13 results on '"Kengo Nakahara"'
Search Results
2. The Emerging Role of Electrophiles as a Key Regulator for Endoplasmic Reticulum (ER) Stress
- Author
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Nobumasa Takasugi, Hideki Hiraoka, Kengo Nakahara, Shiori Akiyama, Kana Fujikawa, Ryosuke Nomura, Moeka Furuichi, and Takashi Uehara
- Subjects
reactive electrophiles ,ER stress ,UPR ,nitric oxide ,4-hydroxynonenal ,methylmercury ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
The unfolded protein response (UPR) is activated by the accumulation of misfolded proteins in the endoplasmic reticulum (ER), which is called ER stress. ER stress sensors PERK, IRE1, and ATF6 play a central role in the initiation and regulation of the UPR; they inhibit novel protein synthesis and upregulate ER chaperones, such as protein disulfide isomerase, to remove unfolded proteins. However, when recovery from ER stress is difficult, the UPR pathway is activated to eliminate unhealthy cells. This signaling transition is the key event of many human diseases. However, the precise mechanisms are largely unknown. Intriguingly, reactive electrophilic species (RES), which exist in the environment or are produced through cellular metabolism, have been identified as a key player of this transition. In this review, we focused on the function of representative RES: nitric oxide (NO) as a gaseous RES, 4-hydroxynonenal (HNE) as a lipid RES, and methylmercury (MeHg) as an environmental organic compound RES, to outline the relationship between ER stress and RES. Modulation by RES might be a target for the development of next-generation therapy for ER stress-associated diseases.
- Published
- 2019
- Full Text
- View/download PDF
3. S-Nitrosylation at the active site decreases the ubiquitin-conjugating activity of ubiquitin-conjugating enzyme E2 D1 (UBE2D1), an ERAD-associated protein
- Author
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Koji Uchida, Kengo Nakahara, Kana Fujikawa, Takashi Uehara, Akihiro Ito, Tadashi Nishiya, and Nobumasa Takasugi
- Subjects
Ubiquitin proteasome system ,0301 basic medicine ,Protein Folding ,Leupeptins ,Endoplasmic Reticulum ,Biochemistry ,Ubiquitin-conjugating enzyme E2 ,0302 clinical medicine ,Ubiquitin ,Catalytic Domain ,Phosphorylation ,Protein disulfide-isomerase ,biology ,Chemistry ,Endoplasmic Reticulum-Associated Degradation ,Endoplasmic Reticulum Stress ,Cell biology ,Endoplasmic reticulum (ER) stress ,Nitrosative Stress ,030220 oncology & carcinogenesis ,Oxidation-Reduction ,Nitroso Compounds ,Proteasome Endopeptidase Complex ,Morpholines ,Ubiquitin-Protein Ligases ,Biophysics ,Protein Serine-Threonine Kinases ,Endoplasmic-reticulum-associated protein degradation ,Immediate-Early Proteins ,Redox ,03 medical and health sciences ,Autophagy ,Humans ,Protein kinase A ,Molecular Biology ,Endoplasmic reticulum ,Ubiquitination ,Nitric oxide ,Cell Biology ,S-Nitrosylation ,HEK293 Cells ,030104 developmental biology ,Chromones ,Ubiquitin-Conjugating Enzymes ,ER-Associated degradation ,Unfolded protein response ,biology.protein ,SGK1 ,Protein Processing, Post-Translational - Abstract
S-Nitrosylation of protein cysteine thiol is a post-translational modification mediated by nitric oxide (NO). The overproduction of NO causes nitrosative stress, which is known to induce endoplasmic reticulum (ER) stress. We previously reported that S-nitrosylation of protein disulfide isomerase (PDI) and the ER stress sensor inositol-requiring enzyme 1 (IRE1) decreases their enzymatic activities. However, it remains unclear whether nitrosative stress affects ER-associated degradation (ERAD), a separate ER stress regulatory system responsible for the degradation of substrates via the ubiquitin-proteasomal pathway. In the present study, we found that the ubiquitination of a known ERAD substrate, serine/threonine-protein kinase 1 (SGK1), is attenuated by nitrosative stress. C-terminus of Hsc70-interacting protein (CHIP) together with ubiquitin-conjugating enzyme E2 D1 (UBE2D1) are involved in this modification. We detected that UBE2D1 is S-nitrosylated at its active site, Cys85 by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Furthermore, in vitro and cell-based experiments revealed that S-nitrosylated UBE2D1 has decreased ubiquitin-conjugating activity. Our results suggested that nitrosative stress interferes with ERAD, leading to prolongation of ER stress by co-disruption of various pathways, including the molecular chaperone and ER stress sensor pathways. Given that nitrosative stress and ER stress are upregulated in the brains of patient with Parkinson’s disease (PD) and of those with Alzheimer’s disease (AD), our findings may provide further insights into the pathogenesis of these neurodegenerative disorders.
- Published
- 2020
4. Regulation of Gene Expression via Protein Oxidation
- Author
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Yuta Iijima, Tohta Mizushima, Kengo Nakahara, Nobumasa Takasugi, Yosuke Matsushita, Toyomasa Katagiri, and Takashi Uehara
- Subjects
Applied Mathematics ,General Mathematics - Published
- 2022
5. Molecular mechanism of Akt signaling evoked by 1, 2-naphthoquinone
- Author
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Takashi Uehara, Kengo Nakahara, Hideki Hiraoka, Kyohei Hamada, and Yoshito Kumagai
- Subjects
chemistry.chemical_compound ,chemistry ,Applied Mathematics ,General Mathematics ,Molecular mechanism ,1,2-Naphthoquinone ,Protein kinase B ,Cell biology - Published
- 2018
6. Modulation of unfolded protein response by methylmercury (MeHg)
- Author
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Hideki Hiraoka, Takashi Uehara, Kosaku Okuda, Kengo Nakahara, and Yoshito Kumagai
- Subjects
chemistry.chemical_compound ,Chemistry ,Modulation ,Applied Mathematics ,General Mathematics ,Unfolded protein response ,Biophysics ,Methylmercury - Published
- 2018
7. Modulation of Unfolded Protein Response by Methylmercury
- Author
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Yoshito Kumagai, Takashi Uehara, Shiori Akiyama, Kengo Nakahara, Yuki Kaneko, Kosaku Okuda, Masatake Fujimura, Nobumasa Takasugi, Takao Iwawaki, and Hideki Hiraoka
- Subjects
X-Box Binding Protein 1 ,0301 basic medicine ,XBP1 ,Pharmaceutical Science ,Mice ,eIF-2 Kinase ,03 medical and health sciences ,Animals ,Protein kinase A ,Protein disulfide-isomerase ,Cell Nucleus ,Pharmacology ,Cell Death ,Kinase ,Chemistry ,ATF6 ,Binding protein ,Endoplasmic reticulum ,Protein Disulfide Reductase (Glutathione) ,General Medicine ,Methylmercury Compounds ,Endoplasmic Reticulum Stress ,Activating Transcription Factor 6 ,Cell biology ,030104 developmental biology ,Unfolded Protein Response ,Unfolded protein response - Abstract
Methylmercury (MeHg) results in cell death through endoplasmic reticulum (ER) stress. Previously, we reported that MeHg induces S-mercuration at cysteine 383 or 386 in protein disulfide isomerase (PDI), and this modification induces the loss of enzymatic activity. Because PDI is a key enzyme for the maturation of nascent protein harboring a disulfide bond, the disruption in PDI function by MeHg results in ER stress via the accumulation of misfolded proteins. However, the effects of MeHg on unfolded protein response (UPR) sensors and their signaling remain unclear. In the present study, we show that UPR is regulated by MeHg. We found that MeHg specifically attenuated inositol-requiring enzyme 1α (IRE1α)–x-box binding protein 1 (XBP1) branch, but not the protein kinase RNA-like endoplasmic reticulum kinase (PERK) and activating transcriptional factor 6 (ATF6) branches. Treatment with GSK2606414, a specific PERK inhibitor, significantly inhibited MeHg-induced cell death. These findings suggest that MeHg exquisitely regulates UPR signaling involved in cell death.
- Published
- 2017
8. Attenuation of Macrophage Migration Inhibitory Factor-Stimulated Signaling via S-Nitrosylation
- Author
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Kengo, Nakahara, Kana, Fujikawa, Hideki, Hiraoka, Ikuko, Miyazaki, Masato, Asanuma, Akihiro, Ito, Nobumasa, Takasugi, and Takashi, Uehara
- Subjects
Mice ,HEK293 Cells ,S-Nitrosothiols ,src-Family Kinases ,Cell Line, Tumor ,Animals ,Humans ,Nitric Oxide Donors ,Cysteine ,Macrophage Migration-Inhibitory Factors ,p38 Mitogen-Activated Protein Kinases ,Signal Transduction - Abstract
Nitric oxide (NO) is a key signaling molecule that has various effects via S-nitrosylation, a reversible post-translational modification that affects the enzymatic activity, localization, and metabolism of target proteins. As chronic nitrosative stress correlates with neurodegeneration, the targets have received focused attention. Macrophage migration inhibitory factor (MIF) plays a pivotal role in the induction of gene expression to control inflammatory responses. MIF acts as a ligand for CD74 receptor and activates the Src-p38 mitogen-activated protein kinase (MAPK) cascade. MIF also elevates the expression of brain-derived neurotrophic factor (BDNF), which contributes to the viability of neurons. Here, we show that MIF is S-nitrosylated by a physiological NO donor. Interestingly, the induction of S-nitrosylation resulted in a loss of MIF activity following stimulation of the Src and p38 MAPK signaling pathways and the induction of BDNF expression. Our results shed light on the pathogenic mechanisms of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease.
- Published
- 2019
9. The Emerging Role of Electrophiles as a Key Regulator for Endoplasmic Reticulum (ER) Stress
- Author
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Hideki Hiraoka, Kana Fujikawa, Takashi Uehara, Shiori Akiyama, Ryosuke Nomura, Kengo Nakahara, Moeka Furuichi, and Nobumasa Takasugi
- Subjects
Regulator ,Review ,UPR ,Endoplasmic Reticulum ,Catalysis ,4-Hydroxynonenal ,Inorganic Chemistry ,lcsh:Chemistry ,chemistry.chemical_compound ,Downregulation and upregulation ,nitric oxide ,Animals ,Humans ,Physical and Theoretical Chemistry ,Protein disulfide-isomerase ,Molecular Biology ,lcsh:QH301-705.5 ,Spectroscopy ,reactive electrophiles ,ATF6 ,Endoplasmic reticulum ,Organic Chemistry ,methylmercury ,General Medicine ,Endoplasmic Reticulum Stress ,4-hydroxynonenal ,Computer Science Applications ,Cell biology ,chemistry ,lcsh:Biology (General) ,lcsh:QD1-999 ,Protein Biosynthesis ,Unfolded protein response ,Unfolded Protein Response ,Protein folding ,ER stress ,Molecular Chaperones ,Signal Transduction - Abstract
The unfolded protein response (UPR) is activated by the accumulation of misfolded proteins in the endoplasmic reticulum (ER), which is called ER stress. ER stress sensors PERK, IRE1, and ATF6 play a central role in the initiation and regulation of the UPR; they inhibit novel protein synthesis and upregulate ER chaperones, such as protein disulfide isomerase, to remove unfolded proteins. However, when recovery from ER stress is difficult, the UPR pathway is activated to eliminate unhealthy cells. This signaling transition is the key event of many human diseases. However, the precise mechanisms are largely unknown. Intriguingly, reactive electrophilic species (RES), which exist in the environment or are produced through cellular metabolism, have been identified as a key player of this transition. In this review, we focused on the function of representative RES: nitric oxide (NO) as a gaseous RES, 4-hydroxynonenal (HNE) as a lipid RES, and methylmercury (MeHg) as an environmental organic compound RES, to outline the relationship between ER stress and RES. Modulation by RES might be a target for the development of next-generation therapy for ER stress-associated diseases.
- Published
- 2019
10. 1,2-Naphthoquinone functions as an activator of the EGF receptor via covalent modification of a specific lysine residue
- Author
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Kengo Nakahara, Yumi Abiko, Tomoki Tsuchida, Yoshito Kumagai, and Takashi Uehara
- Subjects
chemistry.chemical_compound ,chemistry ,Activator (genetics) ,Stereochemistry ,Applied Mathematics ,General Mathematics ,Covalent modification ,1,2-Naphthoquinone ,Receptor ,Lysine residue - Published
- 2021
11. Harmonics Compensation in High Frequency Range of Active Power Filter with SiC-MOSFET Inverter in Digital Control System
- Author
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Mineo Tuji, Shin-ichi Hamasaki, and Kengo Nakahara
- Subjects
Active power filter ,Computer science ,Control theory ,Harmonics ,020208 electrical & electronic engineering ,MOSFET ,0202 electrical engineering, electronic engineering, information engineering ,Range (statistics) ,Inverter ,Digital control ,02 engineering and technology ,Repetitive control ,Compensation (engineering) - Abstract
Compensation of harmonics in high frequency range by active power filter (APF) using SiC-MOSFET inverter is investigated. A new control method of APF controlled by deadbeat control and repetitive control is proposed. Aiming at frequency, the sampling time is further shortened and increasing the switching frequency is designed in the digital control system. The control of harmonics compensation is realized by the repetitive control, which is adapted for high frequency harmonics by using periodicity. And the current regulator for the output current of the APF is realized by the deadbeat control, which can regulate the output current accurately without delay. SiC-MOSFET inverter is applied to the APF to obtain high frequency switching. Performance of the harmonics compensation by the proposed method is investigated in experiment and excellent compensation is performed in the range to 30th order (1.8kHz) harmonics. A theoretical analysis, simulation results and experimental results using SiC-MOSFET inverter are presented.
- Published
- 2018
12. Covalent N-arylation by the pollutant 1,2-naphthoquinone activates the EGF receptor.
- Author
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Kengo Nakahara, Kyohei Hamada, Tomoki Tsuchida, Nobumasa Takasugi, Yumi Abiko, Kazuhiko Shien, Shinichi Toyooka, Yoshito Kumagai, and Takashi Uehara
- Subjects
- *
EPIDERMAL growth factor receptors , *POLLUTANTS , *PARTICULATE matter , *PROTEIN-tyrosine kinases , *AIR pollutants - Abstract
The epidermal growth factor receptor (EGFR) is the most intensively investigated receptor tyrosine kinase. Several EGFR mutations and modifications have been shown to lead to abnormal self-activation, which plays a critical role in carcinogenesis. Environmental air pollutants, which are associated with cancer and respiratory diseases, can also activate EGFR. Specifically, the environmental electrophile 1,2-naphthoquinone (1,2-NQ), a component of diesel exhaust particles and particulate matter more generally, has previously been shown to impact EGFR signaling. However, the detailed mechanism of 1,2-NQ function is unknown. Here, we demonstrate that 1,2-NQ is a novel chemical activator of EGFR but not other EGFR family proteins. We found that 1,2-NQ forms a covalent bond, in a reaction referred to as N-arylation, with Lys80, which is in the ligand-binding domain. This modification activates the EGFR-Akt signaling pathway, which inhibits serum deprivation-induced cell death in a human lung adenocarcinoma cell line. Our study reveals a novel mode of EGFR pathway activation and suggests a link between abnormal EGFR activation and environmental pollutant-associated diseases such as cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
13. Molecular Mechanism of PI 3-Kinase-Akt Signaling Stimulated by 1,2-Naphthoquinone (NQ)
- Author
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Takashi Uehara, Hideki Hiraoka, Kyohei Hamada, Yoshito Kumagai, and Kengo Nakahara
- Subjects
A549 cell ,biology ,Chemistry ,Cell growth ,Oxidative phosphorylation ,Protein oxidation ,Biochemistry ,Receptor tyrosine kinase ,Cell biology ,Physiology (medical) ,biology.protein ,Cytotoxic T cell ,Phosphorylation ,Protein kinase B - Abstract
The redox-mediated chemical modification occurs via oxidative reaction between electrophile and cysteine thiol in the presence of an electron acceptor. It is widely recognized that long exposure to or high concentration of 1,2-NQ, an electrophile in cigarette ingredients/smoke or metabolite of naphthalene, results in cytotoxic effects. Whereas, low concentrations of 1,2-NQ specifically stimulates Akt signaling involving cell proliferation and anti-apoptosis possibly via protein oxidation. In the present study, we attempted to identify the target protein of 1,2-NQ and to clarify the protective role of 1,2-NQ on apoptotic cell death. The levels of phosphorylated Akt were increased in 1,2-NQ-treated cells in a concentration- and time-dependent manner in human lung adenocarcinoma A549 cells. This phosphorylation induced by 1,2-NQ was sensitive to PI 3-kinase and PDK1 inhibitors. Then, we found that 1,2-NQ triggers phosphorylation of tyrosine kinase receptor. Akt activation contributes to protect the apoptotic cell death of A549 cells induced by serum deprivation possibly via Bad phosphorylation. Our findings show that treatment with appropriate amount of 1,2-NQ leads to anti-apoptotic action through PI 3-kinase–Akt signaling.
- Published
- 2016
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