The splicing inhibitor Isoginkgetin leads to defects in multiple phases of the cell cycle

Isoginkgetin is a naturally occurring compound from Ginkgo biloba trees that has anti-neoplastic activities related to inhibition of spliceosome assembly. The p53-tumour suppressor plays a prominent role in ell G1 and G2 cycle checkpoints and p53 is strongly activated in response to transcriptional stresses. Therefore, we determined the effect of p53 and Isoginkgetin treatment on cell cycle progression. Wildtype p53 expressing cells exhibited a remarkable S phase defect while the p53-null subline accumulated with 4C DNA content. Despite the pronounced difference in these isogenic strains, there was no pronounced p53 transcriptional response as assessed by qRT-PCR and preliminary microarray analysis. Instead, Isoginkgetin leads to altered pre-mRNA splicing of S and M phase-specific transcripts. These results suggest that cell cycle alterations are the direct result of abnormal splicing of cell cycle regulatory mRNAs and not p53 dependent checkpoints.