The physiological role of p130Cas in salivary gland development

• Project/Area Number: 19K10054
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 57010:Oral biological science-related
• Research Institution: Kyushu University
• Principal Investigator: Gao Jing 九州大学, 歯学研究院, 助教 (40585882)
• Co-Investigator(Kenkyū-buntansha): 藤井 慎介 九州大学, 歯学研究院, 講師 (60452786)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 顎下腺 / 顆粒性導管 / AR signaling / 唾液腺 / ARシグナル / p130Cas / 上皮細胞極性 / p130cas / 発生

Outline of Research at the Start

唾液の正常な分泌は口腔の組織と機能だけでなく、全身の健康維持に寄与する。唾液腺や腎臓などの上皮管腔組織の発生には「細胞の極性化」が重要である。我々はこれまでにアダプタータンパク質であるp130Casが破骨細胞が骨吸収面に波状縁を形成する際の極性化に必須であることを報告した。さらにデータベース検索で唾液腺と腎臓でp130Casの発現が高いことから、上皮管腔組織の形成と機能発現にp130Casが重要な役割を担うのではないかとを考えた。本研究では、我々が独自に作製した上皮組織特異的p130Cas欠損マウスを用いて、唾液腺の上皮管腔組織の形態形成・ 分化におけるp130Casの役割を検討する。

Outline of Final Research Achievements

We aimed to elucidate the physiological role of p130Cas in salivary glands using epithelium-specific p130Cas-deficient mice. Premature development of granular ducts (GCTs) in the submandibular gland of p130Cas-deficient mice was shown, and nuclear-localized androgen receptors (ARs) were specifically reduced in GCT cells. We found that the expression levels of target genes for AR signaling were markedly reduced in p130Cas-deficient mice, indicating that AR signaling was suppressed. These results suggest that p130Cas plays an important role in the development of androgen-dependent submandibular GCTs by regulating AR signaling.

Academic Significance and Societal Importance of the Research Achievements

唾液の正常な分泌は口腔の組織と機能だけでなく、全身の健康維持に寄与する。唾液分泌の減少は、舌、口腔粘膜を乾燥させ、咀嚼、嚥下、発音や味覚に障害を生じる。現在、口腔乾燥症に対する治療法は根本的なものがなく、組織再生療法など新しい治療法の開発が望まれる。私たちの結果は、唾液腺の発達に関する新たな洞察を提供し、機能低下した唾液腺の回復を促進する治療戦略の提案につながる。さらに、p130Cas はほかの疾患における性差の制御に関連し、p130Cas 関連シグナル伝達は創薬の新たな標的として機能する可能性がある。

Research Products

• [Journal Article] p130Cas is required for androgen-dependent postnatal development regulation of submandibular glands (2023)
  • Author(s): Jing Gao, Aonan Li, Shinsuke Fujii, Fei Huang, Chihiro Nakatomi, Ichiro Nakamura, Hiroaki Honda, Tamotsu Kiyoshima, Eijiro Jimi
  • Journal Title: Scientific Reports Volume: 13 Issue: 1 Pages: 5144-5144
  • DOI: 10.1038/s41598-023-32390-1
  • Peer Reviewed / Open Access
• [Journal Article] Phospholipase C-related but catalytically inactive protein acts as a positive regulator of insulin signalling in adipocytes. (2022)
  • Author(s): Gao, J., Mizokami, A., Takeuchi, H., Li, A., Huang, F., Nagano, H., Kanematsu, T., Jimi, E., Hirata, M.
  • Journal Title: J. Cell. Sci. Volume: 135 Issue: 1
  • DOI: 10.1242/jcs.258584
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Deletion of epithelial cell-specific p130Cas impairs the maturation stage of amelogenesis (2022)
  • Author(s): Inoue Akane、Kiyoshima Tamotsu、Yoshizaki Keigo、Nakatomi Chihiro、Nakatomi Mitsushiro、Ohshima Hayato、Shin Masashi、Gao Jing、Tsuru Kanji、Okabe Koji、Nakamura Ichiro、Honda Hiroaki、Matsuda Miho、Takahashi Ichiro、Jimi Eijiro
  • Journal Title: Bone Volume: 154 Pages: 116210-116210
  • DOI: 10.1016/j.bone.2021.116210
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Bone morphogenetic protein induces bone invasion of melanoma by epithelial?mesenchymal transition via the Smad1/5 signaling pathway (2021)
  • Author(s): Gao Jing、Muroya Ryusuke、Huang Fei、Nagata Kengo、Shin Masashi、Nagano Ryoko、Tajiri Yudai、Fujii Shinsuke、Yamaza Takayoshi、Aoki Kazuhiro、Tamura Yukihiko、Inoue Mayuko、Chishaki Sakura、Kukita Toshio、Okabe Koji、Matsuda Miho、Mori Yoshihide、Kiyoshima Tamotsu、Jimi Eijiro
  • Journal Title: Laboratory Investigation Volume: 101 Issue: 11 Pages: 1475-1483
  • DOI: 10.1038/s41374-021-00661-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Adipocyte-specific GPRC6A ablation promotes diet-induced obesity by inhibiting lipolysis (2021)
  • Author(s): Mukai Satoru、Mizokami Akiko、Otani Takahito、Sano Tomomi、Matsuda Miho、Chishaki Sakura、Gao Jing、Kawakubo-Yasukochi Tomoyo、Tang Ronghao、Kanematsu Takashi、Takeuchi Hiroshi、Jimi Eijiro、Hirata Masato
  • Journal Title: Journal of Biological Chemistry Volume: 296 Pages: 100274-100274
  • DOI: 10.1016/j.jbc.2021.100274
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] p130Cas induces bone invasion by oral squamous cell carcinoma by regulating tumor epithelial?mesenchymal transition and cell proliferation (2020)
  • Author(s): Yaginuma Tatsuki、Gao Jing、Nagata Kengo、Muroya Ryusuke、Fei Huang、Nagano Haruki、Chishaki Sakura、Matsubara Takuma、Kokabu Shoichiro、Matsuo Kou、Kiyoshima Tamotsu、Yoshioka Izumi、Jimi Eijiro
  • Journal Title: Carcinogenesis Volume: - Issue: 8 Pages: 1038-1048
  • DOI: 10.1093/carcin/bgaa007
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] GLP-1 signaling is required for improvement of glucose tolerance by osteocalcin. J. Endocrinol. (2020)
  • Author(s): Mizokami, A., Mukai, S., Gao, J., Kawakubo-Yasukochi, T., Otani, T., Takeuchi, H., Jimi, E., Hirata, M.
  • Journal Title: Journal of Endocrinology Volume: 244 Issue: 2 Pages: 285-296
  • DOI: 10.1530/joe-19-0288
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Bif‐1/Endophilin B1/SH3GLB1 regulates bone homeostasis (2019)
  • Author(s): Touyama Kenya、Khan Masud、Aoki Kazuhiro、Matsuda Miho、Hiura Fumitaka、Takakura Nana、Matsubara Takuma、Harada Yui、Hirohashi Yuna、Tamura Yukihiko、Gao Jing、Mori Kayo、Kokabu Shoichiro、Yasuda Hisataka、Fujita Yuko、Watanabe Koji、Takahashi Yoshinori、Maki Kenshi、Jimi Eijiro
  • Journal Title: Journal of Cellular Biochemistry Volume: 120 Issue: 11 Pages: 18793-18804
  • DOI: 10.1002/jcb.29193
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] p130casはマウス顎下腺の顆粒性導管細胞分化のためのER―ゴルジネットワークの形成に重要な役割を果たす (2022)
  • Author(s): Aonan Li, Jing Gao, Shinsuke Fujii, Tamotsu Kiyoshima, Eijiro Jimi
  • Organizer: 第６４回歯科基礎医学会学術大会
• [Presentation] NF-kBシグナルの調節メカニズムは閉経後骨粗鬆症と体重増加に関与する (2022)
  • Author(s): Fei Huang, Jing Gao, Akiko Mizokami, Eijiro Jimi
  • Organizer: 第６４回歯科基礎医学会学術大会
• [Presentation] マウス唾液腺の機能発現におけるp130Casの役割 (2021)
  • Author(s): 高靖, 李傲男, 藤井慎介, 清島保, 自見英治郎
  • Organizer: 第94回日本生化学大会
• [Presentation] p130Cas is involved in the development of granular convoluted tubule of submandibular gland in mice (2021)
  • Author(s): Aonan Li, Jing Gao, Shinsuke Fujii, Tamotsu Kiyoshima, Eijiro Jimi
  • Organizer: 第63回歯科基礎医学会学術大会
• [Presentation] The role of serine 536 phosphorylation of NF-kB p65 in the bone loss and obesity in postmenopausal women (2021)
  • Author(s): Fei Huang, Jing Gao, Eijiro Jimi
  • Organizer: 第63回歯科基礎医学会学術大会
• [Presentation] p130Casのエナメル質形成過程における役割 (2020)
  • Author(s): 井上茜、高靖、吉崎恵悟、進正史、中富千尋、中富満城、岡部幸司、大島勇人、高橋一郎、自見英治郎
  • Organizer: 第６２回歯科基礎医学会学術大会
• [Presentation] 脂肪細胞のインスリンシグナリングの調節におけるPRIPの役割 (2019)
  • Author(s): 高靖、溝上顕子、竹内弘、自見英治郎、平田雅人
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] 唾液腺の形態形成及び機能発現における p130Cas の役割 (2019)
  • Author(s): 室屋 龍佑、高 靖、中富 千尋、藤井 慎介、清島 保、自見英治郎
  • Organizer: 第61回歯科基礎医学会学術大会