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230 results on '"Akatsuka, Shinya"'

10. Data from LATS2 Is a Tumor Suppressor Gene of Malignant Mesothelioma

Author

Murakami, Hideki, primary, Mizuno, Tetsuya, primary, Taniguchi, Tetsuo, primary, Fujii, Makiko, primary, Ishiguro, Futoshi, primary, Fukui, Takayuki, primary, Akatsuka, Shinya, primary, Horio, Yoshitsugu, primary, Hida, Toyoaki, primary, Kondo, Yutaka, primary, Toyokuni, Shinya, primary, Osada, Hirotaka, primary, and Sekido, Yoshitaka, primary

Published
2023
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16. BRCA1 haploinsufficiency promotes chromosomal amplification under Fenton reaction-based carcinogenesis through ferroptosis-resistance.

Author

Kong, Yingyi, Akatsuka, Shinya, Motooka, Yashiro, Zheng, Hao, Cheng, Zhen, Shiraki, Yukihiro, Mashimo, Tomoji, Imaoka, Tatsuhiko, Toyokuni, Shinya, Tatsuhiko, Imaoka, Kong, Yingyi, Akatsuka, Shinya, Motooka, Yashiro, Zheng, Hao, Cheng, Zhen, Shiraki, Yukihiro, Mashimo, Tomoji, Imaoka, Tatsuhiko, Toyokuni, Shinya, and Tatsuhiko, Imaoka

Abstract

Germline-mutation in BRCA1 tumor suppressor gene is an established risk for carcinogenesis not only in females but also in males. Deficiency in the repair of DNA double-strand breaks is hypothesized as a responsible mechanism for carcinogenesis. However, supporting data is insufficient both in the mutation spectra of cancers in the patients with BRCA1 germline-mutation and in murine knockout/knock-in models of Brca1 haploinsufficiency. Furthermore, information on the driving force toward carcinogenesis in BRCA1 mutation carriers is lacking. Here we applied Fenton reaction-based renal carcinogenesis to a rat heterozygously knockout model of BRCA1 haploinsufficiency (mutant [MUT] model; L63X/+). Rat MUT model revealed significant promotion of renal cell carcinoma (RCC) induced by ferric nitrilotriacetate (Fe-NTA). Array-based comparative genome hybridization of the RCCs identified significant increase in chromosomal amplification, syntenic to those in breast cancers of BRCA1 mutation carriers, including c-Myc, in comparison to those in the wild-type. Subacute-phase analysis of the kidney after repeated Fe-NTA treatment in the MUT model revealed dysregulated iron metabolism with mitochondrial malfunction assessed by expression microarray and electron microscopy, leading to renal tubular proliferation with iron overload. In conclusion, we for the first time demonstrate that biallelic wild-type BRCA1 provides more robust protection for mitochondrial metabolism under iron-catalyzed oxidative stress, preventing the emergence of neoplastic cells with chromosomal amplification. Our results suggest that oxidative stress via excess iron is a major driving force for carcinogenesis in BRCA1 haploinsufficiency, which can be a target for cancer prevention and therapeutics.

Published
2022

25. Augmented oxidative stress increases 8-oxoguanine preferentially in the transcriptionally active genomic regions

Author

Akatsuka, Shinya, Li, Guang Hua, Kawaguchi, Shinichi, Takahashi, Takashi, Yoshihara, Minako, Mikita Suyama, and Toyokuni, Shinya

Subjects
heterocyclic compounds
Abstract

8-Oxoguanine (8-oxoG) is the most common DNA base modification in the mammalian genome, associated with oxidative stress. Here we analysed the alterations in the distribution of 8-oxoG across the entire murine genome, before and after an elevation of oxidative stress by the use of ferric nitrilotriacetate (Fe-NTA) as an oxidative stress inducer in the renal proximal tubules. We isolated DNA fragments containing 8-oxoGs with immunoprecipitation from the murine genome, and amplified them by PCR for a distribution analysis with microarray-based comparative genomic hybridisation. The distribution profiles revealed that frequencies of 8-oxoG fluctuated with a cycle of 1–10 Mb along the chromosomes and the amplitude of the fluctuation was reduced after Fe-NTA administration. The distributions of 8-oxoG along the entire genome in the control and oxidatively stressed conditions were negatively correlated with that of gene density but positively correlated with that of Lamin B1 interaction, which corresponds to lamina-associated domains. These results on the murine genome were consistent with those on the rat genome we previously reported. We further discovered a negative correlation between the distributions of 8-oxoG and transcriptional activity along the genome. Finally, a comparison of the distributions before and after Fe-NTA administration suggested that 8-oxoGs are generated in response to the augmented oxidative stress preferentially in the transcriptionally active genomic regions, where 8-oxoGs have been less accumulated in the control condition.

Published
2020
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26. Defective biosynthesis of ascorbic acid in Sod1-deficient mice results in lethal damage to lung tissue

Author

Homma, Takujiro, primary, Takeda, Yuji, additional, Nakano, Tomoyuki, additional, Akatsuka, Shinya, additional, Kinoshita, Daisuke, additional, Kurahashi, Toshihiro, additional, Saitoh, Shinichi, additional, Yamada, Ken-ichi, additional, Miyata, Satoshi, additional, Asao, Hironobu, additional, Goto, Kaoru, additional, Watanabe, Tetsu, additional, Watanabe, Masafumi, additional, Toyokuni, Shinya, additional, and Fujii, Junichi, additional

Published
2021
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42. Ferroptosis resistance determines high susceptibility of murine A/J strain to iron‐induced renal carcinogenesis.

Author

Cheng, Zhen, Akatsuka, Shinya, Li, Guang Hua, Mori, Kiyoshi, Takahashi, Takashi, and Toyokuni, Shinya

Abstract

Cancer susceptibility is a critical factor in the understanding of carcinogenesis. Intraperitoneal (i.p.) injection of an iron chelate, ferric nitrilotriacetate (Fe‐NTA), produces hydroxyl radicals via Fenton reaction to induce ferroptosis in renal proximal tubules. Rats or mice subjected to repeated i.p. injections of Fe‐NTA develop renal cell carcinoma (RCC). To elucidate the molecular mechanisms that cause susceptibility to renal carcinogenesis, we first established an inter‐strain difference in the susceptibility to Fe‐NTA‐induced renal carcinogenesis in mice. Based on a previous observation of a low incidence of RCC with this model in C57BL/6J strain mice, we investigated A/J strain mice here, which demonstrated significantly higher susceptibility to Fe‐NTA‐induced renal carcinogenesis. Homozygous deletion of the Cdkn2a/2b tumor suppressor locus was detected for the first time in A/J strain mice. Focusing on ferroptosis and iron metabolism, we explored the mechanisms involved that lead to the difference in RCC development. We compared the protective responses in the kidney of A/J and C57BL/6J strains after Fe‐NTA treatment. After 3‐week Fe‐NTA treatment, A/J mice maintained higher levels of expression of glutathione peroxidase 4 and xCT (SLC7A11), leading to a lower level of lipid peroxidation. Simultaneously, A/J mice had decreased expression of transferrin receptor and increased expression of ferritin to greater degrees than C57BL/6 mice. After a single Fe‐NTA injection, higher levels of oxidative cell damage and cytosolic catalytic Fe(II) were observed in C57BL/6J mice, accompanied by a greater increase in lipocalin‐2. Lipocalin‐2 deficiency significantly decreased oxidative renal damage. Our results suggest that a genetic trait favoring ferroptosis resistance contributes to high susceptibility to Fe‐NTA‐induced RCC in A/J strain. [ABSTRACT FROM AUTHOR]

Published
2022
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