The role of magnesium in intestinal homeostasis

• Project/Area Number: 17K08631
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Osaka University
• Principal Investigator: Yamazaki Daisuke 大阪大学, 微生物病研究所, 准教授 (50422415)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 大腸がん / 腸管上皮細胞 / 浸潤 / 細胞増殖 / 幹細胞 / 癌

Outline of Final Research Achievements

CNNM4 is a Mg2+ transporter highly expressed in the colon epithelia. I showed that Cnnm4 deficiency promotes cell proliferation and partly suppresses cell differentiation in the colon epithelia, making them vulnerable to cancer development. Ca2+-imaging analyses reveal that Ca2+ influx stimulated by capsaicin, which is dependent on TRPV1, is greatly impaired by Cnnm4 deficiency. Moreover, EGF receptor signaling is constitutively activated in the colon epithelia of Cnnm4-deficient mice, as is the case with Trpv1-deficient mice. The administration of gefitinib, an inhibitor of EGF receptor, cancels the augmented proliferation of cells observed in Cnnm4-deficient mice. Collectively, these results establish the functional interplay between Mg2+ and Ca2+ in the colon epithelia, which is crucial for maintaining the dynamic homeostasis of the epithelial tissue.

Academic Significance and Societal Importance of the Research Achievements

Mg2+トランスポーターCNNM4の遺伝子破壊マウスを用いた解析から、細胞内Mg2+を適切な濃度に保つことが大腸上皮細胞の正常な細胞分化につながることそして過剰な増殖を抑制することに必要であることがわかった。これは腸上皮細胞において細胞内Mg2+の量を制御することがもつ生理的な役割を明らかにしたはじめての事例である。またCNNM4を欠損した大腸上皮細胞ではTRPV1を介した細胞内へのCa2+流入が抑制されていたが、CNNM4を欠損した精子でも同様の現象がみられることから、Mg2+とCa2+の機能的相互作用は広く保存されている可能性がある。

Research Products

• [Journal Article] Role of adenomatous polyposis coli in proliferation and differentiation of colon epithelial cells in organoid culture (2021)
  • Author(s): Yamazaki Daisuke、Hashizume Osamu、Taniguchi Shiho、Funato Yosuke、Miki Hiroaki
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 3980-3980
  • DOI: 10.1038/s41598-021-83590-6
  • Peer Reviewed / Open Access
• [Journal Article] p18/Lamtor1-mTORC1 Signaling Controls Development of Mucin-producing Goblet Cells in the Intestine (2020)
  • Author(s): Ito Shizuka、Nada Shigeyuki、Yamazaki Daisuke、Kimura Tetsuya、Kajiwara Kentaro、Miki Hiroaki、Okada Masato
  • Journal Title: Cell Structure and Function Volume: 45 Issue: 2 Pages: 93-105
  • DOI: 10.1247/csf.20018
  • NAID: 130007871371
  • ISSN: 0386-7196, 1347-3700
  • Peer Reviewed / Open Access
• [Journal Article] The Oncogenic PRL Protein Causes Acid Addiction of Cells by Stimulating Lysosomal Exocytosis. (2020)
  • Author(s): Yosuke Funato, Atsushi Yoshida, Yusuke Hirata, Osamu Hashizume, Daisuke Yamazaki, Hiroaki Miki
  • Journal Title: Developmental cell Volume: 55 Issue: 4 Pages: 387-397
  • DOI: 10.1016/j.devcel.2020.08.009
  • Peer Reviewed / Open Access
• [Journal Article] Excessive Mg 2+ Impairs Intestinal Homeostasis by Enhanced Production of Adenosine Triphosphate and Reactive Oxygen Species (2020)
  • Author(s): Osamu Hashizume , Yosuke Funato , Daisuke Yamazaki, Hiroaki Miki
  • Journal Title: Antioxid Redox Signal . Volume: - Issue: 1 Pages: 20-34
  • DOI: 10.1089/ars.2019.7951
  • Peer Reviewed
• [Journal Article] Cnnm4 deficiency suppresses Ca2+ signaling and promotes cell proliferation in the colon epithelia (2019)
  • Author(s): Yamazaki D, Hasegawa A, Funato Y, Tran HN, Mori MX, Mori Y, Sato T, Miki H
  • Journal Title: Oncogene Volume: - Issue: 20 Pages: 3962-3969
  • DOI: 10.1038/s41388-019-0682-0
  • Peer Reviewed
• [Presentation] オルガノイド培養を用いた大腸上皮細胞の増殖および分化におけるAPCの役割の解析 (2020)
  • Author(s): 山崎大輔、橋爪修、谷口詩保、船戸洋佑、三木裕明
  • Organizer: 第43回日本分子生物学会年会
• [Presentation] CNNM4は腸管上皮において細胞の増殖と分化を制御する (2019)
  • Author(s): 山崎大輔、長谷川綾郁、船戸洋佑、三木裕明
  • Organizer: 日本生化学会大会
• [Presentation] Mg2+トランスポーターCNNM4は 大腸での発がんを抑制する (2018)
  • Author(s): 山崎大輔、長谷川綾郁、船戸洋佑、三木裕明
  • Organizer: 日本生化学会大会
• [Presentation] Mg2＋トランスポーターCNNM4は大腸での発がんを抑制する (2017)
  • Author(s): 山崎大輔、長谷川綾郁、船戸洋佑、三木裕明
  • Organizer: ConBio2017
• [Book] レドックス疾患学 (2018)
  • Author(s): 山崎大輔、三木裕明
  • Total Pages: 276
  • Publisher: 羊土社
  • ISBN: 9784758103695