Defect of growth/differentiation regulation caused psoriasis-like skin inflammation.

• Project/Area Number: 26293071
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Tokyo University of Pharmacy and Life Science
• Principal Investigator: FUKAMI KIYOKO 東京薬科大学, 生命科学部, 教授 (40181242)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000); Fiscal Year 2016: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2015: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
• Keywords: リン脂質代謝 / 炎症性皮膚疾患 / 皮膚バリア / リン脂質代謝酵素 / 表皮バリア機能 / 細胞増殖分化機構 / バリア機能 / ホスフォリパーゼC / リン脂質 / 増殖・分化 / がん / 表皮

Outline of Final Research Achievements

We showed here that downregulation of phospholipase C (PLC) δ1 impairs the barrier functions of the stratum corneum. PLCδ1 downregulation also impairs localization of tight junction proteins. Loss of PLCδ1 leads to a decrease in intracellular Ca2+ concentrations and nuclear factor of activated T cells (NFAT) activity, along with hyperactivation of p38 mitogen-activated protein kinase (MAPK) and inactivation of RhoA. These findings demonstrate that PLCδ1 is essential for epidermal barrier integrity. This study also suggests a possible link between PLCδ1 downregulation, p38 MAPK hyperactivation, and barrier defects in psoriasis-like skin inflammation.

Research Products

• [Journal Article] Phospholipase Cδ1 regulates p38 MAPK activity and skin barrier integrity. (2017)
  • Author(s): Kaori Kanemaru, Yoshikazu Nakamura, Kengo Totoki, Takatsugu Fukuyama, Madoka Shoji, Hisae Kaneko, Kanako Shiratori, Atsuko Yoneda, Takafumi Inoue, Yoichiro Iwakura, Kenji Kabashima, Kiyoko Fukami
  • Journal Title: Cell Death & Differentiation Volume: in press Issue: 6 Pages: 1079-1090
  • DOI: 10.1038/cdd.2017.56
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] PNPLA1 has a crucial role in skin barrier function by directing acylceramide biosynthesis. (2017)
  • Author(s): Hirabayashi T, Anjo T, Kaneko A, Senoo Y, Shibata A, Takama H, Yokoyama K, Nishito Y, Ono T, Taya C, Muramatsu K, Fukami K, Muñoz-Garcia A, Brash A, Ikeda K, Arita M, Akiyama M, Murakami M.
  • Journal Title: Nat Commun Volume: 8 Issue: 1 Pages: 14609-14609
  • DOI: 10.1038/ncomms14609
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Regulation and physiological functions of mammalian phospholipase C (2017)
  • Author(s): Yoshikazu Nakamura, Kiyoko Fukami
  • Journal Title: J. Biochem. Volume: 161 Pages: 315-321
  • DOI: 10.1093/jb/mvw094
  • NAID: 40021219752
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] ZIC5 drives melanoma aggressiveness by PDGFD-mediated activation of FAK and STAT3 (2017)
  • Author(s): Reiko Satow, Tomomi Nakamura, Chiaki Kato, Miku Endo, Mana Tamura, Ryosuke Batori, Shiori Tomura, Yumi Murayama, Kiyoko Fukami
  • Journal Title: Cancer Res. Volume: 77 Issue: 2 Pages: 366-377
  • DOI: 10.1158/0008-5472.can-16-0991
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Phospholipase C δ1 in macrophages negatively regulates TLR4-induced proinflammatory cytokine production and Fcγ receptor-mediated phagocytosis. (2015)
  • Author(s): 1.Kudo, K., Uchida, T., Sawada, M., Nakamura, Y., Yoneda, A., and Fukami K.
  • Journal Title: Adv. Biol. Regul. Volume: S2212-4926(15)30022-1 Pages: 68-79
  • DOI: 10.1016/j.jbior.2015.11.004
  • Peer Reviewed / Open Access
• [Journal Article] Obesity exacerbates imiquimod-induced psoriasis-like epidermal hyperplasia and interleukin 17 and interleukin 22 production in mice. (2015)
  • Author(s): Kanemaru, K., Matsuyuki, A., Nakamura, Y., and Fukami, K.
  • Journal Title: Exp. Dermatol. Volume: 印刷中 Issue: 6 Pages: 436-442
  • DOI: 10.1111/exd.12691
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Phospholipase C δ1 in macrophages negatively regulates TLR4-induced proinflammatory cytokine production and Fcγ receptor-mediated phagocytosis. (2015)
  • Author(s): Kudo, K., Uchida, T., Sawada, M., Nakamura, Y., Yoneda, A., and Fukami K.
  • Journal Title: Adv Biol Regul. Volume: 15
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] H3K4/H3K9me3 Bivalent Chromatin Domains Targeted by Lineage-Specific DNA Methylation Pauses Adipocyte Differentiation. (2015)
  • Author(s): Matsumura, Y., Nakaki, R., Inagaki, T., Yoshida, A., Kano, Y., Kimura, H., Tanaka, T., Tsutsumi, S., Nakao, M., Doi, T., Fukami, K., Osborne, TF., Kodama, T., Aburatani, H., Sakai, J.
  • Journal Title: Molecular Cell Volume: 60 Issue: 4 Pages: 584-596
  • DOI: 10.1016/j.molcel.2015.10.025
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The FBXL10/KDM2B Scaffolding Protein Associates with Novel Polycomb Repressive Complex-1 to Regulate Adipogenesis. (2015)
  • Author(s): Inagaki T, Iwasaki S, Matsumura Y, Kawamura T, Tanaka T, Abe Y, Yamasaki A, Tsurutani Y, Yoshida A, Chikaoka Y, Nakamura K, Magoori K, Nakaki R, Osborne TF, Fukami K, Aburatani H, Kodama T, Sakai J
  • Journal Title: J Biol Chem Volume: 290 Issue: 7 Pages: 4163-77
  • DOI: 10.1074/jbc.m114.626929
  • Peer Reviewed / Open Access
• [Journal Article] JMJD1A is a signal-sensing scaffold that regulates acute chromatin dynamics via SWI/SNF association for thermogenesis (2015)
  • Author(s): Abe Y, Rozqie R, Matsumura Y, Kawamura T, Nakaki R, Tsurutani Y, Tanimura-Inagaki K, Shiono A, Magoori K, Nakamura K, Ogi S, Kajimura S, Kimura H, Tanaka T, Fukami K, Osborne TF, Kodama T, Aburatani H, Inagaki T, Sakai J.
  • Journal Title: Nat Commun Volume: 6 Issue: 1 Pages: 1-14
  • DOI: 10.1038/ncomms8052
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Obesity exacerbates imiquimod-induced psoriasis-like epidermal hyperplasia and interleukin 17 and interleukin 22 production in mice (2015)
  • Author(s): Kaori Kanemaru, Ayano Matsuyuki, Yoshikazu Nakamura, Kiyoko Fukami
  • Journal Title: Experimental Dermatology Volume: in press
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Phospholipase C-β1 and β4 contribute to non-genetic cell-to-cell variability in histamine-induced calcium signals in HeLa cells (2014)
  • Author(s): Ishida S, Matsu-Ura T, Fukami K, Michikawa T, Mikoshiba K.
  • Journal Title: PLoS ONE Volume: 9 Issue: 1 Pages: e86410-e86410
  • DOI: 10.1371/journal.pone.0086410
  • Peer Reviewed / Open Access
• [Journal Article] Saracatinib impairs the peritoneal dissemination of diffuse-type gastric carcinoma cells resistant to Met and FGFR inhibitors. (2014)
  • Author(s): Yamaguchi H, Takanashi M, Yoshida N, Ito Y, Kamata R, Fukami K, Yanagihara K, Sakai R.
  • Journal Title: Cancer Sci. Volume: 105 Issue: 5 Pages: 528-536
  • DOI: 10.1111/cas.12387
  • Peer Reviewed / Open Access
• [Journal Article] Simultaneous Loss of Phospholipase Cδ1 and Phospholipase Cδ3 Causes Cardiomyocyte Apoptosis and Cardiomyopathy. (2014)
  • Author(s): Y Nakamura, K Kanemaru, et al.
  • Journal Title: Cell Death & Disease Volume: 5 Issue: 5 Pages: 140-147
  • DOI: 10.1038/cddis.2014.181
  • Peer Reviewed / Open Access
• [Journal Article] Phospholipase C delta 1 induces E-cadherin expression and suppresses malignancy in colorectal cancer cells (2014)
  • Author(s): Reiko Satow, Tamaki Hirano, Ryosuke Batori, Tomomi Nakamura, Yumi Murayama, and Kiyoko Fukami
  • Journal Title: Proc. Natl. Acad. Sci. USA. Volume: 111 Issue: 37 Pages: 13505-13510
  • DOI: 10.1073/pnas.1405374111
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Loss of epidermal PLCd1 sebaceous gland hyperplasia and sparse hair (2016)
  • Author(s): Takatsugu Fukuyama, Chiho Toyoda, Yoshikazu Nakamura, Kiyoko Fukami.
  • Organizer: 第41回日本研究皮膚科学会
  • Place of Presentation: 仙台
  • Year and Date: 2016-12-12
• [Presentation] 黄色ブドウ球菌分泌物がケラチノサイトのバリアおよび炎症関連遺伝子に与える影響の解析 (2016)
  • Author(s): 庄司麻土香、十時謙伍、中村由和、中南秀将、中瀬恵亮、野口雅久、深見希代子
  • Organizer: 第89回日本生化学会
  • Place of Presentation: 仙台
  • Year and Date: 2016-09-25
• [Presentation] Phospholipase C δ1 regulates epidermal barrier formation. (2016)
  • Author(s): Nakamura Y., Kanemaru K., Fukami K.
  • Organizer: 57th International Conference on the Biosciene of Lipids
  • Place of Presentation: France
  • Year and Date: 2016-09-05
  • Int'l Joint Research
• [Presentation] PLC delta1 regulates autophagy in colorectal cancer cells. (2016)
  • Author(s): Makoto Simozawa, Reiko Satow, Kiyoko Fukami.
  • Organizer: The 9th Korea-Japan Conference on Cellular Signalling for Young Scientists
  • Place of Presentation: Seoul
  • Year and Date: 2016-07-21
  • Int'l Joint Research
• [Presentation] BRAF 変異メラノーマ細胞に対する Vemurafenib 処理がエクソソームへの CD63 のソーティングに与える影響 (2016)
  • Author(s): 工藤光野、兵頭拓弥、崎山大輝、米田敦子、深見希代子
  • Organizer: 第68回日本細胞生物学会大会
  • Place of Presentation: 京都
  • Year and Date: 2016-06-15
• [Presentation] ホスホリパーゼCγ1は正常な皮脂腺形成に必要である (2016)
  • Author(s): 福山尭嗣、豊田千穂、Suh Pann-Ghill、中村由和、深見希代子
  • Organizer: 第68回日本細胞生物学会大会
  • Place of Presentation: 京都
  • Year and Date: 2016-06-15
• [Presentation] ケラチノサイトの細胞内Ca2+濃度上昇、表皮バリア形成におけるホスホリパーゼCd1の役割 (2016)
  • Author(s): 十時謙伍、金丸佳織、中村由和、深見希代子
  • Organizer: 第58回日本脂質生化学会
  • Place of Presentation: 秋田
  • Year and Date: 2016-06-09
• [Presentation] Loss of phospholipase Cd1 impairs Epidermal barrier and skin inflammation. (2015)
  • Author(s): Kiyoko Fukami
  • Organizer: The 2nd special international symposium on Phospholipid-related signaling in physiology and pathology.
  • Place of Presentation: 韓国
  • Year and Date: 2015-12-11
  • Int'l Joint Research / Invited
• [Presentation] ホスホリパーゼCδ１欠損による刺激性接触皮膚炎抑制機構の解明 (2015)
  • Author(s): 白鳥可奈子、小倉嵩寛、中村由和、深見希代子
  • Organizer: 第88回日本生化学会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-01
• [Presentation] メラノーマの増悪を促進する遺伝子の同定と機能解析 (2015)
  • Author(s): 佐藤礼子、深見希代子
  • Organizer: 第７４回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] マクロファージにおけるホスホリパーゼCδ１の機能解析 (2015)
  • Author(s): 工藤光野、内田崇史、澤田麻優、米田敦子、深見希代子
  • Organizer: 第６７回日本細胞生物学会大会
  • Place of Presentation: 東京
  • Year and Date: 2015-06-30
• [Presentation] ホスホリパーゼCδ１はケラチノサイトにおけるフィラグリン分解酵素の発現に必要である (2015)
  • Author(s): 六笠千愛、庄司麻土香、金丸佳織、中村由和、深見希代子
  • Organizer: 第６７回日本細胞生物学会大会
  • Place of Presentation: 東京
  • Year and Date: 2015-06-30
• [Presentation] ホスホリパーゼCdeltalの減少はp38MAPKの過剰活性化を介し表皮バリア機能を低下させる (2015)
  • Author(s): 中村由和、金丸佳織、深見希代子
  • Organizer: 第５７回日本脂質生化学会
  • Place of Presentation: 東京
  • Year and Date: 2015-05-28
• [Presentation] Phospholipase C delta 1 induces E-cadherin expression and suppresses malignancy in colorectal cancer cells (2015)
  • Author(s): Reiko, Satow., Tamaki, Hirano,, Ryosuke, Batori., Tomomi, Nakamura., Yumi, Murayama., Kiyoko, Fukami.
  • Organizer: 6th International Conference on Phospholipase A2 and Lipid Mediators
  • Place of Presentation: Tokyo
  • Year and Date: 2015-02-11
• [Presentation] Phospholipase C δ1 is required for epidermal barrier formation (2015)
  • Author(s): Yoshikazu, Nakamura., Kaori, Kanemaru., Kiyoko, Fukami
  • Organizer: 6th International Conference on Phospholipase A2 and Lipid Mediators
  • Place of Presentation: Tokyo
  • Year and Date: 2015-02-11
• [Presentation] Loss of phospholipase C δ1 impairs keratinocyte differentiation and epidermal barrier (2014)
  • Author(s): Kaori, Kanemaru., Yoshikazu, Nakamura., Kiyoko, Fukami
  • Organizer: 第39回研究皮膚科学会
  • Place of Presentation: 大阪
  • Year and Date: 2014-12-12
• [Presentation] PLC delta 1 はEカドヘリンの発現を促進し大腸癌の悪性化を抑制する (2014)
  • Author(s): 中村智美、佐藤礼子、深見希代子
  • Organizer: 第87回日本生化学会
  • Place of Presentation: 京都
  • Year and Date: 2014-10-15
• [Presentation] ケラチノサイトにおけるホスホリパーゼCδ1の減少は炎症性サイトカインの発現を低下させる (2014)
  • Author(s): 小倉崇寛、金丸佳織、中村由和、深見希代子
  • Organizer: 第87回日本生化学会
  • Place of Presentation: 京都
  • Year and Date: 2014-10-15
• [Presentation] ホスホリパーゼCδ1の欠損は炎症性皮膚疾患を誘導する (2014)
  • Author(s): 10.金丸佳織、中村由和、深見希代子
  • Organizer: 第87回日本生化学会
  • Place of Presentation: 京都
  • Year and Date: 2014-10-15
• [Presentation] カルシウム動態制御情報伝達系は様々な生理機能に関与する (2014)
  • Author(s): 深見希代子
  • Organizer: 第58回日本薬学会関東支部大会
  • Place of Presentation: 東京
  • Year and Date: 2014-10-04
  • Invited
• [Presentation] Phospholipase C Delta 1 Induces E-cadherin Expression and Suppresses Malignancy in Colorectal Cancer Cells (2014)
  • Author(s): 佐藤礼子、深見希代子
  • Organizer: 第７３回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25
• [Presentation] E-カドヘリンの発現制御を介したがん細胞の運動性・浸潤性阻害 (2014)
  • Author(s): 深見希代子
  • Organizer: CBIセミナー
  • Place of Presentation: 東京
  • Year and Date: 2014-09-12
  • Invited
• [Presentation] フィブロネクチンマトリックス形成における δ型ホスホリパーゼCの役割 (2014)
  • Author(s): 米田敦子、鈴木沙知、土屋夏希、深見希代子
  • Organizer: 第66回日本細胞生物学会大会
  • Place of Presentation: 奈良
  • Year and Date: 2014-06-11
• [Book] 遺伝子工学 (2017)
  • Author(s): 深見希代子
  • Total Pages: 17
  • Publisher: 広川書店
• [Book] モデル動物利用マニュアル-脂質代謝異常と関連疾患 (2015)
  • Author(s): 中村由和、深見希代子
  • Total Pages: 8
  • Publisher: エル・アイ・シー
• [Book] なぜ “あぶら”の異常が病気を引き起こすのか？ (2015)
  • Author(s): 中村由和、金丸佳織、深見希代子
  • Total Pages: 7
  • Publisher: 羊土社
• [Book] Phospholipases in Health and Disease (2014)
  • Author(s): Fukami, K., Nakamura, Y
  • Total Pages: 10
  • Publisher: Phospholipases in Health and Disease
• [Book] 表皮におけるイノシトールリン脂質代謝の役割 (2014)
  • Author(s): 金丸佳織、中村由和、深見希代子
  • Total Pages: 4
  • Publisher: 生化学
• [Book] モデル動物利用マニュアル-脂質代謝異常と関連疾患.下巻 (2014)
  • Author(s): 中村由和、深見希代子
  • Total Pages: 12
  • Publisher: エルアイシー
• [Book] 脂質疾患学～脂質研究から疾患制御へ (2014)
  • Author(s): 中村由和, 金丸佳織, 深見希代子
  • Publisher: 羊土社
• [Book] ホスホリパーゼC (PLC)による恒常性維持機構とその破綻がもたらす疾病 (2014)
  • Author(s): 深見希代子、中村由和
  • Total Pages: 8
  • Publisher: 医学のあゆみ
• [Remarks] 東京薬科大学生命科学部ゲノム病態医科学研究室HP
  • URL: http://toyaku-ls-genome.com/
• [Patent(Industrial Property Rights)] 腫瘍細胞の悪性化抑制剤及び抗腫瘍剤 (2016)
  • Inventor(s): 深見希代子, 佐藤礼子
  • Industrial Property Rights Holder: 深見希代子, 佐藤礼子
  • Industrial Property Rights Type: 特許
  • Filing Date: 2016-04-22
  • Overseas
• [Patent(Industrial Property Rights)] 腫瘍細胞の悪性化抑制剤及び抗腫瘍剤 (2015)
  • Inventor(s): 深見希代子、佐藤礼子
  • Industrial Property Rights Holder: 深見希代子、佐藤礼子
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2015-093980
  • Filing Date: 2015-05-01