Elucidation of the mechanism of anticancer activity of the cancer suppressor gene INPP4B

• Project/Area Number: 18K06623
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Akita University
• Principal Investigator: TAKASUGA Shunsuke 秋田大学, 医学系研究科, 助教 (90375262)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: INPP4B / がん抑制遺伝子 / PTEN / ホスホイノシタイド

Outline of Final Research Achievements

We generated genetically engineered mice that express the human INPP4B gene in a cell- and tissue-specific manner and crossed them with liver-specific Pten gene-deficient mice, which are carcinogenesis model mice, to create mice that compensatory express INPP4B in a cell-specific manner in liver cells lacking the Pten gene. The results showed that fatty liver, a precancerous lesion caused by Pten deficiency, was strongly suppressed by the expression of INPP4B. This result suggests that phosphatidylinositol-3,4,5-trisphosphate, which abnormally accumulated due to Pten deficiency, is degraded by INPP4B, and that INPP4B substitutes for Pten function.

Academic Significance and Societal Importance of the Research Achievements

PTENは代表的ながん抑制遺伝子の一つである。我々はINPP4Bが、PTENと同じ基質を脱リン酸化することを見出し、PTENの機能をINPP4Bにより代替できる可能性に着目した。本研究において、新たに作製した条件付きINPP4B過剰発現マウスを用いることで、外来性のINPP4Bを発現が、Pten欠損による前がん病変（脂肪肝）の発症を抑制しうることがマウス個体レベルで初めて示された。この結果は、PTENの不活化により引き起こされるヒトのがんの発症や進展を、INPP4Bの人為的な活性化により抑制する可能性を示すものであり、INPP4Bを新たな創薬標的分子として提示するものである。

Research Products

• [Journal Article] Trained innate lymphoid cells in allergic diseases (2021)
  • Author(s): Ebihara T, Tatematsu M, Fuchimukai A, Yamada T, Yamagata K, Takasuga S, Yamada T
  • Journal Title: Allergol. Int. Volume: 70 Issue: 2 Pages: 174-180
  • DOI: 10.1016/j.alit.2020.11.007
  • NAID: 130008024334
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access
• [Journal Article] Increased fatty acyl saturation of phosphatidylinositol phosphates in prostate cancer progression. (2019)
  • Author(s): Koizumi A, Narita S, Nakanishi H, Ishikawa M, Eguchi S, Kimura H, Takasuga S, Huang M, Inoue T, Sasaki J, Yoshioka T, Habuchi T, Sasaki T.
  • Journal Title: Sci Rep. Volume: 9 Pages: 13257-13257
  • DOI: 10.1038/s41598-019-49744-3
  • Peer Reviewed / Open Access
• [Journal Article] Phosphorylation of TMEM55B by Erk/MAPK regulates lysosomal positioning. (2019)
  • Author(s): Takemasu S, Nigorikawa K, Yamada M, Tsurumi G, Kofuji S, Takasuga S, Hazeki K.
  • Journal Title: J Biochem. Volume: 166 Pages: 175-185
  • DOI: 10.1093/jb/mvz026
  • NAID: 40021974923
  • Peer Reviewed
• [Journal Article] Sac1 Phosphoinositide Phosphatase Regulates Foam Cell Formation by Modulating SR-A Expression in Macrophages (2019)
  • Author(s): Nigorikawa K, Matsumura T, Sakamoto H, Morioka S, Kofuji S, Takasuga S, Hazeki K.
  • Journal Title: Biol. Pharm. Bull. Volume: 42 Issue: 6 Pages: 923-928
  • DOI: 10.1248/bpb.b18-00907
  • NAID: 130007657676
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed
• [Journal Article] Lysophosphatidylinositol‐acyltransferase‐1 is involved in cytosolic Ca2+ oscillations in macrophages (2019)
  • Author(s): Takemasu Shinya、Ito Masaki、Morioka Shin、Nigorikawa Kiyomi、Kofuji Satoshi、Takasuga Shunsuke、Eguchi Satoshi、Nakanishi Hiroki、Matsuoka Isao、Sasaki Junko、Sasaki Takehiko、Hazeki Kaoru
  • Journal Title: Genes to cells Volume: - Pages: 1-11
  • DOI: 10.1111/gtc.12681
  • Peer Reviewed / Open Access
• [Journal Article] PIKfyve accelerates phagosome acidification through activation of TRPML1 while arrests aberrant vacuolation independent of the Ca2+ channel. (2019)
  • Author(s): Isobe Y, Nigorikawa K, Tsurumi G, Takemasu S, Takasuga S, Kofuji S, Hazeki K.
  • Journal Title: J Biochem. Volume: 165 Pages: 75-84
  • DOI: 10.1093/jb/mvy084
  • Peer Reviewed
• [Journal Article] PIKfyve regulates melanosome biogenesis (2018)
  • Author(s): Liggins Marc C.、Flesher Jessica L.、Jahid Sohail、Vasudeva Priya、Eby Victoria、Takasuga Shunsuke、Sasaki Junko、Sasaki Takehiko、Boissy Raymond E.、Ganesan Anand K.
  • Journal Title: PLOS Genetics Volume: 14
  • DOI: 10.1371/journal.pgen.1007290
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TMEM55a localizes to macrophage phagosomes to downregulate phagocytosis (2018)
  • Author(s): Morioka Shin、Nigorikawa Kiyomi、Okada Eri、Tanaka Yoshimasa、Kasuu Yoshihiro、Yamada Miho、Kofuji Satoshi、Takasuga Shunsuke、Nakanishi Hiroki、Sasaki Takehiko、Hazeki Kaoru
  • Journal Title: Journal of Cell Science Volume: 131 Pages: 213272-213272
  • DOI: 10.1242/jcs.213272
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The effect and possible clinical efficacy of in vivo inhibition of neutrophil extracellular traps by blockade of PI3K-gamma on the pathogenesis of microscopic polyangiitis (2018)
  • Author(s): Kimura Hirotaka、Matsuyama Yasushi、Araki Sachiko、Koizumi Atsushi、Kariya Yumi、Takasuga Shunsuke、Eguchi Satoshi、Nakanishi Hiroki、Sasaki Junko、Sasaki Takehiko
  • Journal Title: Modern Rheumatology Volume: 28 Pages: 1-12
  • DOI: 10.1080/14397595.2017.1367116
  • Peer Reviewed / Open Access
• [Presentation] 肝特異的ホスファチジルグリセロールリン酸ホスファターゼ遺伝子欠損によるラロン型低身長症様疾患モデルマウス (2021)
  • Author(s): 高須賀俊輔、海老原敬、佐々木雄彦
  • Organizer: 第94回日本生化学会大会
• [Book] 脂質クオリティ (2018)
  • Author(s): 高須賀俊輔・佐々木雄彦（編集＝有田誠）
  • Total Pages: 220
  • Publisher: 羊土社
  • ISBN: 9784758103718