The mitogen-activated protein kinase p38 regulates activator protein 1 by direct phosphorylation of c-Jun

Humar, Matjaž; Loop, Torsten; Schmidt, René; Hoetzel, Alexander; Roesslein, Martin; Andriopoulos, Nikolaos; Pahl, Heike L.; Geiger, K.; Pannen, Benedikt H. J.

doi:10.1016/j.biocel.2007.06.013

Cited by 49 publications

(36 citation statements)

References 34 publications

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“…Based on in vivo experiments, DL0410 increased CREB activity in the brains of Aβ 1-42 -treated mice. Studies have confirmed that the activation of CREB is positively regulated through Akt [48][49][50][51][52] . Akt plays important roles in preventing cell apoptosis [53] .…”

Section: Discussionmentioning

confidence: 81%

DL0410, a novel dual cholinesterase inhibitor, protects mouse brains against Aβ-induced neuronal damage via the Akt/JNK signaling pathway

et al. 2016

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Aim: 1,1′-([1,1′-Biphenyl]-4,4′-diyl)bis(3-(piperidin-1-yl)propan-1-one)dihydrochloride (DL0410) is a novel synthetic dual acetylcholinesterase (AChE)/butyrocholinesterase (BuChE) inhibitor, which has shown a potential therapeutic effect on Alzheimer's disease (AD). In this study we examined whether DL0410 produced neuroprotective effects in an AD cellular model and an Aβ 1-42 -induced amnesia mouse model. Methods: The in vitro inhibitory activities against AChE and BuChE were estimated using Ellman's assay. Copper-induced toxicity in APPsw-SY5Y cells was used as AD cellular model, the cell viability was assessed using MTS assay, and cell apoptosis was evaluated based on mitochondrial membrane potential detection. Aβ 1-42 -induced amnesia mouse model was made in male mice by injecting aggregated Aβ 1-42 (2 μg in 2 μL 0.1% DMSO) into the right cerebral ventricle. Before and after Aβ 1-42 injection, the mice were orally administered DL0410 (1, 3, 9 mg·kg -1 ·d -1 ) or rivastigmine (2 mg·kg -1 ·d -1 ) for 3 and 11 d, respectively. Memory impairments were examined using Morris water maze (MWM) test and passive avoidance test. The expression levels of APP, CREB, BDNF, JNK and Akt in the mouse brains were measured with either immunohistochemistry or Western blotting. Results: DL0410 exhibited in vitro inhibitory abilities against AChE and BuChE with IC 50 values of 0.286±0.004 and 3.962±0.099 μmol/L, respectively, which were comparable to those of donepezil and rivastigmine. In APPsw-SY5Y cells, pretreatment with DL0410 (1, 3, and 10 μmol/L) decreased the phosphorylation of JNK and increased the phosphorylation of Akt, markedly decreased copperstimulated Aβ 1-42 production, reversed the loss of mitochondrial membrane potential, and dose-dependently increased the cell viability. In Aβ 1-42 -treated mice, DL0410 administration significantly ameliorated learning and memory deficits in MWM test and passive avoidance test. Furthermore, DL0410 administration markedly decreased Aβ 1-40/42 deposits in mouse cerebral cortices, and significantly up-regulated neurotrophic CREB/BDNF. Meanwhile, Akt/JNK signaling pathway may play a key role in the neuroprotective effect of DL0410. Conclusion: DL0410 ameliorates cognitive deficit and exerts neuronal protection in AD models, implicating this compound as a candidate drug for the prevention and therapy of AD.

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Section: Discussionmentioning

confidence: 81%

DL0410, a novel dual cholinesterase inhibitor, protects mouse brains against Aβ-induced neuronal damage via the Akt/JNK signaling pathway

et al. 2016

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“…Activation of p38 MAPK directs transcriptional regulation in part through activation of AP-1 transcription factor family members, including FosB, ATF-2, JunB, and c-Jun (Kumar et al, 1997;Shaulian and Karin, 2001;Humar et al, 2007). Indeed, in MMNK-1 cells stimulated with TGF-␤1, AP-1-dependent luciferase activity was increased (Fig.…”

Section: Resultsmentioning

confidence: 96%

Regulation of Transforming Growth Factor-β1-Dependent Integrin β6 Expression by p38 Mitogen-Activated Protein Kinase in Bile Duct Epithelial Cells

Sullivan

Kassel

Manley

et al. 2011

J Pharmacol Exp Ther

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Bile duct epithelial cells (BDECs) contribute to liver fibrosis by expressing ␣V␤6 integrin, a critical activator of latent transforming growth factor ␤ (TGF-␤). ␤6 integrin (Itg␤6) mRNA induction and ␣V␤6 integrin expression in BDECs are partially TGF-␤-dependent. However, the signaling pathways required for TGF-␤-dependent Itg␤6 mRNA induction in BDECs are not known. We tested the hypothesis that the p38 mitogen-activated protein kinase (MAPK) signaling pathway contributes to TGF-␤1 induction of Itg␤6 mRNA by activating SMAD and activator protein 1 (AP-1) transcription factors. Pretreatment of transformed human BDECs (MMNK-1 cells) with two different p38 MAPK inhibitors, but not a control compound, inhibited TGF-␤1 induction of Itg␤6 mRNA. Inhibition of p38 also reduced TGF-␤1 activation of a SMAD-dependent reporter construct. Expression of a dominant-negative SMAD3 (SMAD3⌬C) significantly reduced TGF-␤1-induced Itg␤6 mRNA expression. Expression of JunB mRNA, but not other AP-1 proteins, increased in TGF-␤1-treated MMNK-1 cells, and induction of JunB expression was p38-dependent. Consistent with a requirement for de novo induction of JunB protein, cycloheximide pretreatment inhibited TGF-␤1 induction of Itg␤6 mRNA. Expression of a dominant-negative AP-1 mutant (TAM67) also inhibited TGF-␤1 induction of Itg␤6 mRNA. Overall, the results suggest that p38 contributes to TGF-␤1-induced Itg␤6 mRNA expression in MMNK-1 cells by regulating activation of both SMAD and AP-1 transcription factors.

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“…Interestingly, studies on the transcriptional regulation of another cholesterol transport protein, PBR/TSPO (which is believed to work in concert with StAR (Miller 2007), have also identified an AP-1 binding site in its proximal promoter region (Giatzakis et al 2007). Given the oxidant-sensitive nature of AP-1 (Dalton et al 1999, Klaunig & Kamendulis 2004, involvement of stress-activated kinases, the MAPKs, in the regulation of AP-1 , Pramanik et al 2003, Tanos et al 2005, Humar et al 2007, Whitmarsh 2007) and the fact that functional expression of AP-1 is substantially reduced (Medicherla et al 2001), while p38 MAPK is specifically activated in intact rat adrenal glands (Abidi et al 2008) and Leydig cells (unpublished observations) during aging, it seems likely that oxidant stressors acting on p38 MAPK and AP-1 contribute to the age-related decline in StAR (and PBR/TSPO) expression and subsequently loss of steroidogenic function.…”

Section: Introductionmentioning

confidence: 99%

Oxidative stress-induced inhibition of adrenal steroidogenesis requires participation of p38 mitogen-activated protein kinase signaling pathway

Abidi

Zhang²,

Zaidi³

et al. 2008

Journal of Endocrinology

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Previous studies from this laboratory identified excessive oxidative stress as an important mediator of age-related decline in steroid hormone production. Here, we investigated whether oxidative stress exerts its antisteroidogenic action through modulation of oxidant-sensitive mitogen-activated protein kinase (MAPK) signaling pathways. To accomplish these studies, we employed a highly responsive mouse adrenocortical cell line, Y1-BS1 cells that secrete large quantities of steroids when stimulated with lipoprotein plus hormone. Treatment of these cells with superoxide, H 2 O 2 or 4-hydroxy-2-nonenal (HNE) significantly inhibited steroid production and increased phosphorylation and activation of p38 MAPK. None of the treatments altered the phosphorylation of either extracellular signal-regulated kinases or c-Jun N-terminal kinases (JNKs). Pretreatment of Y1-BS1 cells with MnTMPyP, a cell-permeable superoxide-dismutase/ catalase mimetic reactive oxygen species (ROS scavenger), completely prevented the superoxide-and H 2 O 2 -mediated inhibition of steroid production. Likewise, antioxidant N-acetylcysteine completely blocked the HNE-induced loss of steroidogenic response. Incubation of Y1-BS1 cells with either MnTMPyP or NAC also upregulated Bt 2 cAMP and Bt 2 cAMPChHDL 3 -stimulated steroid synthesis, indicating that endogenously produced ROS can inhibit steroidogenesis. Inhibition of p38 MAPK with SB203580 or SB202190 upregulated the basal steroid production and also prevented the oxidant-mediated inhibition of steroid production. mRNA measurements by qPCR indicated that Y1-BS1 adrenal cells predominantly express p38 MAPKa isoform, along with relatively low-level expression of p38 MAPKg. By contrast, little or no expression was detected for p38 MAPKb and p38 MAPKd isoforms in these cells. Transfection of Y1-BS1 cells with either caMKK3 or caMMK6 construct, the upstream p38 MAPK activators, decreased steroidogenesis, whereas transfection with dnMKK3 or dnMKK6 plasmid DNA increased steroidogenesis. Similarly, transfection of cells with a dnp38 MAPKa or dnp38 MAPKb construct also increased steroid hormone production; however, the effect was less pronounced after expression of either dnp38 MAPKg or dnp38 MAPKd construct. These results indicate that activated p38 MAPK mediates oxidant (excessive oxidative stress)-induced inhibition of adrenal steroidogenesis.

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The mitogen-activated protein kinase p38 regulates activator protein 1 by direct phosphorylation of c-Jun

Cited by 49 publications

References 34 publications

DL0410, a novel dual cholinesterase inhibitor, protects mouse brains against Aβ-induced neuronal damage via the Akt/JNK signaling pathway

DL0410, a novel dual cholinesterase inhibitor, protects mouse brains against Aβ-induced neuronal damage via the Akt/JNK signaling pathway

Regulation of Transforming Growth Factor-β1-Dependent Integrin β6 Expression by p38 Mitogen-Activated Protein Kinase in Bile Duct Epithelial Cells

Oxidative stress-induced inhibition of adrenal steroidogenesis requires participation of p38 mitogen-activated protein kinase signaling pathway

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