Apoptosis signal-regulating kinase 1 promotes Ochratoxin A-induced renal cytotoxicity.
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ABSTRACT:
SUBMITTER: Liang R
PROVIDER: S-EPMC5389036 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Apoptosis signal-regulated kinase 1 (ASK1) has been shown to affect a wide range of cellular processes including stress-related responses, cytokine and growth factor signaling, cell cycle and cell death. Recently, we reported that lack of ASK1 slowed chondrocyte hypertrophy, terminal differentiation and apoptosis resulting in an increase in trabecular bone formation. Herein, we investigated the role of ASK1 in the pathogenesis of osteoarthritis (OA). Immunohistochemistry performed on articular cartilage samples from patients with OA showed ASK1 expression increased with OA severity. In vitro analysis of chondrocyte hypertrophy, maturation and ASK1 signaling in embryonic fibroblasts from ASK1 knockout (KO) and wild type (WT) mice was examined. Western analysis demonstrated an increase in ASK1 signaling commensurate with chondrogenic maturation during differentiation or in response to stress by the cytokines, tumor necrosis factor alpha or interleukin 1 beta in WT, but not in ASK1 KO embryonic fibroblasts. Surgically induced moderate or severe OA or OA due to natural aging in WT and ASK1 KO mice was assessed by microCT of subchondral bone, immunohistochemistry, histology, and OARSI scoring. Immunohistochemistry, microCT and OARSI scoring all indicated that the lack of ASK1 protected against OA joint degeneration, both in surgically induced OA and in aging mice. We propose that the ASK1 MAP kinase signaling cascade is an important regulator of chondrocyte terminal differentiation and inhibitors of this pathway could be useful for slowing chondrocyte maturation and cell death observed with OA progression. J. Cell. Physiol. 231: 944-953, 2016. © 2015 Wiley Periodicals, Inc.
| S-EPMC5952048 | biostudies-literature
Project description:Thrombin-induced endothelial permeability is associated with various pathological conditions. Apoptosis signal-regulating kinase-1 (ASK1), one of the upstream MAP3K, has been reported to be an important regulator of endothelial stress and apoptosis. Despite this, its role in endothelial permeability is unknown. The aim of this study was to determine the role of ASK1 in thrombin-induced endothelial permeability. To do so, a live cell monitoring system and transwell assay were used to evaluate in vitro endothelial permeability, while a Miles assay was used for in vivo permeability. Immunofluorescence and western blotting were used to visualize integrity of the junctions and phosphorylation of various proteins, respectively. We observed that in vivo thrombin-induced vascular permeability was attenuated in Ask1-/- mice. Pretreatment of human primary endothelial cells (ECs) with GS-4997 (ASK1 inhibitor) and deficiency of ASK1 in primary mouse lung ECs significantly attenuated the thrombin-induced endothelial permeability. Furthermore, in the presence of GS-4997, the following were also significantly reduced: thrombin-induced para-cellular gap formation, VE-cadherin proteolysis, and dislocation of VE-cadherin, JAM-A, and ZO1 from the junctions. Inhibition of ASK1 restored peripheral location of F-actin, similar to that induced by sphingosine-1-phosphate. These results suggest a unique role for ASK1 in regulating thrombin-induced endothelial permeability.
| S-EPMC10276900 | biostudies-literature
Project description:Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays an important role in oxidative stress-induced apoptosis. In the present study, we used ASK1 knockout (KO) mice to examine the possibility that ASK1 is involved in the neural cell apoptosis that occurs during retinal development and ischemic injury. ASK1 was expressed in retinal neurons, including retinal ganglion cells (RGCs), but retinal structure and extent of cell death during development were normal in ASK1 KO mice. On the other hand, the strain was less susceptible to ischemic injury, and the number of surviving retinal neurons was significantly increased compared with that in wild-type mice. Interestingly, ischemia-induced phosphorylation of p38 mitogen-activated protein kinase (p38), which mediates RGC apoptosis, was almost completely suppressed in ASK1 KO mice. In such retinas, the numbers of cleaved caspase-3- and TUNEL-positive neurons were apparently decreased compared with those in wild-type mice. Furthermore, cultured RGCs from ASK1 KO mice were resistant to H(2)O(2)-induced apoptosis. Our findings suggest that ASK1 is involved in the neural cell apoptosis after various kinds of oxidative stress. Thus, inhibition of the ASK1-p38 pathway could be useful for the treatment of neurodegenerative diseases including glaucoma.
| S-EPMC1592659 | biostudies-literature
Project description:Metabolic activation and oxidant stress are key events in the pathophysiology of acetaminophen (APAP) hepatotoxicity. The initial mitochondrial oxidative stress triggered by protein adduct formation is amplified by c-jun-N-terminal kinase (JNK), resulting in mitochondrial dysfunction and ultimately cell necrosis. Apoptosis signal-regulating kinase 1 (ASK1) is considered the link between oxidant stress and JNK activation. The objective of the current study was to assess the efficacy and mechanism of action of the small-molecule ASK1 inhibitor GS-459679 in a murine model of APAP hepatotoxicity. APAP (300 mg/kg) caused extensive glutathione depletion, JNK activation and translocation to the mitochondria, oxidant stress and liver injury as indicated by plasma ALT activities and area of necrosis over a 24h observation period. Pretreatment with 30 mg/kg of GS-459679 almost completely prevented JNK activation, oxidant stress and injury without affecting the metabolic activation of APAP. To evaluate the therapeutic potential of GS-459679, mice were treated with APAP and then with the inhibitor. Given 1.5h after APAP, GS-459679 was still protective, which was paralleled by reduced JNK activation and p-JNK translocation to mitochondria. However, GS-459679 treatment was not more effective than N-acetylcysteine, and the combination of GS-459679 and N-acetylcysteine exhibited similar efficacy as N-acetylcysteine monotherapy, suggesting that GS-459769 and N-acetylcysteine affect the same pathway. Importantly, inhibition of ASK1 did not impair liver regeneration as indicated by PCNA staining. In conclusion, the ASK1 inhibitor GS-459679 protected against APAP toxicity by attenuating JNK activation and oxidant stress in mice and may have therapeutic potential for APAP overdose patients.
| S-EPMC4444402 | biostudies-literature
Project description:Both hyperoxia and mechanical ventilation can independently cause lung injury. In combination, these insults produce accelerated and severe lung injury. We recently reported that pre-exposure to hyperoxia for 12 hours, followed by ventilation with large tidal volumes, induced significant lung injury and epithelial cell apoptosis compared with either stimulus alone. We also reported that such injury and apoptosis are inhibited by antioxidant treatment. In this study, we hypothesized that apoptosis signal-regulating kinase-1 (ASK-1), a redox-sensitive, mitogen-activated protein kinase kinase kinase, plays a role in lung injury and apoptosis in this model. To determine the role of ASK-1 in lung injury, the release of inflammatory mediators and apoptosis, attributable to 12 hours of hyperoxia, were followed by large tidal volume mechanical ventilation with hyperoxia. Wild-type and ASK-1 knockout mice were subjected to hyperoxia (Fi(O(2)) = 0.9) for 12 hours before 4 hours of large tidal mechanical ventilation (tidal volume = 25 μl/g) with hyperoxia, and were compared with nonventilated control mice. Lung injury, apoptosis, and cytokine release were measured. The deletion of ASK-1 significantly inhibited lung injury and apoptosis, but did not affect the release of inflammatory mediators, compared with the wild-type mice. ASK-1 is an important regulator of lung injury and apoptosis in this model. Further study is needed to determine the mechanism of lung injury and apoptosis by ASK-1 and its downstream mediators in the lung.
| S-EPMC3359950 | biostudies-literature
Project description:BackgroundCardiotoxicity is a side effect of the anthracycline broad-spectrum anti-tumor agent, doxorubicin (DOX). Hyperoside, a flavonoid glycoside extracted from many herbs, has anti-apoptotic and anticancer properties. However, its impact on the alleviation of DOX-induced apoptosis in cardiomyocytes remains elusive.MethodsThe HL-1 cell line was treated with 100 µ M hyperoside for 1 h prior to treatment with 100 µ M hyperoside and 1 µ M DOX for 24 h. The cell counting kit-8 (CCK-8) assay was used to detect cell viability; DCFH-DA fluorescent probe was used to detect (reactive oxygen species) ROS; biochemical methods were used to detect the activity of glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), malondialdehyde (MDA); the degree of apoptosis following DOX insult was assessed using immunofluorescence staining and terminal deoxynucleotidyl transferase mediated deoxy uridine triphosphate nick end labeling (TUNEL) assay; the change in protein expression of apoptosis signal-regulating kinase 1 (ASK1), p38, and apoptosis markers was determined using western blot.ResultsHyperoside ameliorated DOX-induced oxidative stress in HL-1 cells, up-regulated GSH, SOD and CAT activity, reduced ROS production and inhibited MDA overproduction. Moreover, in addition to promoting HL-1 cell apoptosis, DOX administration also increased B-cell lymphoma (Bcl)-2-associated X-protein and cleaved caspase-3 protein levels and decreased Bcl-2 protein level. Hyperoside therapy, however, significantly reversed the impact of DOX on the cardiomyocytes. Mechanically, DOX treatment increased the phosphorylation of the ASK1/p38 axis whereas hyperoside treatment attenuated those changes. In a further step, hyperoside synergizes with DOX to kill MDA-MB-231 cells.ConclusionsHyperoside protects HL-1 cells from DOX-induced cardiotoxicity by inhibiting the ASK1/p38 signaling pathway. Meanwhile, hyperoside maintained the cytotoxicity of DOX in MDA-MB-231 cells.
| S-EPMC10200097 | biostudies-literature
Project description:Notch1 genes encode receptors for a signaling pathway that regulates various aspects of cell growth and differentiation; however, the role of Notch1 signaling in p38 mitogen-activated protein kinase (MAPK) signaling pathway is still not well defined. In this study, we found that Notch1 intracellular domain (Notch1-IC) prevents oxidative stress-induced cell death through the suppression of the Apoptosis signal-regulating kinase (ASK) 1 signaling pathway. Notch1-IC inhibited H2O2-induced activation of ASK1 and the activation of downstream kinases in the p38 MAPK signaling cascade. The results of both in vivo binding and kinase studies have revealed that ASK1 is the direct target of Notch1-IC, whereas it produced no effect on either MAP kinase kinase (MKK) 3 or p38 MAPK. Notch1-IC blocked both the homooligomerization of ASK1 and inhibited ASK1 activity. Furthermore, Notch1-IC facilitated the translocation of activated ASK1 toward the nucleus. Notch1 knockdown was determined to be highly susceptible to oxidative stress-induced activation of ASK1-MKK3/MKK6-p38 MAPK signaling cascade and cell death. Taken together, our findings suggest that Notch1-IC may act as a negative regulator in ASK1 signaling cascades.
| S-EPMC3637772 | biostudies-literature
Project description:Pancreatic cancer has an extremely grim prognosis, with an overall 5-year survival rate less than 5%, as a result of its rapid metastasis and late diagnosis. To combat this disease, it is crucial to better understand the molecular mechanisms that contribute to its pathogenesis. Herein, we report that apoptosis signal-regulating kinase 1 (ASK1) is overexpressed in pancreatic cancer tissues and that its expression correlates with the histological grade of pancreatic cancer. The expression of ASK1 is also elevated in pancreatic cancer cell lines at both protein and mRNA levels. In addition, ASK1 promotes the proliferation and stimulates the tumorigenic capacity of pancreatic cancer cells. These functions of ASK1 are abrogated by pharmacological inhibition of its kinase activity or by introduction of a kinase-dead mutation, suggesting that the kinase activity of ASK1 is required for its role in pancreatic cancer. However, the alteration of ASK1 expression or activity does not significantly affect the migration or invasion of pancreatic cancer cells. Collectively, these findings reveal a critical role for ASK1 in the development of pancreatic cancer and have important implications for the diagnosis and treatment of this malignancy.
| S-EPMC5342730 | biostudies-literature
Project description:Apoptosis signal-regulating kinase 1 (ASK1) is a key mediator in the apoptotic and inflammatory cellular stress response. To investigate the therapeutic value of modulating this pathway in neurological disease, we have completed medicinal chemistry studies to identify novel CNS-penetrant ASK1 inhibitors starting from peripherally restricted compounds reported in the literature. This effort led to the discovery of 21, a novel ASK1 inhibitor with good potency (cell IC50 = 138 nM), low clearance (rat Cl/Clu = 0.36/6.7 L h-1 kg-1) and good CNS penetration (rat K p,uu = 0.38).
| S-EPMC7153032 | biostudies-literature
Project description:Apoptosis signal-regulating kinases (ASK1-3) are apical kinases of the p38 and JNK MAP kinase pathways. They are activated by diverse stress stimuli, including reactive oxygen species, cytokines, and osmotic stress; however, a molecular understanding of how ASK proteins are controlled remains obscure. Here, we report a biochemical analysis of the ASK1 kinase domain in conjunction with its N-terminal thioredoxin-binding domain, along with a central regulatory region that links the two. We show that in solution the central regulatory region mediates a compact arrangement of the kinase and thioredoxin-binding domains and the central regulatory region actively primes MKK6, a key ASK1 substrate, for phosphorylation. The crystal structure of the central regulatory region reveals an unusually compact tetratricopeptide repeat (TPR) region capped by a cryptic pleckstrin homology domain. Biochemical assays show that both a conserved surface on the pleckstrin homology domain and an intact TPR region are required for ASK1 activity. We propose a model in which the central regulatory region promotes ASK1 activity via its pleckstrin homology domain but also facilitates ASK1 autoinhibition by bringing the thioredoxin-binding and kinase domains into close proximity. Such an architecture provides a mechanism for control of ASK-type kinases by diverse activators and inhibitors and demonstrates an unexpected level of autoregulatory scaffolding in mammalian stress-activated MAP kinase signaling.
| S-EPMC5358389 | biostudies-literature