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Your search keyword '"Uehara, Takashi"' showing total 496 results
Start Over Author "Uehara, Takashi" Publication Type Academic Journals
496 results on '"Uehara, Takashi"'

3. Pivotal role for S-nitrosylation of DNA methyltransferase 3B in epigenetic regulation of tumorigenesis

Author

Okuda, Kosaku, Nakahara, Kengo, Ito, Akihiro, Iijima, Yuta, Nomura, Ryosuke, Kumar, Ashutosh, Fujikawa, Kana, Adachi, Kazuya, Shimada, Yuki, Fujio, Satoshi, Yamamoto, Reina, Takasugi, Nobumasa, Onuma, Kunishige, Osaki, Mitsuhiko, Okada, Futoshi, Ukegawa, Taichi, Takeuchi, Yasuo, Yasui, Norihisa, Yamashita, Atsuko, Marusawa, Hiroyuki, Matsushita, Yosuke, Katagiri, Toyomasa, Shibata, Takahiro, Uchida, Koji, Niu, Sheng-Yong, Lang, Nhi B, Nakamura, Tomohiro, Zhang, Kam YJ, Lipton, Stuart A, and Uehara, Takashi

Subjects
Biological Sciences, Medicinal and Biomolecular Chemistry, Chemical Sciences, Cancer, Genetics, Prevention, Rare Diseases, 2.1 Biological and endogenous factors, Animals, Humans, Mice, Cell Transformation, Neoplastic, DNA (Cytosine-5-)-Methyltransferase 1, DNA (Cytosine-5-)-Methyltransferases, DNA Methylation, DNA Modification Methylases, Epigenesis, Genetic, DNA Methyltransferase 3B
Abstract

DNA methyltransferases (DNMTs) catalyze methylation at the C5 position of cytosine with S-adenosyl-L-methionine. Methylation regulates gene expression, serving a variety of physiological and pathophysiological roles. The chemical mechanisms regulating DNMT enzymatic activity, however, are not fully elucidated. Here, we show that protein S-nitrosylation of a cysteine residue in DNMT3B attenuates DNMT3B enzymatic activity and consequent aberrant upregulation of gene expression. These genes include Cyclin D2 (Ccnd2), which is required for neoplastic cell proliferation in some tumor types. In cell-based and in vivo cancer models, only DNMT3B enzymatic activity, and not DNMT1 or DNMT3A, affects Ccnd2 expression. Using structure-based virtual screening, we discovered chemical compounds that specifically inhibit S-nitrosylation without directly affecting DNMT3B enzymatic activity. The lead compound, designated DBIC, inhibits S-nitrosylation of DNMT3B at low concentrations (IC50 ≤ 100 nM). Treatment with DBIC prevents nitric oxide (NO)-induced conversion of human colonic adenoma to adenocarcinoma in vitro. Additionally, in vivo treatment with DBIC strongly attenuates tumor development in a mouse model of carcinogenesis triggered by inflammation-induced generation of NO. Our results demonstrate that de novo DNA methylation mediated by DNMT3B is regulated by NO, and DBIC protects against tumor formation by preventing aberrant S-nitrosylation of DNMT3B.

Published
2023

8. Epigenetic Regulation of CXC Chemokine Expression by Environmental Electrophiles Through DNA Methyltransferase Inhibition.

Author

Tsuchida, Tomoki, Kubota, Sho, Kamiuezono, Shizuki, Takasugi, Nobumasa, Ito, Akihiro, Kumagai, Yoshito, and Uehara, Takashi

Subjects
CANCER cell growth, DNA demethylation, DNA methylation, GENE expression, DEOXYRIBOZYMES
Abstract

Ubiquitously distributed environmental electrophiles covalently modify DNA and proteins, potentially leading to adverse health effects. However, the impacts of specific electrophiles on target proteins and their physiological roles remain largely unknown. In the present study, we focused on DNA methylation, which regulates gene expression and physiological responses. A total of 45 environmental electrophiles were screened for inhibitory effects on the activity of DNA methyltransferase 3B (DNMT3B), a key enzyme in DNA methylation, and four compounds were identified. We focused on 1,2-naphthoquinone (1,2-NQ), an air pollutant whose toxicity has been reported previously. Interestingly, we found that 1,2-NQ modified multiple lysine and histidine residues in DNMT3B, one of which was near the active site in DNMT3B. It was found that 1,2-NQ altered gene expression and evoked inflammatory responses in lung adenocarcinoma cell lines. Furthermore, we found that 1,2-NQ upregulated CXCL8 expression through DNA demethylation of the distal enhancer and promoted cancer cell growth. Our study reveals novel mechanisms of epigenetic regulation by environmental electrophiles through the inhibition of DNMT3B activity and suggests their physiological impact. [ABSTRACT FROM AUTHOR]

Published
2024
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41. The Pursuit of the "Inside" of the Amyloid Hypothesis—Is C99 a Promising Therapeutic Target for Alzheimer's Disease?

Author

Takasugi, Nobumasa, Komai, Masato, Kaneshiro, Nanaka, Ikeda, Atsuya, Kamikubo, Yuji, and Uehara, Takashi

Subjects
ALZHEIMER'S disease, PROTEIN precursors, MEMBRANE proteins, DRUG discovery, PEPTIDES, AMYLOID beta-protein
Abstract

Aducanumab, co-developed by Eisai (Japan) and Biogen (U.S.), has received Food and Drug Administration approval for treating Alzheimer's disease (AD). In addition, its successor antibody, lecanemab, has been approved. These antibodies target the aggregated form of the small peptide, amyloid-β (Aβ), which accumulates in the patient brain. The "amyloid hypothesis" based therapy that places the aggregation and toxicity of Aβ at the center of the etiology is about to be realized. However, the effects of immunotherapy are still limited, suggesting the need to reconsider this hypothesis. Aβ is produced from a type-I transmembrane protein, Aβ precursor protein (APP). One of the APP metabolites, the 99-amino acids C-terminal fragment (C99, also called βCTF), is a direct precursor of Aβ and accumulates in the AD patient's brain to demonstrate toxicity independent of Aβ. Conventional drug discovery strategies have focused on Aβ toxicity on the "outside" of the neuron, but C99 accumulation might explain the toxicity on the "inside" of the neuron, which was overlooked in the hypothesis. Furthermore, the common region of C99 and Aβ is a promising target for multifunctional AD drugs. This review aimed to outline the nature, metabolism, and impact of C99 on AD pathogenesis and discuss whether it could be a therapeutic target complementing the amyloid hypothesis. [ABSTRACT FROM AUTHOR]

Published
2023
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44. Alterations in UPR Signaling by Methylmercury Trigger Neuronal Cell Death in the Mouse Brain.

Author

Nomura, Ryosuke, Takasugi, Nobumasa, Hiraoka, Hideki, Iijima, Yuta, Iwawaki, Takao, Kumagai, Yoshito, Fujimura, Masatake, and Uehara, Takashi

Subjects
CELL death, BRAIN death, UNFOLDED protein response, METHYLMERCURY, SOMATOSENSORY cortex, ENDOPLASMIC reticulum
Abstract

Methylmercury (MeHg), an environmental toxicant, induces neuronal cell death and injures specific areas of the brain. MeHg is known to induce oxidative and endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) pathway has a dual nature in that it regulates and protects cells from an overload of improperly folded proteins in the ER, whereas excessively stressed cells are eliminated by apoptosis. Oxidative stress/ER stress induced by methylmercury exposure may tilt the UPR toward apoptosis, but there is little in vivo evidence of a direct link to actual neuronal cell death. Here, by using the ER stress-activated indicator (ERAI) system, we investigated the time course signaling alterations of UPR in vivo in the most affected areas, the somatosensory cortex and striatum. In the ERAI-Venus transgenic mice exposed to MeHg (30 or 50 ppm in drinking water), the ERAI signal, which indicates the activation of the cytoprotective pathway of the UPR, was only transiently enhanced, whereas the apoptotic pathway of the UPR was persistently enhanced. Furthermore, detailed analysis following the time course showed that MeHg-induced apoptosis is strongly associated with alterations in UPR signaling. Our results suggest that UPR modulation could be a therapeutic target for treating neuropathy. [ABSTRACT FROM AUTHOR]

Published
2022
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