Role of Aurora kinase in RNA metabolism

• Project/Area Number: 17K08762
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Okayama University
• Principal Investigator: Katayama Hiroshi 岡山大学, 医歯薬学総合研究科, 准教授 (90713975)
• Co-Investigator(Kenkyū-buntansha): 伊藤 佐智夫 岡山大学, 医歯薬学総合研究科, 助教 (30335624) ; 笹井 香織 岡山大学, 医歯薬学総合研究科, 助教 (50722162)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: オーロラキナーゼ / RNA / プロモーター / リン酸化 / RNA結合タンパク質 / オーロラA / hnRNP / オーロラB / mRNAメタボリズム / 細胞周期 / がん抑制タンパク質 / 膠芽腫 / オーロラAキナーゼ

Outline of Final Research Achievements

Here, we report for the first time the essential role of Aurora-A-hnRNP interaction in Aurora-B transcriptional regulation. The results can be summarized as follows: (1) hnRNP controlled Aurora-B mRNA decay by direct binding and transactivated Aurora-B promoter by indirectly affecting CHR region in the promoter. (2) Aurora-A phosphorylated hnRNP on at least two serine residues in vivo. (3) Aurora-A phosphorylation of hnRNP upregulated hnRNP’ transactivation activity to Aurora-B promoter. (4) Both hnRNP loss or overexpression overrode Taxol induced spindle checkpoint arrest and resulted in the production of polyploidy cells, resembling to the phenotypes observed by gain or loss of function of Aurora-B. (5) Both hnRNP loss or overexpression enhances cell motility. These results indicate that Aurora-A/hnRNP play an important role in chromosome stability by regulating Aurora-B RNA metabolism and the deregulation of this complex would promote tumorigenesis and metastasis.

Academic Significance and Societal Importance of the Research Achievements

オーロラAの機能破綻によって誘導される染色体不安定性のメカニズムとして中心体の過剰生産が広く知られていたが、本研究からオーロラAが染色体分配機構のメインプレイヤーであるオーロラBの発現量を直接調節していることが明らかになり、オーロラAが多様なシグナル経路を調節することで染色体安定性を保証していることが示された。この知見は、臨床試験されているオーロラAとBの両阻害剤の組み合わせが癌細胞特有の染色体不安定性の脆弱さを効率よく標的化できることを予見するものであり、臨床試験で今後検討されることが期待される。

Research Products

• [Int'l Joint Research] MDアンダーソンがんセンター(米国)
• [Int'l Joint Research] Univ of Texas MD Anderson Cancer Center(米国)
• [Presentation] 細胞分裂期制御タンパク質による新規転写調節機構の解明 (2018)
  • Author(s): 笹井香織、Warapen Treekitkarnmongkol、伊藤佐智夫、Sanker N. Maity、Subrata Sen、片山博志
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] 肺癌における癌遺伝子候補MYNNとp53の統合的解析 (2018)
  • Author(s): 伊藤 佐智夫、邱 艶艶、堺 明子、殷 佩浩、片山 博志
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] eEF1A2 facilitates PTEN-GSK3β mediated Aurora-A protein degradation during S-G2 phase inactivated in PTEN-deficient breast cancer (2018)
  • Author(s): W Treekitkarnmongkol, LM Solis, K Kai, AM Thompson, W Tian, II Wistuba, K Sasai, Y Jltsumori, AA Sahin, DH Hawke, JM Lee, L Qin, T Bawa-Khalfe, R Rad, KK Wong, CM Abbott, H Katayama and S Sen
  • Organizer: 2018 San Antonio Breast Cancer Symposium
  • Int'l Joint Research
• [Presentation] Aurora-A Signaling Cascade Regulating Transactivation of Mitotic Genes (2018)
  • Author(s): H Katayama, K Sasai, S Sen
  • Organizer: 7th Asian Forum of Chromosome and Chromatin Biology
  • Int'l Joint Research / Invited
• [Presentation] Functional Interaction between Aurora-A Kinase and Mps1 Kinase in the Regulation of Cell Cycle and Genomic Instability (2018)
  • Author(s): H Katayama
  • Organizer: 2018 Academic Conference on Chinese Medical Oncology
  • Int'l Joint Research / Invited
• [Presentation] RNA結合タンパク質hnRNP Fは細胞分裂進行を調節している (2017)
  • Author(s): 高岡修平, 坂本萌, 實盛好美, 笹井香織, 片山博志
  • Organizer: 第40回日本分子生物学会年会
• [Presentation] Emerging role of hnRNP F in mitotic cell cycle progression (2017)
  • Author(s): 坂本萌, 高岡修平, 實盛好美, 笹井香織, Subrata Sen, 片山博志
  • Organizer: 西日本医学生学術フォーラム2017