Oncogenic role of APC/C ubiquitin ligase inhibitor, Emi1

• Project/Area Number: 20689033
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Morphological basic dentistry
• Research Institution: Hiroshima University
• Principal Investigator: KUDO Yasusei Hiroshima University, 大学院・医歯薬学総合研究科, 助教 (50314753)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥23,790,000 (Direct Cost: ¥18,300,000、Indirect Cost: ¥5,490,000); Fiscal Year 2010: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2009: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2008: ¥13,520,000 (Direct Cost: ¥10,400,000、Indirect Cost: ¥3,120,000)
• Keywords: 癌 / 細胞周期 / ユビキチン分解 / 細胞分裂 / Emil / 頭頸部扁平上皮癌 / ユビキチン / APC/C / Emi1 / APC / C

Research Abstract

The abnormality of checkpoint and cell division during cell cycle is thought to be a trigger of carcinogenesis. APC/C ubiquitin ligase complex regulates the protein level of many key molecules for cell division. Emi1, an inhibitor of APC/C, inhibits APC/C activity from S phase to the beginning of M phase. In the present study, we found that APC/C inhibitor, Emi1 was frequently overexpressed in cancer cell lines and head and neck cancer cases. Moreover, we found a cancer cell line that constitutively expressed Emi1 during cell cycle progression. In this cell line, Ser310 and Thr315 of Emi1 were phosphorylated by ERK-RSK pathway and this phosphorylation inhibited ubiquitin-mediated proteolysis. Constitutive Emi1 expression inhibited APC/C activity during cell cycle progression and induced overexpression of APC/C substrates.In summary, Emi1 overexpression caused by the defects of degradation induced the constitutive inhibition of APC/C activity and was involved in abnormal regulation of cell cycle and carcinogenesis.

Research Products

• [Journal Article] miR-22 provides a direct link between celular senescence and tumorgenesis. (2011)
  • Author(s): Xu, D., Takeshita, F., Hino, Y., Fukunaga, S., Kudo, Y., Tamaki, A., Matsunaga, J., Takahashi, R., Takata, T., Shimamoto, A., Ochiya, T., Tahara, H.
  • Journal Title: J Cell Biol 93 Pages: 409-424
  • Peer Reviewed
• [Journal Article] Ameloblastin regulates osteogenic differentiation by inhibiting Src kinase via crosstalk between integrin β1 and CD63. (2011)
  • Author(s): Iizuka, S., Kudo, Y., Yoshida, M., Tsunematsu, T., Yoshiko, Y., Uchida, T., Ogawa, I., Miyauchi, M., Takata, T.
  • Journal Title: Mol Cell Biol Corresponding author 31 Pages: 783-792
  • NAID: 120006718352
  • Peer Reviewed
• [Journal Article] N-cadherin expression is correlated with metastasis of spindle cell carcinoma of head and neck region. (2011)
  • Author(s): Nguyen, P.T., Kudo, Y., Yoshida, M., Iizuka, S., Ogawa, I., Takata, T.
  • Journal Title: J Oral Pathol Med Corresponding author 40 Pages: 77-82
  • NAID: 120006714448
  • Peer Reviewed
• [Journal Article] N-cadherin expression is involved in malignant behavior of head and neck cancer in relation to epithelial-mesenchymal transition. (2011)
  • Author(s): Nguyen, P.T., Kudo, Y., Yoshida, M., Kamata, N., Ogawa, I., Takata, T.
  • Journal Title: Histology and Histopathology Corresponding author 26 Pages: 147-156
  • NAID: 120006727042
  • Peer Reviewed
• [Journal Article] SCFβTrcp mediates stress-induced Cdc25B ubiquitylation through cooperation of an atypical consensus sequence and PEST. (2011)
  • Author(s): Uchida S, Watanabe N, Kudo Y, et al.
  • Journal Title: Journal of Cell Science Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] miR-22 represses cancer progression by inducing cellular senescence. (2011)
  • Author(s): Xu, D., Takeshita, F., Hino, Y., Fukunaga, S., Kudo, Y., et al.
  • Journal Title: Journal of Cell Biology Volume: 193 Pages: 409-424
  • Peer Reviewed
• [Journal Article] Nuclear Survivin expression is correlated with malignant behaviors of head and neck cancer together with Aurora-B. (2010)
  • Author(s): Qi G, Kudo, Y., Ando T, Tsunematsu T, Shimizu N, Siriwardena S, Yoshida M, Keikhaee M, Ogawa I, Takata T.
  • Journal Title: Oral Oncol Corresponding author 46 Pages: 263-270
  • Peer Reviewed
• [Journal Article] Deregulation of anaphase promoting complex/cyclosome dependent proteolysis in cancer. (2010)
  • Author(s): Kudo, Y., Tsunematsu, T., Takata, T.
  • Journal Title: J Oral Biosci Corresponding author 52 Pages: 388-401
  • NAID: 10027626065
  • Peer Reviewed
• [Journal Article] Nuclear Survivin expression is correlated with malignant behaviors of head and neck cancer together with Aurora-B. (2010)
  • Author(s): Qi G, Kudo Y, Ando T, et al
  • Journal Title: Oral Oncology (印刷中)
  • Peer Reviewed
• [Journal Article] Oncogenic role of nuclear accumulated Aurora-A. (2009)
  • Author(s): Tatsuka, M., Sato, S., Kanda, A., Miki, T., Kamata, N., Kitajima, S., Kudo, Y., Takata, T.
  • Journal Title: Mol Carcinogen 48 Pages: 810-820
  • Peer Reviewed
• [Journal Article] RUNX3 has an oncogenic role in head and neck cancer. (2009)
  • Author(s): Tsunematsu, T., Kudo, Y., Iizuka, S., Ogawa, I., Fujita, T., Kurihara, H., Abiko, Y., Takata, T.
  • Journal Title: PLoS ONE Corresponding author 4
  • NAID: 120006714449
  • Peer Reviewed
• [Journal Article] Oncogenic role of nuclear accumulated Aurora-A (2009)
  • Author(s): Tatsuka M, Sato S, Kanda A, Miki T, Kamata N, Kitajima S, Kudo Y, Takata T.
  • Journal Title: Molecular Carcinogenesis 48 Pages: 810-820
  • Peer Reviewed
• [Journal Article] RUNX3 has an oncogenic role in head and neck cancer (2009)
  • Author(s): Tsunematsu T, Kudo Y, Iizuka S, et al
  • Journal Title: PLoS ONE 4
  • NAID: 120006714449
  • Peer Reviewed
• [Journal Article] SCF^BTrcp mediates stress-induced Cdc25B ubiquitylation through cooperation of an atypical consensus sequence and PEST.
  • Author(s): Uchida, S., Watanabe, N., Kudo, Y., Yoshioka, K., Matsunaga, T., Ishizuka, Y., Nakagama, H., Poon, R.Y.C., Yamashita, K.
  • Journal Title: J Cell Sci in press
  • Peer Reviewed
• [Presentation] Identification and characterization of new invasion relating molecules of head and neck squamous cell carcinoma. (2010)
  • Author(s): 工藤保誠
  • Organizer: The 120th Anniversary of Siriraj Medical School Siriraj Scientific Congress
  • Place of Presentation: バンコク市(タイ)(招待講演)
  • Year and Date: 2010-08-17
• [Presentation] SCF^BTrcpによるCDC25Bの分解におけるPEST配列の役割 (2010)
  • Author(s): 内田早苗, 渡辺信元, 工藤保誠, 松永司, 中釜斉, 山下克美
  • Organizer: 第33回日本分子生物学会年会
  • Place of Presentation: 神戸市
• [Presentation] Emi1 siRNA enhances the induction if apoptosis by anticancer agent (2010)
  • Author(s): Shimizu N, Kudo Y, Tsunematsu T, Takata T.
  • Organizer: 第33回日本分子生物学会年会
  • Place of Presentation: 神戸市
• [Presentation] Emi1 siRNAによる抗癌剤感受性の増強効果 (2010)
  • Author(s): 清水なつみ, 工藤保誠, 常松貴明, 高田隆
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 大阪市
• [Presentation] Emi1 siRNAによる抗癌剤感受性の増強効果 (2010)
  • Author(s): 工藤保誠, 清水なつみ, 常松貴明, 高田隆
  • Organizer: 第2回日本RNAi研究会
  • Place of Presentation: 広島市
• [Presentation] 口腔扁平上皮癌におけるSurvivinとAurora-Bの過剰発現 (2010)
  • Author(s): 工藤保誠, 斉広塋, 小川郁子, 高田隆
  • Organizer: 第99回日本病理学会
  • Place of Presentation: 東京都
• [Presentation] 癌細胞におけるユビキチン分解異常によってもたらされる細胞周期調節の異常 (2009)
  • Author(s): 工藤保誠
  • Organizer: 第7回口腔医科学フロンティア
  • Place of Presentation: 徳島市
  • Year and Date: 2009-03-07
• [Presentation] B56alpha-PP2A regulates chromosome alignment and stability (2009)
  • Author(s): 北島正二朗, 工藤保誠, 高田隆
  • Organizer: 第32回日本分子生物学会年会
  • Place of Presentation: 横浜市
• [Presentation] Sequence requirement for degradation of Cdc25B by SCFbetaTrCP in response to cellular stress (2009)
  • Author(s): 内田早苗, 渡辺信元, 工藤保誠, 松永司, 中釜斉, 山下克美
  • Organizer: 第32回日本分子生物学会年会
  • Place of Presentation: 横浜市
• [Presentation] Co-expression of nuclear Survivin and Aurora-B shows malignant behavior of head and neck cancer (2009)
  • Author(s): 斉広塋, 工藤保誠, 安藤敏範, 吉田真希, 高田隆
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 横浜市
• [Presentation] Mechanism of JNK-initiated and SCFbetaTrCP-dependent ubiquitination of Cdc25B (2009)
  • Author(s): 内田早苗, 渡辺信元, 工藤保誠, 善岡克次, 松永司, 中釜斉, 山下克美
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 横浜市
• [Presentation] Abnormal expression of Evi5 and its role for cancer development (2009)
  • Author(s): 安藤敏範, 工藤保誠, 常松貴明, 高田隆
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 横浜市
• [Presentation] サテライトシンポジウム「次世代を担う若手シンポジウム:生命科分野で活躍するD.D.S.研究者の多様性」APC/Cユビキチンリガーゼ複合体の制御機構と癌化 (2009)
  • Author(s): 工藤保誠, 高田隆
  • Organizer: 第51回歯科基礎医学会学術大会・総会
  • Place of Presentation: 新潟市
• [Presentation] 口腔癌におけるユビキチン分解異常によるEmi1の過剰発現 (2009)
  • Author(s): 工藤保誠, 常松貴明, 飯塚新二, 小川郁子, 高田隆
  • Organizer: 第28回分子病理研究会
  • Place of Presentation: 神戸市
• [Presentation] APC/Cユビキチンリガーゼ複合体の制御機構と癌 (2009)
  • Author(s): 工藤保誠, 高田隆
  • Organizer: 第51回歯科基礎医学会学術大会・総会
  • Place of Presentation: 新潟市
• [Presentation] 口腔癌におけるユビキチン分解異常によるEmilの過剰発現 (2009)
  • Author(s): 工藤保誠, 常松貴明, 飯塚新二, 小川郁子, 高田隆
  • Organizer: 第28回分子病理研究会
  • Place of Presentation: 神戸市
• [Presentation] A演説口腔癌の増殖および浸潤に関する分子病理学的研究-口腔癌における細胞周期調節因子のユビキチン分解異常- (2008)
  • Author(s): 工藤保誠
  • Organizer: 第54回日本病理学会秋期特別大会
  • Place of Presentation: 松山市
  • Year and Date: 2008-11-20
• [Presentation] Abnormal regulation of Anaphase promoting complex dependent proteolysis by Emi1 disregulation in canoe (2008)
  • Author(s): Kudo Y, Tsunematsu T, Kitajima S, Ogawa I, Takata T
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋市
  • Year and Date: 2008-10-28
• [Presentation] 特別講演タンパク分解による細胞分裂制御とその破綻による癌化への関与 (2008)
  • Author(s): 工藤保誠
  • Organizer: 第7回南九州腫瘍研究会
  • Place of Presentation: 鹿児島市
  • Year and Date: 2008-07-10
• [Presentation] 口腔癌におけるSurvivinとAurora-Bの過剰発現とその意義 (2008)
  • Author(s): 斉広瑩, 工藤保誠, 小川郁子, サマダラニ・シリワルデナ, 吉田真希, 北島正二朗, 宮内睦美, 高田隆
  • Organizer: 第90回広島大学歯学会
  • Place of Presentation: 広島市
  • Year and Date: 2008-06-15
• [Presentation] 口腔癌におけるEmilの過剰発現とその意義 (2008)
  • Author(s): 工藤保誠, 常松貴明, 大林真理子, 小川郁子, 北島正二朗,高田隆
  • Organizer: 第97回日本病理学会総会
  • Place of Presentation: 金沢市
  • Year and Date: 2008-05-16
• [Presentation] SCFbeta-TrcpによるCdc25Bの制御 (2008)
  • Author(s): 内田早苗, 善岡克次, 工藤保誠, 渡辺信元, 松永司, 山下克美
  • Organizer: 第31回日本分子生物学会年会
  • Place of Presentation: 神戸市
• [Presentation] Degradation of Cdc25B by JNK-initiated and SCF/b-TrCP-dependent Ubiquitination (2008)
  • Author(s): Uchida S, Kudo Y, Yoshioka K, Matsunaga T, Yamashita K
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋市
• [Presentation] Abnormal regulation of Anaphase promoting complex dependent proteolysis by Emi1 disregulation in cancer (2008)
  • Author(s): Kudo Y, Tsunematsu T, Kitajima S, Ogawa I, Takata T
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋市
• [Presentation] Degradation of Cdc25B by JNK-initiated and SCF/b-TrCP-dependent Ubiquitination (2008)
  • Author(s): Uchida S, Kudo Y, Yoshioka K, Matsunaga T, Yamashita K
  • Organizer: 第60回日本細胞生物学会大会
  • Place of Presentation: 横浜市
• [Presentation] Abnormal regulation of Anaphase promoting complex dependent proteolysis by Emi1 disregulation in cancer (2008)
  • Author(s): Kudo Y, Tsunematsu T, Kitajima S, Ogawa I, Takata T
  • Organizer: The 14th International Congress of Oral Pathology and Medicine
  • Place of Presentation: サンフランシスコ市,アメリカ合衆国
• [Presentation] 口腔癌におけるEmi1の過剰発現とその意義 (2008)
  • Author(s): 工藤保誠、常松貴明、大林真理子、小川郁子、北島正二朗、高田隆
  • Organizer: 第97回日本病理学会総会
  • Place of Presentation: 金沢
• [Presentation] Abnormal regulation of Anaphase promoting complex dependent proteolysis by Emi1 disregulation in cancer (2008)
  • Author(s): Kudo Y, Tsunematsu T, Kitajiama S, Ogawa I, Takata T
  • Organizer: 3rd International Workshop on Cell Regulations in Division and Arrest
  • Place of Presentation: うるま市
• [Presentation] Abnormal regulation of Anaphase promoting complex dependent proteolysis by Emi 1 disregulation in cancer (2008)
  • Author(s): Kudo Y, Tsunematsu T, Kitajiama S, Ogawa I, Takata T
  • Organizer: 3^<rd> International Workshop on Cell Regulations in Division and Arrest
  • Place of Presentation: 沖縄県うるま市