Intracellular labile heme: signaling function in cell differentiation and proliferation

• Project/Area Number: 18K19423
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 48:Biomedical structure and function and related fields
• Research Institution: University of Fukui
• Principal Investigator: Sugai Manabu 福井大学, 学術研究院医学系部門, 教授 (90303891)
• Co-Investigator(Kenkyū-buntansha): 南部 由希子 福井大学, 学術研究院医学系部門, 准教授 (70580380) ; 林 達成 福井大学, 学術研究院医学系部門, 特命助教 (80781111)
• Project Period (FY): 2018-06-29 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2019: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2018: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: ヘム / 細胞分化 / 細胞増殖 / 分化 / 増殖 / ミトコンドリア

Outline of Final Research Achievements

The signaling function of free-heme in cell differentiation processes is a new concept that has only recently emerged and the supporting physiological evidences for it were provided by the two research groups, including us. However, its relevance cannot be evaluated precisely because a reliable free-heme sensor is not yet available. In this project, we developed free-heme sensor to verify and examine the physiological role of free-heme as a signaling molecule within various types of cells.

Academic Significance and Societal Importance of the Research Achievements

ヘムに結合する転写因子（分化、老化、リズムに関わる）が多数見出されたため、細胞分化や細胞機能制御因子としてのヘムの役割に注目が集まっている。最近生理的条件下でヘムが分化制御因子として機能していることを申請者を含む二つのグループが明らかにした。このヘムによる分化制御機能の一般性をさらに詳細に解析するためには、実際に生体内で制御因子として機能している「細胞内遊離ヘム」を感度良く特異的に検出するプローブを開発することが必要である。本研究課題において開発に成功したことから、ようやく「細胞内遊離ヘム」の生理的機能を明らかにすることが可能になったと考えられる。

Research Products

• [Journal Article] Anti-USAG-1 therapy for tooth regeneration through enhanced BMP signaling (2021)
  • Author(s): Murashima-Suginami A.、Kiso H.、Tokita Y.、Mihara E.、Nambu Y.、Uozumi R.、Tabata Y.、Bessho K.、Takagi J.、Sugai M.、Takahashi K.
  • Journal Title: Science Advances Volume: 7 Issue: 7
  • DOI: 10.1126/sciadv.abf1798
  • NAID: 120006958083
  • Peer Reviewed / Open Access
• [Journal Article] Homeostatic Function of Dermokine in the Skin Barrier and Inflammation. (2020)
  • Author(s): Akira Utsunomiya, Takenao Chino, Natsuko Utsunomiya, Vu Huy Luong, Atsushi Tokuriki, Tatsuro Naganuma, Makoto Arita, Kiyoshi Higashi, Koichi Saito, Noriyuki Suzuki, Ayako Ohara, Manabu Sugai, Koji Sugawara, Daisuke Tsuruta, Noritaka Oyama, Minoru Hasegawa
  • Journal Title: Journal of Investigative Dermatology Volume: 140 Issue: 4 Pages: 838-849
  • DOI: 10.1016/j.jid.2019.09.011
  • Peer Reviewed
• [Journal Article] Development of tooth regenerative medicine strategies by controlling the number of teeth using targeted molecular therapy (2020)
  • Author(s): Takahashi Katsu、Kiso Honoka、Murashima-Suginami Akiko、Tokita Yoshihito、Sugai Manabu、Tabata Yasuhiko、Bessho Kazuhisa
  • Journal Title: Inflammation and Regeneration Volume: 40 Issue: 1 Pages: 21-21
  • DOI: 10.1186/s41232-020-00130-x
  • Peer Reviewed / Open Access
• [Journal Article] Dephosphorylation of protamine 2 at serine 56 is crucial for murine sperm maturation in vivo (2019)
  • Author(s): Itoh Katsuhiko、Kondoh Gen、Miyachi Hitoshi、Sugai Manabu、Kaneko Yoshiyuki、Kitano Satsuki、Watanabe Hitomi、Maeda Ryota、Imura Akihiro、Liu Yu、Ito Chizuru、Itohara Shigeyoshi、Toshimori Kiyotaka、Fujita Jun
  • Journal Title: Science Signaling Volume: 12 Issue: 574 Pages: 7232-7234
  • DOI: 10.1126/scisignal.aao7232
  • Peer Reviewed / Open Access
• [Journal Article] Blocking LC3 lipidation and ATG12 conjugation reactions by ATG7 mutant protein containing C572S (2019)
  • Author(s): Nitta A, Hori K, Tanida I, Igarashi A, Deyama Y, Ueno T, Kominami E, Sugai M, Aoki K.
  • Journal Title: Biochem Biophys Res Commun. Volume: 508(2) Issue: 2 Pages: 521-526
  • DOI: 10.1016/j.bbrc.2018.11.158
  • Peer Reviewed
• [Journal Article] Immune responses against Lewis Y tumor-associated carbohydrate antigen displayed densely on self-assembling nanocarriers (2018)
  • Author(s): Yamazaki Yuji、Nambu Yukiko、Ohmae Masashi、Sugai Manabu、Kimura Shunsaku
  • Journal Title: Organic & Biomolecular Chemistry Volume: 16 Issue: 43 Pages: 8095-8105
  • DOI: 10.1039/c8ob01955j
  • Peer Reviewed
• [Journal Article] Direct evidence for the age-dependent demise of GNAS -mutated cells in oral fibrous dysplasia (2018)
  • Author(s): Isobe Yu、Takahashi Katsu、Kiso Honoka、Nakao Kazumasa、Ikeno Masayuki、Koyama Noriaki、Sugai Manabu、Shimizu Akira、Haga Hironori、Bessho Kazuhisa
  • Journal Title: Archives of Oral Biology Volume: 93 Pages: 133-140
  • DOI: 10.1016/j.archoralbio.2018.05.018
  • Peer Reviewed / Int'l Joint Research