not necessary for this interaction or the downregulation of AP1-dependent transcription. Furthermore, reduction of the endogenous VRK2 level with short hairpin RNA can increase the response induced by hypoxia, suggesting that the intracellular levels of VRK2 can determine the magnitude of this stress response.

scholarly journals OP32 Mincle signalling promotes intestinal mucosal inflammation through induction of macrophage pyroptosis and neutrophil chemotaxis in Crohn’s disease

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S031-S031
Author(s):  
W GONG ◽  
K Guo ◽  
J Ren
Keyword(s):  
Intestinal Inflammation ◽  
Ex Vivo ◽  
Experimental Colitis ◽  
Mitogen Activated Protein Kinase ◽  
Mucosal Inflammation ◽  
Neutrophil Chemotaxis ◽  
Knock Out ◽  
Mitogen Activated Protein ◽  
Proinflammatory Role

Abstract Background Macrophage-inducible C-type lectin (Mincle) signalling plays a proinflammatory role in different organs such as the brain and liver, but its role in intestinal inflammation remains unknown. Methods We studied the characteristics of Mincle signalling expression in CD patients and experimental colitis. The functional role of Mincle signalling in the intestine was addressed in experimental colitis models in vivo by using mice with Mincle knock out (Mincle−/−), neutralising anti-Mincle antibody, Mincle pharmacologic agonist and RNA-seq genome expression analysis. Bone marrow-derived macrophages were collected from mice and used to further verify the effect of Mincle signalling in macrophages. Results Mincle signalling was significantly elevated in active human CD and experimental colitis, and macrophages were the principal leukocyte subset that up-regulates Mincle signalling. Mincle deficiency ameliorated the colitis by reducing induced macrophage pyroptosis (Figure 1), whereas activation of Mincle with the pharmacologic agonist worsened the intestinal inflammation (Figure 2). Moreover, the ex vivo studies confirmed that Mincle signalling activation promoted and its absence restricted release of proinflammatory cytokines from pyroptosis of macrophage (Figure 3). Finally, Mincle/Syk signalling could promote the production of chemokines to recruit neutrophils by activating Mitogen-Activated Protein Kinase (MAPK) during inflammation (Figure 4). Conclusion Mincle signalling promotes intestinal mucosal inflammation through induction of macrophage pyroptosis and neutrophil chemotaxis. Modulation of the Mincle/Syk axis emerges as a potential therapeutic strategy to target inflammation and treat CD.

scholarly journals Weaning Induced Hepatic Oxidative Stress, Apoptosis, and Aminotransferases through MAPK Signaling Pathways in Piglets

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Zhen Luo ◽  
Wei Zhu ◽  
Qi Guo ◽  
Wenli Luo ◽  
Jing Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Signaling Pathways ◽  
Redox Status ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Control Group ◽  
Hepatic Oxidative Stress ◽  
Mitogen Activated Protein ◽  
D 20 ◽  
Mapk Signaling Pathways

This study investigated the effects of weaning on the hepatic redox status, apoptosis, function, and the mitogen-activated protein kinase (MAPK) signaling pathways during the first week after weaning in piglets. A total of 12 litters of piglets were weaned at d 21 and divided into the weaning group (WG) and the control group (CG). Six piglets from each group were slaughtered at d 0 (d 20, referred to weaning), d 1, d 4, and d 7 after weaning. Results showed that weaning significantly increased the concentrations of hepatic free radicals H2O2and NO, malondialdehyde (MDA), and 8-hydroxy-2′-deoxyguanosine (8-OHdG), while significantly decreasing the inhibitory hydroxyl ability (IHA) and glutathione peroxidase (GSH-Px), and altered the level of superoxide dismutase (SOD). The apoptosis results showed that weaning increased the concentrations of caspase-3, caspase-8, caspase-9 and the ratio of Bax/Bcl-2. In addition, aspartate aminotransferase transaminase (AST) and alanine aminotransferase (ALT) in liver homogenates increased after weaning. The phosphorylated JNK and ERK1/2 increased, while the activated p38 initially decreased and then increased. Our results suggested that weaning increased the hepatic oxidative stress and aminotransferases and initiated apoptosis, which may be related to the activated MAPK pathways in postweaning piglets.

Type IX collagen knock-out mouse shows progressive hearing loss

2005 ◽  
Vol 51 (3) ◽  
pp. 293-298 ◽  
Author(s):  
Nobuyoshi Suzuki ◽  
Kenji Asamura ◽  
Yasutake Kikuchi ◽  
Yutaka Takumi ◽  
Satoko Abe ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Progressive Hearing Loss ◽  
Knock Out ◽  
Knock Out Mouse

scholarly journals Activation of Srk1 by the Mitogen-activated Protein Kinase Sty1/Spc1 Precedes Its Dissociation from the Kinase and Signals Its Degradation

2008 ◽  
Vol 19 (4) ◽  
pp. 1670-1679 ◽  
Author(s):  
Sandra López-Avilés ◽  
Eva Lambea ◽  
Alberto Moldón ◽  
Maribel Grande ◽  
Alba Fajardo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Mitogen Activated Protein Kinase ◽  
Regulatory Domain ◽  
Cycle Progression ◽  
Mitogen Activated Protein ◽  
Extracellular Stimuli ◽  
Response To Stress ◽  
Cytotoxic Stress

Control of cell cycle progression by stress-activated protein kinases (SAPKs) is essential for cell adaptation to extracellular stimuli. The Schizosaccharomyces pombe SAPK Sty1/Spc1 orchestrates general changes in gene expression in response to diverse forms of cytotoxic stress. Here we show that Sty1/Spc1 is bound to its target, the Srk1 kinase, when the signaling pathway is inactive. In response to stress, Sty1/Spc1 phosphorylates Srk1 at threonine 463 of the regulatory domain, inducing both activation of Srk1 kinase, which negatively regulates cell cycle progression by inhibiting Cdc25, and dissociation of Srk1 from the SAPK, which leads to Srk1 degradation by the proteasome.

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