Journal
ACS CHEMICAL BIOLOGY
Volume 6, Issue 3, Pages 229-233Publisher
AMER CHEMICAL SOC
DOI: 10.1021/cb100248e
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Funding
- Japanese Ministry of Education, Culture, Sports, Science and Technology
- Grants-in-Aid for Scientific Research [22790117, 21228003] Funding Source: KAKEN
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GEX1A is a microbial product with antitumor activity. HeLa cells cultured with GEX1A accumulated p27(Kip) 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 novel splicing inhibitor that specifically impairs the SF3b function by binding to SAP155.
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