• BMB Reports
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• v.35 no.1
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• pp.24-27
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• 2002

Apoptotic cell death is an active process mediated by various signaling pathways, which include the caspase cascade and the stress-activated protein kinase pathways. The caspase cascade is activated by two distinct routes: one from cell surface and the other from mitochondria. Activation of the route from cell surface requires the cellular components that include membrane receptors, adaptor proteins such as TRADD and FADD, and caspase-8, while activation of the other from mitochondria requires Apaf-1, caspase-9, and cytosolic cytochrome c. On the other hand, persistent stimulation of the stress-activated protein kinase pathway is also shown to mediate apoptosis in many cell types. Gene-targeting studies with jnk- or jip-null mice, in particular, strongly suggest that this signaling pathway plays a pivotal role in the cellular machinery for apoptosis.

• The Plant Pathology Journal
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• v.24 no.4
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• pp.375-383
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• 2008

It is well known that NtMEK2, a tobacco MAPK kinase, is the upstream kinase of both salicylic acid-induced protein kinase and wound-induced protein kinase. In addition, expression of $NtMEK2^{DD}$, a constitutively active mutant of NtMEK2, is known to induce multiple defense responses in tobacco. In this study, transgenic rice plants that contained an active or inactive mutant of NtMEK2 under the control of a steroid inducible promoter were generated and used to determine if a similar MAPK cascade is involved in disease resistance in rice. The expression of $NtMEK2^{DD}$ in transgenic rice plants resulted in HR-like cell death. The observed cell death was preceded by the activation of endogenous rice 48-kDa MBP kinase, which is also activated by Xanthomonas oryzae pv. oryzae, the bacterial blight pathogen of rice. In addition, prolonged activation of the MAPK induced the generation of hydrogen peroxide and up-regulated the expression of defense-related genes including the pathogenesis-related genes, peroxidases and glutathione S-transferases. These results demonstrate that NtMEK2 is functionally replaceable with rice MAPK kinase in inducing the activation of the downstream MAPK, which in turn induces multiple defense responses in rice.

• Toxicological Research
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• v.17
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• pp.251-256
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• 2001

The expression of phase II detoxifying enzymes is affected by a variety of compounds and the induction of the enzymes plays an essential role in chemoprevention. A variety of phytochemicals such as sulfur-containing chemoprotective agents (SCC) may trigger cellular signals and activate phase II gene expression through ARE activation. see induces glutathione S-transferases. Studies were conducted to investigate the role of mitogen-activated protein (MAP) kinase and phosphatidylinositol 3-kinase (PI3-kinase) in the induction of GST (e.g. rGSTA2) by sec. We also studied the MAP kinase pathway responsible for the GST expression by see and compared that with the pathway activated by oxidative stress as a result of sulfur amino acids deprivation (SAAD). see inhibited phosphorylation of ERK1/2 although the effect of see on JNK and p38 MAP kinase was minimal. Wortmannin and LY294002. PI3-kinase inhibitors. abolished the increases in rGSTA2 mRNA and protein levels by SCC. Deprivation of cystine and methionine caused oxidative stress in H4IIE cells. as evidenced by a decrease in the reduced glutathione and an increase in prooxidant production. Electrophoretic mobility shift assay revealed that the ARE complex consisting of Nrf-1/2 and Maf proteins was activated 12~48 h. The rGSTA2 mRNA and protein levels were increased by SAAD. Activation of ARE and induction of rGSTA2 were both completely inhibited by PI3-kinase inhibitors. Inhibition of p38 MAP kinase by SB203580 prevented the ARE-mediated rGSTA2 induction. The results of this study showed that PI3-kinase might play an essential role in the ARE-mediated rGSTA2 induction by see or SAAD and that the dual MAP kinase pathways were responsible for the enzyme induction.

• Journal of Plant Biotechnology
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• v.49 no.4
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• pp.300-306
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• 2022

The mitogen-activated protein kinase (MAPK) signaling cascade is essential for a wide range of cellular responses in plants, including defense responses, responses to abiotic stress, hormone signaling, and developmental processes. Recent investigations have shown that the stress, ethylene, and MAPK signaling pathways negatively affect the formation of nitrogen-fixing nodules by directly modulating the symbiotic signaling components. However, the molecular mechanisms underlying the defense responses mediated by MAPK signaling in the organogenesis of nitrogen-fixing nodules remain unclear. In the present study, I demonstrate that the Medicago truncatula mitogen-activated protein kinase kinase 5 (MtMKK5)-Medicago truncatula mitogen-activated protein kinase 3/6 (MtMPK3/6) signaling module, expressed specifically in the symbiotic nodules, promotes defense signaling, but not ethylene signaling pathways, thereby inhibiting nodule development in M. truncatula. U0126 treatment resulted in increased cell division in the nodule meristem zone due to the inhibition of MAPK signaling. The phosphorylated TEY motif in the activation domain of MtMPK3/6 was the target domain associated with specific interactions with MtMKK5. I have confirmed the physical interactions between M. truncatula nodule inception (MtNIN) and MtMPK3/6. In the presence of high expression levels of the defense-related genes FRK1 and WRKY29, MtMKK5a overexpression significantly enhanced the defense responses of Arabidopsis against Pseudomonas syringae pv. tomato DC3000 (Pst DC3000). Overall, my data show that the negative regulation of symbiotic nitrogen-fixing nodule organogenesis by defense signaling pathways is mediated by the MtMKK5-MtMPK3/6 module.

• Microbiology and Biotechnology Letters
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• v.50 no.4
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• pp.441-456
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• 2022

Shiga toxins (Stxs) are major virulence factors from the enterohemorrhagic Escherichia coli (EHEC), a subset of Stx-producing Escherichia coli. Stxs are multi-functional, ribosome-inactivating proteins that underpin the development of hemolytic uremic syndrome (HUS) and central nervous system (CNS) damage. Currently, therapeutic options for the treatment of diseases caused by Stxs are limited and unsatisfactory. Furthermore, the pathophysiological mechanisms underpinning toxin-induced inflammation remain unclear. Numerous works have demonstrated that the various host ribotoxic stress-induced targets including p38 mitogen-activated protein kinase, its downstream substrate Mitogen-activated protein kinase-activated protein kinase 2, and apoptotic signaling via ER-stress sensors are activated in many different susceptible cell types following the regular retrograde transportation of the Stxs, eventually leading to disturbing intercellular communication. Therapeutic options targeting host cellular pathways induced by Stxs may represent a promising strategy for intervention in Stx-mediated acute renal dysfunction, retinal damage, and CNS damage. This review aims at fostering an in-depth understanding of EHEC Stxs-mediated pathogenesis through the toxin-host interactions.

• The Plant Pathology Journal
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• v.35 no.2
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• pp.91-99
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• 2019

Mitogen-activated protein kinase (MAPK) cascades in fungi are ubiquitously conserved signaling pathways that regulate stress responses, vegetative growth, pathogenicity, and many other developmental processes. Previously, we reported that the AbSte7 gene, which encodes a mitogen-activated protein kinase kinase (MAPKK) in Alternaria brassicicola, plays a central role in pathogenicity against host cabbage plants. In this research, we further characterized the role of AbSte7 in the pathogenicity of this fungus using ${\Delta}AbSte7$ mutants. Disruption of the AbSte7 gene of A. brassicicola reduced accumulation of metabolites toxic to the host plant in liquid culture media. The ${\Delta}AbSte7$ mutants could not efficiently detoxify cruciferous phytoalexin brassinin, possibly due to reduced expression of the brassinin hydrolase gene involved in detoxifying brassinin. Disruption of the AbSte7 gene also severely impaired fungal detoxification of reactive oxygen species. AbSte7 gene disruption reduced the enzymatic activity of cell walldegrading enzymes, including cellulase, ${\beta}$-glucosidase, pectin methylesterase, polymethyl-galacturonase, and polygalacturonic acid transeliminase, during host plant infection. Altogether, the data strongly suggest the MAPKK gene AbSte7 plays a pivotal role in A. brassicicola during host infection by regulating multiple steps, and thus increasing pathogenicity and inhibiting host defenses.

• Mycobiology
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• v.47 no.3
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• pp.346-349
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• 2019

AMP-activated protein kinase sucrose non-fermenting 1 (Snf1) is a representative regulator of energy status that maintains cellular energy homeostasis. In addition, Snf1 is involved in the mediation of environmental stress such as salt stress. Snf1 regulates metabolic enzymes such as acetyl-CoA carboxylase, indicating a possible role for Snf1 in metabolic regulation. In this article, we performed nuclear magnetic resonance (NMR) spectroscopy to profile the metabolic changes induced by Snf1 under environmental stress. According to our NMR data, we suggest that Snf1 plays a role in regulating cellular concentrations of a variety of metabolites during environmental stress responses.

• Molecules and Cells
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• v.28 no.5
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• pp.417-422
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• 2009

Mitogen activated protein kinase (MAPK) are known to get activated during various stress signals and transduce the message from the cell membrane to the nucleus for appropriate cellular reorganization. Though, a certain basal activity of MAPK is often observed in the control plants. Prolonged exposure of rice plants to lowered or elevated temperature exhibited a rhythm in the activation of MAPKs. We analyzed existence of a possible endogenous rhythm in the activity of MAPKs in rice plants. The plants growing at constant temperature entrained in 16/8 h day-night cycle showed diurnal rhythm in activity. When the activation of MAPK was tested under continuous conditions by shifting plants to continuous darkness for a period of 72 h, the periodic rhythm persisted and followed a circadian pattern. Analysis of the transcripts of group A, B and C members of MAPKs under above conditions by quantitative real time PCR revealed that the members of group C exhibit periodic rhythm. Our data indicates that the MAP kinase activity in rice follows rhythmic expression in a circadian manner.

• Kidney Research and Clinical Practice
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• v.35 no.2
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• pp.69-77
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• 2016

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease, and its pathogenesis is complex and has not yet been fully elucidated. Abnormal glucose and lipid metabolism is key to understanding the pathogenesis of DN, which can develop in both type 1 and type 2 diabetes. A hallmark of this disease is the accumulation of glucose and lipids in renal cells, resulting in oxidative and endoplasmic reticulum stress, intracellular hypoxia, and inflammation, eventually leading to glomerulosclerosis and interstitial fibrosis. There is a growing body of evidence demonstrating that dysregulation of 50 adenosine monophosphate-activated protein kinase (AMPK), an enzyme that plays a principal role in cell growth and cellular energy homeostasis, in relevant tissues is a key component of the development of metabolic syndrome and type 2 diabetes mellitus; thus, targeting this enzyme may ameliorate some pathologic features of this disease. AMPK regulates the coordination of anabolic processes, with its activation proven to improve glucose and lipid homeostasis in insulin-resistant animal models, as well as demonstrating mitochondrial biogenesis and antitumor activity. In this review, we discuss new findings regarding the role of AMPK in the pathogenesis of DN and offer suggestions for feasible clinical use and future studies of the role of AMPK activators in this disorder.

• Biomedical Science Letters
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• v.9 no.2
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• pp.59-65
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• 2003

When cells are exposed to proteotoxic stresses such as heat shock, amino acid analogs, and heavy metals, they increase the synthesis of the heat shock proteins (HSPs) by activating the heat shock transcription factor 1 (HSF1), whose activity is controlled via multiple steps including homotrimerization, nuclear translocation, DNA binding, and hyperphosphorylation. Under unstressed conditions, the HSF1 activity is repressed through its constitutive phosphorylation by glycogen synthase kinase 3$\beta$ (GSK3$\beta$), extracellular regulated kinase 1/2 (ERK1/2), and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK). However, the protein kinase (s) responsible for HSF1 hyperphosphorylation and activation is not yet identified. In the present study, we observed that profile of p38 mitogen-activated protein kinase (p38MAPK) activation in response to heat shock was very similar to those of HSF1 hyperphosphorylation and nuclear translocation. Therefore, we investigated whether p38MAPK is involved in the heat shock-induced HSF1 activation and HSP expression. Here we show that the p38MAPK inhibitors, SB202190 and SB203580, but not other inhibitors including the MEK1/2 inhibitor PD98059 and the PI3-K inhibitor LY294002 and wortmannin, suppress HSF1 hyperphosphorylation in response to heat shock and L-azetidine 2-carboxylic acid (Azc), but not to heavy metals. Furthermore, heat shock-induced HSF1-DNA binding and HSP72 expression was specifically prevented by the p38MAPK inhibitors, but not by the MEK1/2 inhibitor and the PI3-K inhibitors. These results suggest that SB202190- and SB203580-sensitive p38MAPK may positively regulate HSP gene regulation in response to heat shock and amino acid analogs.