Identification of SAP155 as the target of GEX1A (Herboxidiene), an antitumor natural product

Makoto Hasegawa, Tatsuhiro Miura, Kouji Kuzuya, Ayu Inoue, Se Won Ki, Sueharu Horinouchi, Tetsuo Yoshida, Tatsuki Kunoh, Koichi Koseki, Koshiki Mino, Ryuzo Sasaki, Minoru Yoshida, Tamio Mizukami

Research output: Contribution to journalArticlepeer-review

116 Citations (Scopus)


GEX1A is a microbial product with antitumor activity. HeLa cells cultured with GEX1A accumulated p27Kip and its C-terminally truncated form p27*. GEX1A inhibited the pre-mRNA splicing of p27, producing p27* from the unspliced mRNA containing the first intron. p27* lacked the site required for E3 ligase-mediated proteolysis of p27, leading to its accumulation in GEX1A-treated cells. The accumulated p27* was able to bind to and inhibit the cyclin E-Cdk2 complex that causes E3 ligase-mediated degradation of p27, which probably triggers the accumulation of p27. By using a series of photoaffinity-labeling derivatives of GEX1A, we found that GEX1A targeted SAP155 protein, a subunit of SF3b responsible for pre-mRNA splicing. The linker length between the GEX1A pharmacophore and the photoreactive group was critical for detection of the GEX1A-binding protein. GEX1A serves as a novel splicing inhibitor that specifically impairs the SF3b function by binding to SAP155.

Original languageEnglish
Pages (from-to)229-233
Number of pages5
JournalACS Chemical Biology
Issue number3
Publication statusPublished - Mar 18 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine


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