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 journalArticle

84 Citations (Scopus)

Abstract

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
Volume6
Issue number3
DOIs
Publication statusPublished - Mar 18 2011
Externally publishedYes

Fingerprint

Ubiquitin-Protein Ligases
RNA Precursors
Biological Products
Proteolysis
Cyclin E
Protein Subunits
HeLa Cells
Introns
Labeling
Carrier Proteins
Cells
Derivatives
Degradation
Messenger RNA
Proteins
herboxidiene

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Hasegawa, M., Miura, T., Kuzuya, K., Inoue, A., Ki, S. W., Horinouchi, S., ... Mizukami, T. (2011). Identification of SAP155 as the target of GEX1A (Herboxidiene), an antitumor natural product. ACS Chemical Biology, 6(3), 229-233. https://doi.org/10.1021/cb100248e

Identification of SAP155 as the target of GEX1A (Herboxidiene), an antitumor natural product. / Hasegawa, Makoto; Miura, Tatsuhiro; Kuzuya, Kouji; Inoue, Ayu; Ki, Se Won; Horinouchi, Sueharu; Yoshida, Tetsuo; Kunoh, Tatsuki; Koseki, Koichi; Mino, Koshiki; Sasaki, Ryuzo; Yoshida, Minoru; Mizukami, Tamio.

In: ACS Chemical Biology, Vol. 6, No. 3, 18.03.2011, p. 229-233.

Research output: Contribution to journalArticle

Hasegawa, M, Miura, T, Kuzuya, K, Inoue, A, Ki, SW, Horinouchi, S, Yoshida, T, Kunoh, T, Koseki, K, Mino, K, Sasaki, R, Yoshida, M & Mizukami, T 2011, 'Identification of SAP155 as the target of GEX1A (Herboxidiene), an antitumor natural product', ACS Chemical Biology, vol. 6, no. 3, pp. 229-233. https://doi.org/10.1021/cb100248e
Hasegawa M, Miura T, Kuzuya K, Inoue A, Ki SW, Horinouchi S et al. Identification of SAP155 as the target of GEX1A (Herboxidiene), an antitumor natural product. ACS Chemical Biology. 2011 Mar 18;6(3):229-233. https://doi.org/10.1021/cb100248e
Hasegawa, Makoto ; Miura, Tatsuhiro ; Kuzuya, Kouji ; Inoue, Ayu ; Ki, Se Won ; Horinouchi, Sueharu ; Yoshida, Tetsuo ; Kunoh, Tatsuki ; Koseki, Koichi ; Mino, Koshiki ; Sasaki, Ryuzo ; Yoshida, Minoru ; Mizukami, Tamio. / Identification of SAP155 as the target of GEX1A (Herboxidiene), an antitumor natural product. In: ACS Chemical Biology. 2011 ; Vol. 6, No. 3. pp. 229-233.
@article{7f77bc92b5ec4195839f282e36703c3f,
title = "Identification of SAP155 as the target of GEX1A (Herboxidiene), an antitumor natural product",
abstract = "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.",
author = "Makoto Hasegawa and Tatsuhiro Miura and Kouji Kuzuya and Ayu Inoue and Ki, {Se Won} and Sueharu Horinouchi and Tetsuo Yoshida and Tatsuki Kunoh and Koichi Koseki and Koshiki Mino and Ryuzo Sasaki and Minoru Yoshida and Tamio Mizukami",
year = "2011",
month = "3",
day = "18",
doi = "10.1021/cb100248e",
language = "English",
volume = "6",
pages = "229--233",
journal = "ACS Chemical Biology",
issn = "1554-8929",
publisher = "American Chemical Society",
number = "3",

}

TY - JOUR

T1 - Identification of SAP155 as the target of GEX1A (Herboxidiene), an antitumor natural product

AU - Hasegawa, Makoto

AU - Miura, Tatsuhiro

AU - Kuzuya, Kouji

AU - Inoue, Ayu

AU - Ki, Se Won

AU - Horinouchi, Sueharu

AU - Yoshida, Tetsuo

AU - Kunoh, Tatsuki

AU - Koseki, Koichi

AU - Mino, Koshiki

AU - Sasaki, Ryuzo

AU - Yoshida, Minoru

AU - Mizukami, Tamio

PY - 2011/3/18

Y1 - 2011/3/18

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=79955573435&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79955573435&partnerID=8YFLogxK

U2 - 10.1021/cb100248e

DO - 10.1021/cb100248e

M3 - Article

C2 - 21138297

AN - SCOPUS:79955573435

VL - 6

SP - 229

EP - 233

JO - ACS Chemical Biology

JF - ACS Chemical Biology

SN - 1554-8929

IS - 3

ER -