Induction of a Ribotoxic Stress Response That Stimulates Stress-Activated Protein Kinases by 13-Deoxytedanolide, an Antitumor Marine Macrolide
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概要
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13-Deoxytedanolide is a structurally unique macrolide with strong antitumor activity isolated from a marine sponge. Recently, we showed that 13-deoxytedanolide bound to the large subunit of the yeast ribosome and inhibited polypeptide elongation in vitro, but the mechanism by which it exerts antitumor activity is still unknown. Here we show that 13-deoxytedanolide strongly induces plasminogen activator inhibitor 1 (PAI-1) promoter-derived gene expression. 13-Deoxytedanolide, unlike TGF-beta, did not cause apparent nuclear translocation of Smad2/3, but it relocalized the temperature-sensitive mutant of mouse p53 (p53Val153) from the cytoplasm to the nucleus at a nonpermissive temperature, suggesting that 13-deoxytedanolide inhibits protein synthesis. Indeed, the drug inhibited in vivo protein synthesis at low nanomolar concentrations and strongly activated stress-activated protein kinases such as p38 mitogen-activated protein kinase and Jun NH2-terminal protein kinase (JNK). Anisomycin, a well-known inducer of ribotoxic stress that activates both p38 and JNK, also activated PAI-1 gene expression, while other protein synthesis inhibitors that do not activate the kinases failed to do so. PAI-1 gene expression by 13-deoxytedanolide and anisomycin was blocked by SB202190, a specific inhibitor of p38, and SP600125, an inhibitor of both p38 and JNK. 13-Deoxytedanolide and anisomycin caused activation of apoptosis signal-regulating kinase 1, MKK3/MKK6, and SEK1/MKK4, the regulatory kinases upstream of p38 and JNK. These results suggest that 13-deoxytedanolide, like anisomycin, triggers a ribotoxic stress response that activates stress-activated protein kinase cascades, thereby inducing PAI-1 gene expression and apoptosis.
- 社団法人 日本農芸化学会の論文
- 2006-01-23
著者
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Yoshida Minoru
Department of Thoracic and Cardiovascular Surgery, Wakayama Medical University School of Medicine
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HORINOUCHI Sueharu
Department of Biotechnology, University of Tokyo
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FUSETANI Nobuhiro
Department of Fisheries, Faculty of Agriculture, The University of Tokyo
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MATSUNAGA Shigeki
Department of Aquatic Bioscience, Graduate School of Agricultural and Life Sciences, The University
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Ichijo Hidenori
Graduate School Of Pharmaceutical Sciences University Of Tokyo
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Fusetani Nobuhiro
Department Of Aquatic Bioscience Graduate School Of Agricultural And Life Sciences University Of Tok
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Horinouchi Sueharu
Department Of Agricultural Chemistry Faculty Of Agriculture The University Of Tokyo
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Lee Kun-hyung
Department Of Biotechnology Graduate School Of Agriculture And Life Sciences University Of Tokyo
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NISHIMURA Shinichi
Chemical Genetics Laboratory, RIKEN
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Nishimura Shinichi
Chemical Genetics Laboratory Riken
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Horinouchi Sueharu
Department Of Biotechnology Graduate School Of Agriculture And Life Sciences University Of Tokyo
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Fusetani Nobuhiro
Department Of Aquatic Bioscience Graduate School Of Agriculture And Life Sciences University Of Toky
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Matsunaga Shigeki
Department Of Aquatic Bioscience Graduate School Of Agriculture And Life Sciences University Of Toky
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Yoshida Minoru
Department Of Chemistry St. Marianna University School Of Medicine
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Yoshida Minoru
Department Of Agricultural Chemistry Faculty Of Agriculture Iwate University
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Yoshida Minoru
Department Of Biotechnology Graduate School Of Agriculture And Life Sciences University Of Tokyo
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Matsunaga Shigeki
Department of Applied Chemistry, Faculty of Engineering, Yamagata University
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