Splicing Inhibition Mechanism of GEX1A, An Antitumor Natural Product

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We reported that antitumor activity of GEX1A(herboxidiene) links to the splicing machinery of the cell. This compound causes cell cycle arrest at the G1(major period of cell growth) and G2/M(DNA damage checkpoint) phases in different human cell lines. Several factors, including cyclin-kinase inhibitors such as p27, regulate the cyclin-dependent kinases that drive the mammalian cell cycle. GEX1A inhibited the pre-mRNA splicing of p27, leading to accumulation of an aberrant form of p27. By using a series of photoaffinity-labeling derivatives of GEX1A, we found that GEX1A targeted a protein responsible for pre-mRNA splicing. GEX1A serves as a splicing inhibitor that specifically impairs the splicing process of p27 by binding to the splicing machinery associating protein, resulting in inactivation of Cdk1 and Cdk2.