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Kitagawa K., Uchida C., Horiguchi R., Ohhata T., Sakai S., Niida H., Yasumoto S., Handa Y., Suzuki M., Hashimoto M., Tazawa T., Yokochi Y., Tsuji M., Kitagawa M.
Scientific Reports 10 ( 1 ) 14381 2020年12月
担当区分：筆頭著者, 責任著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Scientific Reports
The expression level of transcription factor c-Myb oscillates during hematopoiesis. Fbw7 promotes ubiquitin-mediated degradation of c-Myb, which is dependent on phosphorylation of Thr572. To investigate the physiological relevance of Fbw7-mediated c-Myb degradation, we generated mutant mice carrying c-Myb-T572A (TA). Homozygous mutant (TA/TA) mice exhibited a reduction in the number of peripheral red blood cells and diminished erythroblasts in bone marrow, presumably as a result of failure during erythroblast differentiation. We found that c-Myb high-expressing cells converged in the Lin−CD71+ fraction, and the expression of c-Myb was higher in TA/TA mice than in wild-type mice. Moreover, TA/TA mice had an increased proportion of the CD71+ subset in Lin− cells. The c-Myb level in the Lin−CD71+ subset showed three peaks, and the individual c-Myb level was positively correlated with that of c-Kit, a marker of undifferentiated cells. Ultimately, the proportion of c-Mybhi subgroup was significantly increased in TA/TA mice compared with wild-type mice. These results indicate that a delay in reduction of c-Myb protein during an early stage of erythroid differentiation creates its obstacle in TA/TA mice. In this study, we showed the T572-dependent downregulation of c-Myb protein is required for proper differentiation in early-stage erythroblasts, suggesting the in vivo significance of Fbw7-mediated c-Myb degradation.
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Kuwamura M., Tanaka K., Onoda A., Taki K., Koriyama C., Kitagawa K., Kawamoto T., Tsuji M.
BMC Pediatrics 24 ( 1 ) 26 2024年12月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：BMC Pediatrics
Background: Bisphenol A diglycidyl ether (BADGE) and Bisphenol F diglycidyl ether (BFDGE) are used in medical devices, such as intravenous sets, syringes, and catheters. Several studies have reported that these compounds are endocrine disruptors, cytotoxic, and genotoxic, raising concerns about their adverse effects on infants, in a stage of remarkable growth and development. The present study aimed to measure the serum concentrations of BADGE, derivatives of BADGE, and BFDGE in infants and examine the factors that influence them. Methods: Ten infants admitted to the neonatal intensive care unit (NICU) were enrolled in the present study. Blood samples from each infant and questionnaires from their mothers were collected twice, at 1–2 months and 7 months of age. BADGE, BADGE·H2O, BADGE·2H2O, and BFDGE were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: Serum BADGE·2H2O was identified in all infants, at both 1–2 months (2.30–157.58 ng/ml) and 7 months of age (0.86–122.85 ng/ml). One of the two infants who received invasive ventilation showed a substantially increased BADGE·2H2O concentration. There was no significant difference in BADGE·2H2O concentrations at 7 months of age between the group that ate commercial baby food at least ≥ 1 time per week and the group that did not. Conclusions: BADGE·2H2O was detected in the serum of all infants with a history of NICU hospitalization. Future studies are needed to determine the source of BADGE exposure and investigate its effects on infant development.
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Uchida C., Niida H., Sakai S., Iijima K., Kitagawa K., Ohhata T., Shiotani B., Kitagawa M.
Biochimica et Biophysica Acta - Molecular Cell Research 1870 ( 6 ) 119484 2023年8月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Biochimica et Biophysica Acta - Molecular Cell Research
Ataxia-telangiectasia mutated and Rad3-related (ATR) kinase is a crucial regulator of the cell cycle checkpoint and activated in response to DNA replication stress by two independent pathways via RPA32-ETAA1 and TopBP1. However, the precise activation mechanism of ATR by the RPA32-ETAA1 pathway remains unclear. Here, we show that p130RB2, a member of the retinoblastoma protein family, participates in the pathway under hydroxyurea-induced DNA replication stress. p130RB2 binds to ETAA1, but not TopBP1, and depletion of p130RB2 inhibits the RPA32-ETAA1 interaction under replication stress. Moreover, p130RB2 depletion reduces ATR activation accompanied by phosphorylation of its targets RPA32, Chk1, and ATR itself. It also causes improper re-progression of S phase with retaining single-stranded DNA after cancelation of the stress, which leads to an increase in the anaphase bridge phenotype and a decrease in cell survival. Importantly, restoration of p130RB2 rescued the disrupted phenotypes of p130RB2 knockdown cells. These results suggest positive involvement of p130RB2 in the RPA32-ETAA1-ATR axis and proper re-progression of the cell cycle to maintain genome integrity.
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Kitagawa K., Shibata E., Yamamoto M., Harada H., Yoshino K., Iwashita T., Oshima M., Tsuji M.
Genes to Cells 28 ( 1 ) 42 - 52 2023年1月
担当区分：筆頭著者, 責任著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Genes to Cells
Bisphenol F diglycidyl ether (BFDGE) is widely used in the synthesis process of plastic products. While exposure to bisphenol A diglycidyl ether (BADGE), which has a similar structure to BFDGE and which is used for the same purpose, has been reported to cause health risks, there is still little information on BFDGE. Because it is estimated that the industrial workers are exposed to large amounts of BFDGE, the health risks associated with BFDGE exposure need to be clarified. We investigated the toxicity of cutaneous exposure to BFDGE using an in vitro evaluation system and a mouse exposure model. The tumorigenic potential of BFDGE was confirmed by the Bhas 42 cell transformation assay, which showed that BFDGE has both promoter and initiator activity, in vitro. A single dermal application of BFDGE was associated with minor contact hypersensitivity symptoms. In contrast, repeated dermal exposure to BFDGE for 2 weeks induced persistent acute inflammation with features similar to inflammation in human psoriasis. This is the first report evaluating the toxicity of BFDGE in animals, and we showed that BFDGE carries a health risk of inducing skin dermatitis similar to that in human psoriasis in an exposure period-dependent manner.
DOI： 10.1111/gtc.12995
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Nomura K., Kitagawa K., Tsuji M., Iida M., Aoki M., Miyauchi K., Hirayama J., Nagashima K., Takebayashi T., Tsutsumi A.
ｊｏｕｒｎａｌ ｏｆ Ｏｃｃｕｐａｔｉｏｎａｌ Ｈｅａｌｔｈ 65 ( 1 ) n/a 2023年
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：公益社団法人 日本産業衛生学会
Objective: We aim to investigate the quantity and quality of scientific evidence dealing with comprehensive health issues of working women in occupational health. Methods: This scoping review of original articles that investigated comprehensive health issues of working women aged 19–64 years in Japan was published in PubMed (1967–2022) and Igaku Chuo Zasshi (or Ichu-shi, 1982–2022). Using identical broad search terms, we first identified 17 122 English and 6154 Japanese articles. We excluded those with clinically relevant topics, or ethnicity other than Japanese and included 853 English and 855 Japanese articles for review and classified them into nine research areas considered to be critical factors for women in the workforce and five study design groups to investigate the quality of the evidence accumulated. Results: Among 853 English-language articles in PubMed, “Mental health” was the most frequent area studied, followed by “Work-related disease” and “Lifestyle-related disease.” Among 855 Japanese-language articles from Ichu-shi, “Mental health” was the most frequently studied area followed by “Work and balance,” and “Work-related disease.” “Infertility, pregnancy, and childbirth” and “Menstruation, menopause, and genital disease” were well studied in Ichu-shi but scarcely published in PubMed. “Harassment and discrimination” were sparsely reported in both databases. As for research designs, many articles in both PubMed and Ichu-shi employed descriptive or cross-sectional study designs. However, a few studies employed cohort/longitudinal or interventional studies. Conclusion: The results underscored the need for higher-quality study designs with more scientific evidence on working women's health in the field of occupational health.
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ゲノム編集オルガノイド由来プレクニカルモデルによるスキルス胃がん発生進展の解明
研究課題/領域番号：23K06662 2023年04月 - 2026年03月
独立行政法人日本学術振興会 科学研究費補助金 基盤研究（C）
担当区分：研究代表者