Elucidation of the mechanism underlying apoptosis-induced compensatory proliferation using a murine model

• Project/Area Number: 25670167
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: Toho University (2014); Juntendo University (2013)
• Principal Investigator: NAKANO Hiroyasu 東邦大学, 医学部, 教授 (70276476)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 細胞死 / cFLIP / アポトーシス / ネクロプトーシス / 腸炎 / X染色体不活性化 / 代償性増殖 / ノックインマウス / RegIII / X染色体 / マイクロアレイ / Crisper/Cas9 / cFLIPs / トランスジェニックマウス

Outline of Final Research Achievements

Apoptotic cells might produce growth factors that subsequently induce proliferation, which is referred to as compensatory proliferation. The aim of the study is to identify growth factors released from dying cells and elucidate the mechanisms underlying compensatory proliferation. We generated mice that harbored cFLIPs gene at a locus on X chromosome. Intestinal epithelial cells of cFLIPs KI mice underwent apoptosis, however, female cFLIPs KI mice were born and developed without abnormality, and fertile. To identify candidate genes that are potentially involved in proliferation, we performed genome-wide transcriptome analysis using intestines of cFLIPs KI embryos and we found that RegIIIb and RegIIIg involved in tissue repair were significantly elevated in the intestine of cFLIPs KI embryos compared to wild-type embryos. Now, we are going to generate mice lacking both RegIIIb and RegIIIg to elucidate a role for these genes in compensatory proliferation.

Research Products

• [Journal Article] 慢性炎症と悪性腫瘍 (2015)
  • Author(s): 土屋勇一、中野裕康
  • Journal Title: 臨床免疫・アレルギー科 Volume: 63 Pages: 1-6
• [Journal Article] ネクロプトーシスによる生体応答制御機構 (2015)
  • Author(s): 進藤綾大、中野裕康
  • Journal Title: 臨床免疫・アレルギー科 Volume: 印刷中
• [Journal Article] Disruption of Tumor Necrosis Factor Receptor Associated Factor 5 Exacerbates Pressure Overload Cardiac Hypertrophy and Fibrosis. (2014)
  • Author(s): Bian, Z., Dai, J., Nakano, H., Guan, H., Yuan, Y., Gan, L., Zhou, H., Zong, J., Zhang, Y., Li, F., Yan, L., Shen, D., Li, H., and Tang, Q.
  • Journal Title: J Cell Biochem Volume: 115 Issue: 2 Pages: 349-358
  • DOI: 10.1002/jcb.24669
  • Peer Reviewed
• [Journal Article] cFLIPの生体の恒常性維持における役割 (2014)
  • Author(s): 中野裕康
  • Journal Title: 生化学 Volume: 86 Pages: 400-403
  • NAID: 40020153836
  • Peer Reviewed
• [Journal Article] TNF receptor-associated factor 5 limits inflammatory CD4+ T cell differentiation by antagonizing IL-6-receptor signaling. (2014)
  • Author(s): Nagashima H, Okuyama Y, Asao A, Kawabe T, Yamaki S, Nakano H, Croft M, Ishii N, and So T
  • Journal Title: Nature Immunology Volume: 15 Issue: 5 Pages: 449-456
  • DOI: 10.1038/ni.2863
  • Peer Reviewed
• [Journal Article] Tumor Necrosis Factor Receptor Associated Factor 5 is an Essential Mediator of Ischemic Brain Infarction (2013)
  • Author(s): Lang Wang et al
  • Journal Title: J Neurochem Volume: in press Issue: 3 Pages: 400-414
  • DOI: 10.1111/jnc.12207
  • Peer Reviewed
• [Journal Article] Differential topical susceptibility to TGFbeta in intact and injured regions of the epithelium: key role in myofibroblast transition. (2013)
  • Author(s): Speight, P., Nakano, H., Kelley, T. J., Hinz, B., and Kapus, A.
  • Journal Title: Mol Biol Cell Volume: 24 Issue: 21 Pages: 3326-3336
  • DOI: 10.1091/mbc.e13-04-0220
  • Peer Reviewed
• [Journal Article] Critical contribution of oxidative stress to TNFα-induced necroptosis downstream of RIPK1 activation. (2013)
  • Author(s): Shindo R, Kakehashi H, Okumura K, Kumagai Y, Nakano H.
  • Journal Title: Biochem Biophys Res Commun Volume: 436 Issue: 2 Pages: 212-6
  • DOI: 10.1016/j.bbrc.2013.05.075
  • Peer Reviewed
• [Journal Article] Shigella IpaH0722 E3 ubiquitin ligase effector targets TRAF2 to inhibit PKC-NF-κB activity in invaded epithelial cells. (2013)
  • Author(s): Ashida H, Nakano H, Sasakawa C.
  • Journal Title: PLoS Pathog. Volume: 9 Issue: 6 Pages: e1003409-e1003409
  • DOI: 10.1371/journal.ppat.1003409
  • Peer Reviewed
• [Journal Article] Hyperosmotic stress regulates the distribution and stability of myocardin-related transcription factor, a key modulator of the cytoskeleton (2012)
  • Author(s): Donald L Ly et al
  • Journal Title: Am J Physiol Cell Physiol Volume: 304 Issue: 2 Pages: C115-C127
  • DOI: 10.1152/ajpcell.00290.2012
  • Peer Reviewed
• [Presentation] 計画的ネクローシスの担う生体応答機構の解明 (2014)
  • Author(s): 中野 裕康
  • Organizer: 新学術領域「ダイイングコード」キックオフシンポジウム
  • Place of Presentation: 東京大学、東京都、文京区
  • Year and Date: 2014-11-13
  • Invited
• [Presentation] cFLIPによる細胞死と炎症の制御 (2014)
  • Author(s): 中野 裕康
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 国立京都国際会館、京都府、京都市
  • Year and Date: 2014-10-16
  • Invited
• [Presentation] X染色体の不活性化を利用したcFLIPsトランスジェニックマウスの樹立 (2014)
  • Author(s): 進藤綾大、駒澤幸子、小池正人、内山安男、大村谷昌樹、中野裕康
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 国立京都国際会館、京都府、京都市
  • Year and Date: 2014-10-16
• [Presentation] IL-11を介した腸管の恒常性維持機構の解明 (2014)
  • Author(s): 仁科隆史、大塚正人、中村衣里、多田昇弘、中野裕康
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 国立京都国際会館、京都府、京都市
  • Year and Date: 2014-10-16
• [Presentation] cFLIPによる生と死の運命決定機構 (2014)
  • Author(s): 中野 裕康
  • Organizer: 第67回日本酸化ストレス学会
  • Place of Presentation: 同志社大学、京都府、京都市
  • Year and Date: 2014-09-05
  • Invited
• [Presentation] 皮膚の恒常性維持におけるcFLIPの役割 (2014)
  • Author(s): 中野 裕康
  • Organizer: 第23回日本Cell Death学会
  • Place of Presentation: 東京医科歯科大学、東京都、文京区
  • Year and Date: 2014-07-18
  • Invited
• [Presentation] Generation of mice that amplifies signals released from dying hepatocytes. (2013)
  • Author(s): Piao X, Tanaka M, Ohmuraya M, Miyake S, Okumura K, Tanaka M, and Nakano H.
  • Organizer: 第44回日本免疫学会総会
  • Place of Presentation: 千葉
• [Presentation] 抗酸化剤はRIPK1のリン酸化およびネクロプトーシスを抑制する. (2013)
  • Author(s): 進藤綾大, 掛橋秀直, 熊谷嘉人, 奥村康, and 中野裕康.
  • Organizer: 第83回日本生化学学会大会
  • Place of Presentation: 横浜
• [Presentation] 親電子リガンドによるIL-11産生機構の解明. (2013)
  • Author(s): 仁科隆史, 新開泰弘, 熊谷嘉人, 奥村康, and 中野裕康.
  • Organizer: 第83回日本生化学学会大会
  • Place of Presentation: 横浜
• [Presentation] c-FLIPによる生体の恒常性維持における役割. (2013)
  • Author(s): 中野裕康.
  • Organizer: 第83回日本生化学学会大会
  • Place of Presentation: 横浜
  • Invited
• [Presentation] 酸化ストレスはRIPK1の下流でネクロプトーシスに関与する. (2013)
  • Author(s): 進藤綾大, 掛橋秀直, 熊谷嘉人, 奥村康, and 中野裕康.
  • Organizer: 第22回日本Cell Death学会
  • Place of Presentation: 京都
• [Presentation] c-FLIP による細胞の生と死の運命決定機構の解明. (2013)
  • Author(s): 中野裕康.
  • Organizer: 第22回日本Cell Death学会
  • Place of Presentation: 京都
  • Invited
• [Presentation] c-FLIP maintains tissue homeostasis by preventing apoptosis and programmed necrosis. (2013)
  • Author(s): Piao X, Komazawa-Sakon S, Nishina T, Okumura K, He YW, and Nakano H.
  • Organizer: 14th International TNF Conference
  • Place of Presentation: カナダ
• [Presentation] Interleukin-11 is responsible for stress-induced proliferation of intestinal epithelial cells. (2013)
  • Author(s): Nishina T, Shinkai Y, Kumagai Y, Okumura K, and Nakano H.
  • Organizer: 14th International TNF Conference
  • Place of Presentation: カナダ
• [Presentation] c-FLIP maintains tissue homeostasis by preventing apoptosis and programmed necrosis. (2013)
  • Author(s): Piao X, Komazawa-Sakon S, Nishina T, Okumura K, He YW, and Nakano H.
  • Organizer: Cold Spring Harbor Asia Conference “Non-apoptotic cell death”
  • Place of Presentation: 中国
• [Book] Current Topics in Microbiology and Immunology "Apoptosis" (2015)
  • Author(s): Nakano H, Piao X, Shindo R, Komazawa-Sakon S.
  • Publisher: Springer International Publishing AG
• [Remarks] 東邦大学生化学講座ホームページ
  • URL: http://tohobiochemi.jp
• [Remarks] 東邦大学医学部生化学講座
  • URL: http://www.med.toho-u.ac.jp/lab/lab_biochemi/lab_biochemi.html