Mechanisms of constitutive NF-kappaB activation and related diseases

• Project Area: Regulation of signal transduction by post-translational modifications and its pathogenic dysregulation
• Project/Area Number: 22117004
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: SHOJI Yamaoka 東京医科歯科大学, 医歯(薬)学総合研究科, 教授 (90263160)
• Co-Investigator(Kenkyū-buntansha): SAITOH Yasunori 東京医科歯科大学, 大学院医歯学総合研究科, 助教 (00516312)
• Project Period (FY): 2010-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥133,640,000 (Direct Cost: ¥102,800,000、Indirect Cost: ¥30,840,000); Fiscal Year 2014: ¥26,130,000 (Direct Cost: ¥20,100,000、Indirect Cost: ¥6,030,000); Fiscal Year 2013: ¥27,430,000 (Direct Cost: ¥21,100,000、Indirect Cost: ¥6,330,000); Fiscal Year 2012: ¥29,380,000 (Direct Cost: ¥22,600,000、Indirect Cost: ¥6,780,000); Fiscal Year 2011: ¥28,990,000 (Direct Cost: ¥22,300,000、Indirect Cost: ¥6,690,000); Fiscal Year 2010: ¥21,710,000 (Direct Cost: ¥16,700,000、Indirect Cost: ¥5,010,000)
• Keywords: 翻訳後修飾 / 癌 / NF-kappaB / 分化 / 細胞分化

Outline of Final Research Achievements

Based on the fact that ubiquitination and phosphorylation, two well-known post-translational modifications, regulate the transcription factor NF-kappaB which is deeply involved in the development of neoplastic and/or inflammatory diseases, we have demonstrated that overexpression of NF-kappaB inducing kinase causes constitutive NF-kappaB activation in adult T-cell leukemia and ovarian cancer cells and that one of the NF-kappaB targets A20, a ubiquitin-editing enzyme, plays an essential role in the survival and proliferation of those cancer cells.

Research Products

• [Journal Article] Involvement of double-stranded RNA-dependent protein kinase and antisense viral RNA in the constitutive NFκB activation in adult T-cell leukemia/lymphoma cells. (2015)
  • Author(s): Kinpara S, Ito S, Takahata T, Saitoh Y, Hasegawa A, Kijiyama M, Utsunomiya A, Masuda M, Miyazaki Y, Matsuoka M, Nakamura M, Yamaoka S, Masuda T, Kannagi M.
  • Journal Title: Leukemia Volume: 1 Issue: 6 Pages: 1-5
  • DOI: 10.1038/leu.2015.1
  • Peer Reviewed
• [Journal Article] Procyanidin trimer C1 derived from Theobroma cacao reactivates latent human immunodeficiency virus type 1 provirus. (2015)
  • Author(s): Hori T, Barnor J, Nguyen Huu T, Morinaga O, Hamano A, Ndzinu J, Yamaoka S. et al.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 459 Issue: 2 Pages: 288-293
  • DOI: 10.1016/j.bbrc.2015.02.102
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] NF-κB Inducing Kinase, a Central Signaling Component of the Non-Canonical Pathway of NF-κB, Contributes to Ovarian Cancer Progression. (2014)
  • Author(s): Uno M, Saitoh Y, Mochida K, Tsuruyama E, Kiyono T, Imoto I, Inazawa J, Yuasa Y, Kubota T, Yamaoka S.
  • Journal Title: PLoS One Volume: 9(2) Issue: 2 Pages: e88347-e88347
  • DOI: 10.1371/journal.pone.0088347
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] CD137 expression is induced by Epstein-Barr virus infection through LMP1 in T or NK cells and mediates survival promoting signals. (2014)
  • Author(s): Yoshimori M, Imadome K, Komatsu H, Wang L, Saitoh Y, Yamaoka S, Fukuda T, Kurata M, Koyama T, Shimizu N, Fujiwara S, Miura O, Arai A.
  • Journal Title: PLoS One Volume: 9(11) Issue: 11 Pages: e112564-e112564
  • DOI: 10.1371/journal.pone.0112564
  • Peer Reviewed / Open Access
• [Journal Article] NF-κB inducing kinase, a central signaling component of the non-canonical pathway of NF-κB, contributes to ovarian cancer progression. (2014)
  • Author(s): Uno M, Saitoh Y, Mochida K, Tsuruyama E, Kiyono T, Imoto I, Inazawa J, Yuasa Y, Kubota T, Yamaoka S.
  • Journal Title: PLoS One Volume: 9
  • Peer Reviewed
• [Journal Article] Visualization of stem cell features in human hepatocellular carcinoma reveals in vivo significance of tumor-host interaction and clinical course. (2013)
  • Author(s): Muramatsu S, Tanaka S, Mogushi K, Adikrisna R, Aihara A, Ban D, Ochiai T, Irie T, Kudo A, Nakamura N, Nakayama K, Tanaka H, Yamaoka S, Arii S.
  • Journal Title: Hepatology Volume: 58 Pages: 218-228
  • Peer Reviewed
• [Journal Article] Visualization of stem cell features in human hepatocellular carcinoma enlightened in vivo significance of tumor-host interaction and clinical implication. (2013)
  • Author(s): Muramatsu S
  • Journal Title: Hepatology Volume: 58 Issue: 1 Pages: 218-228
  • DOI: 10.1002/hep.26345
  • Peer Reviewed
• [Journal Article] Tumor suppressor TAp73 gene specifically responds to deregulated E2F activity in human normal fibroblasts (2012)
  • Author(s): Ozono E
  • Journal Title: Genes Cells Volume: 8
  • Peer Reviewed
• [Journal Article] Identification of pancreatic cancer stem cells and selective toxicity of chemotherapeutic agents. (2012)
  • Author(s): Adikrisna R, Tanaka S et al.
  • Journal Title: Gastroenterology Volume: 143(1) Issue: 1 Pages: 234-245
  • DOI: 10.1053/j.gastro.2012.03.054
  • Peer Reviewed
• [Journal Article] An IκB kinase 2 inhibitor IMD-0354 suppresses the survival of adult T-cell leukemia cells (2012)
  • Author(s): Uota, S., et al
  • Journal Title: Cancer Science Volume: 103 Pages: 100-106
  • Peer Reviewed
• [Journal Article] Epstein-Barr virus latent membrane protein 1 induces cancer stem/progenitor-like cells in nasopharyngeal epithelial cell lines (2011)
  • Author(s): Kondo, S., et al
  • Journal Title: J.Virol. Volume: 85 Pages: 11255-11264
  • Peer Reviewed
• [Journal Article] Distinct Roles of Transforming Growth Factor-{beta}-activated Kinase 1 (TAK1)-c-Rel and Interferon Regulatory Factor 4 (IRF4) Pathways in Human T Cell Lymphotropic Virus 1-transformed T helper 17 Cells Producing Interleukin-9 (2011)
  • Author(s): Refaat, A., et al
  • Journal Title: J Biol Chem Volume: 286 Pages: 21092-21099
  • Peer Reviewed
• [Journal Article] Identification of CD44 as a downstream target of noncanonical NF-κB pathway activated by human T-cell leukemia virus type 1-encoded Tax protein (2011)
  • Author(s): Zhang J., et al
  • Journal Title: Virology Volume: 413 Pages: 244-252
  • Peer Reviewed
• [Journal Article] Identification of CD44 as a downstream target of noncanonical NF-κB pathway activated by Human T-cell leukemia virus type 1-encoded Tax protein. (2011)
  • Author(s): Zhang J., ほか
  • Journal Title: Virology Volume: (In press)(未定)
  • Peer Reviewed
• [Journal Article] Overexpression of NF-kappaB inducing kinase underlies constitutive NF-kappaB activation in lung cancer cells. (2010)
  • Author(s): Saitoh Y, ほか
  • Journal Title: Lung Cancer Volume: 70 Pages: 263-270
  • Peer Reviewed
• [Journal Article] Identification of a new NEMO/TRAF6 interface affected in incontinentia pigmenti pathology. (2010)
  • Author(s): Gautheron J., ほか
  • Journal Title: Hum Mol Genet. Volume: 19 Pages: 3138-3149
  • Peer Reviewed
• [Presentation] ガーナ産植物由来成分による潜伏HIV-1プロウイルス再活性化とサイトカイン産生誘導の解析 (2014)
  • Author(s): 堀恭徳、Nursarat Ahmed,Tunggyen Huu,宇都拓洋、森永紀、吉仲由之、神奈木真理、正山征洋、山岡昇司
  • Organizer: 第28回日本エイズ学会学術集会・総会
  • Place of Presentation: 大阪国際会議場 大阪
  • Year and Date: 2014-12-03
• [Presentation] ヒト単球系細胞株THP-1分化モデルを用いたTNFIP3/A20の抗アポトーシス機能の解析 (2014)
  • Author(s): 山口 遼, 大迫 美穂, 斉藤 愛記, 持田 佳奈子, 山岡 昇司
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜 横浜
  • Year and Date: 2014-11-26
• [Presentation] A20 はそのユビキチン修飾活性に依存せずTNF-α によるcaspase-3 活性化を抑制する (2014)
  • Author(s): 鶴山惠理、斉藤愛記、山岡昇司
  • Organizer: 第７３回日本癌学会総会
  • Place of Presentation: パシフィコ横浜 横浜
  • Year and Date: 2014-09-25
• [Presentation] HTLV-I感染細胞におけるA20はユビキチン化修飾酵素活性非依存的に細胞生存を支える (2014)
  • Author(s): 齊藤愛記、持田佳奈子、鶴山惠理、徳永文稔、山岡昇司
  • Organizer: 第1回日本HTLV-1学会学術集会
  • Place of Presentation: 東京大学医科学研究所 東京
  • Year and Date: 2014-08-23
• [Presentation] ユビキチン化修飾酵素A20はHTLV-I感染細胞の細胞死を抑制する (2013)
  • Author(s): 鶴山惠理、斉藤愛記、山岡昇司
  • Organizer: 第5回HTLV-I研究会
  • Place of Presentation: 東京
• [Presentation] Ubiquitin-editing enzyme A20 interacts with and suppresses caspase 8 in HTLV-I-infected cells (2013)
  • Author(s): 斉藤愛記、宇野雅哉、山岡昇司
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] TNFAIP3/A20はHTLV-I感染細胞においてcaspase-8活性化を制御する (2013)
  • Author(s): 鶴山惠理、斉藤愛記、持田佳奈子、徳永文稔、山岡昇司
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸
• [Presentation] ヒト単球系細胞株THP-1の分化誘導における持続的NF-κB活性化動態とA20複合体の発現制御 (2012)
  • Author(s): 大迫美穂
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
  • Year and Date: 2012-12-12
• [Presentation] 卵巣癌細胞におけるNF-κB inducing kinase異常発現は恒常的NF-κB活性化と腫瘍形成能に寄与する (2012)
  • Author(s): 宇野雅哉
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
  • Year and Date: 2012-12-12
• [Presentation] A20/TNFAIP3は癌細胞株の増殖に寄与する (2012)
  • Author(s): 深澤麻純
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
  • Year and Date: 2012-09-19
• [Presentation] ユビキチン修飾酵素A20は成人T細胞白血病（ATL）細胞の生存に必要である (2012)
  • Author(s): 掛谷綾香
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
  • Year and Date: 2012-09-19
• [Presentation] ユビキチン化修飾酵素A20はHTLV-I感染細胞の生存に寄与する (2012)
  • Author(s): 齋藤愛記
  • Organizer: HTLV-I研究会
  • Place of Presentation: 東京
  • Year and Date: 2012-08-25
• [Presentation] Ubiquitin-editing enzyme A20 contributes to the survival of cancer cells (2011)
  • Author(s): Fukazawa, M., et al
  • Organizer: 第34回日本分子生物学会
  • Place of Presentation: 横浜
  • Year and Date: 2011-12-15
• [Presentation] Kinetic analysis of persistent NF-κB activation in PMA-induced differentiation of human monocytic THP-1 cells (2011)
  • Author(s): Osako, M., et al
  • Organizer: 第34回日本分子生物学会
  • Place of Presentation: 横浜
  • Year and Date: 2011-12-15
• [Presentation] EBウイルスはTあるいはNK細胞に感染後NK-kB活性化を介して腫瘍発症に寄与する (2011)
  • Author(s): 新井文子, ほか
  • Organizer: 日本血液学会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-14
• [Presentation] A20 enhances constitutive activation of NF-KB in adult T-cell leukemia cells (2011)
  • Author(s): Saitoh, Y., et al
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-03
• [Presentation] NIK contributes to constitutive NF-KB activation and anchorage-independent growth of ovarian cancer cells (2011)
  • Author(s): Uno, M., et al
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-03
• [Presentation] ユビキチン化修飾タンパク質A20はHTLV-1感染細胞株の増殖に重要である (2011)
  • Author(s): 掛谷綾香, ほか
  • Organizer: 第4回HTLV-1研究会
  • Place of Presentation: 東京
  • Year and Date: 2011-09-19
• [Presentation] NF-KB inducing kinase contributes to the manifestation of cancer phenotypes in ovarian cancer cells through constitutive activation of NF-KB (2011)
  • Author(s): Uno, M., et al
  • Organizer: 13th International TNF Conference TNF2011
  • Place of Presentation: 淡路島
  • Year and Date: 2011-05-17
• [Presentation] Deregulated expression of NF-kB inducing kinase contributes to constitutive NF-kB activation and growth properties of ovarian cancer cells (2011)
  • Author(s): Uno, M., et al
  • Organizer: Cincinnati Cancer Symposium Series
  • Place of Presentation: Cincinnati, USA
  • Year and Date: 2011-05-03
• [Presentation] Aberrant expression of NF-kappaB inducing kinase underlies constitutive NF-kappaB activation in cancer cells (2010)
  • Author(s): Yasunori Saitoh
  • Organizer: 2010 meeting of Mechanims and Models of Cancer
  • Place of Presentation: Cold Spring Harbour Laboratory, USA
  • Year and Date: 2010-08-17
• [Presentation] A20の発現は成人T細胞白血病細胞におけるNF-kB依存性転写を促進する (2010)
  • Author(s): 萩原剛志
  • Organizer: 第3回HTLV-I研究会
  • Place of Presentation: 東京大学
• [Presentation] 卵巣癌細胞におけるNF-kappaB inducing kinaseによる恒常的NF-kappaB活性化調節 (2010)
  • Author(s): 宇野雅哉
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪コンベンションセンター
• [Presentation] Cancer cell lines but not normal cells, harbor deregulated E2F activity that activates tumor suppressor genes (2010)
  • Author(s): 大園瑛子
  • Organizer: 第69回日本癌学会
  • Place of Presentation: 大阪コンベンションセンター
• [Presentation] A20 enhances NF-kB activation in adult T-cell leukemia cells (2010)
  • Author(s): 萩原剛志
  • Organizer: 第69回日本癌学会
  • Place of Presentation: 大阪コンベンションセンター
• [Book] Protein Modifications in Pathogenic Dysregulation of Signaling (2015)
  • Author(s): Jun-ichiro Inoue, Mutsuhiro Takekawa, Masahide Takahashi, Fuminori Tokunaga, Tohru Ishitani, Kazuhisa Ichikawa, Masahiro Oyama, Shoji Yamaoka et al.
  • Publisher: Springer
• [Remarks] 研究テーマ
  • URL: http://molv.org/research.html