Splicing Inhibition Mechanism of GEX1A, An Antitumor Natural Product

• Project/Area Number: 22790117
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Drug development chemistry
• Research Institution: Nagahama Institute of Bio-Science and Technology
• Principal Investigator: HASEGAWA Makoto 長浜バイオ大学, バイオサイエンス学部, 准教授 (10367899)
• Project Period (FY): 2010 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2011: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2010: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: スプライシング / 抗癌剤 / 翻訳後修飾 / 薬剤反応性 / 蛋白質 / 翻訳語修飾

Research Abstract

We reported that antitumor activity of GEX1A(herboxidiene) links to the splicing machinery of the cell. This compound causes cell cycle arrest at the G1(major period of cell growth) and G2/M(DNA damage checkpoint) phases in different human cell lines. Several factors, including cyclin-kinase inhibitors such as p27, regulate the cyclin-dependent kinases that drive the mammalian cell cycle. GEX1A inhibited the pre-mRNA splicing of p27, leading to accumulation of an aberrant form of p27. By using a series of photoaffinity-labeling derivatives of GEX1A, we found that GEX1A targeted a protein responsible for pre-mRNA splicing. GEX1A serves as a splicing inhibitor that specifically impairs the splicing process of p27 by binding to the splicing machinery associating protein, resulting in inactivation of Cdk1 and Cdk2.

Research Products

• [Journal Article] Identification of SAP155 as the target of GEX1A (Herboxidiene), an antitumor natural product (2011)
  • Author(s): Hasegawa, M., Miura, T., Kuzuya, K., Inoue, A., Ki, S. W., Horinouchi, S., Yoshida, T., Kunoh, T., Koseki, K., Mino, K., Sasaki, R., Yoshida, M., and Mizukami, T
  • Journal Title: ACS Chem. Biol Volume: 6 Issue: 3 Pages: 229-233
  • DOI: 10.1021/cb100248e
  • Peer Reviewed
• [Journal Article] Synthesis and biological activity of optically active NCL-1, a lysine-specific demethylase 1 selective inhibitor (2011)
  • Author(s): Ogasawara D
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 19 Pages: 3702-3708
  • Peer Reviewed
• [Journal Article] Identification of SAP155 as the Target of GEX1A (Herboxidiene), An Antitumor Natural Product. (2011)
  • Author(s): Hasegawa, M., Miura, T., Kuzuya, K., Inoue, A., Se Won Ki, Horinouchi, S., Yoshida, T., Kunoh, T., Koseki, K., Mino, K., Sasaki, R., Yoshida, M., Mizukami, T.
  • Journal Title: ACS Chemical Biology Volume: 18 Pages: 229-233
  • Peer Reviewed
• [Journal Article] Synthesis and biological activity of optically active NCL-1, a lysine-specific demethylase 1 selective inhibitor. (2011)
  • Author(s): Ogasawara, D., Suzuki, T., Mino, K., Ueda, R., Khan, M.N., Matsubara, T., Koseki, K., Hasegawa, M., Sasaki, R., Nakagawa, H.Mizukami, T., Miyata, N.
  • Journal Title: Bioorganic & medicinal chemistry Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] Design, Synthesis, Enzyme-inhibitory Activity, and Effect on Human Cancer Cells of a Novel Series of Jumonji Domain-Containing Protein 2 Histone Demethylase Inhibitors. (2010)
  • Author(s): Hamada, S., Suzuki, T., Mino, K., Koseki, K., Oehme, F., Flamme, I., Ozasa, H., Itoh, Y., Ogasawara, D., Komaarashi, H., Katoh, A., Tsumoto, H., Nakagawa, H., Hasegawa, M., Sasaki, R., Mizukami, T., Miyata, N.
  • Journal Title: Journal of Medicinal Chemistry Volume: 53 Pages: 5629-5638
  • Peer Reviewed
• [Journal Article] Characteristic increase in nucleocytoplasmic protein glycosylation by O-GlcNAc in 3T3-L1 adipocyte differentiation. (2010)
  • Author(s): Ishihara K, Takahashi I, Tsuchiya Y, Hasegawa M, Kamemura K.
  • Journal Title: Biochemical and Biophysical Research Communication Volume: 398 Pages: 489-494
  • Peer Reviewed
• [Journal Article] Direct binding of gangliosides to Helicobacter pylori vacuolating cytotoxin (VacA) neutralizes its toxin activity. (2010)
  • Author(s): Wada, A., Hasegawa, M., Wong, P-F., Shirai, E., Shirai, N., Tan, L-J., Llanes, R., Hojo, H., Yamasaki, E., Ichinose, A., Ichinose, Y., Senba, M.
  • Journal Title: Glycobiology Volume: 20 Pages: 668-678
  • NAID: 120006984983
  • Peer Reviewed
• [Presentation] 抗腫瘍活性物質GEX1Aの標的タンパク質とそのリン酸化修飾の解析 (2011)
  • Author(s): 棚橋一晃、葛谷晃司、三浦達拓、小坂葉子、吉田哲郎、吉田稔、佐々木隆造、水上民夫、長谷川慎
  • Organizer: 日本ケミカルバイオロジー学会第6回年会
  • Place of Presentation: 東京
  • Year and Date: 2011-05-23
• [Remarks] 研究成果を随時公開
  • URL: http://www.nagahama-i-bio.ac.jp