AI Article Synopsis
- GEX1A is a microbial product that demonstrates antitumor properties by altering the processing of p27, leading to its accumulation in cancer cells.
- It inhibits pre-mRNA splicing of p27, resulting in the production of a truncated form, p27*, which accumulates due to its resistance to proteolysis.
- GEX1A targets the SAP155 protein, a part of the pre-mRNA splicing machinery, establishing it as a unique splicing inhibitor that disrupts SF3b function.
Article Abstract
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 a novel splicing inhibitor that specifically impairs the SF3b function by binding to SAP155.
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