Promoting a mixed message

McCarthy, Nicola

doi:10.1038/nrc2218

Research Highlight
Published: September 2007

Therapeutics

Promoting a mixed message

Nicola McCarthy

Nature Reviews Cancer volume 7, page 640 (2007)Cite this article

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FR901464 is a natural bacterial product that can kill cancer cell lines. Although it has several effects on cells, its target is unknown, so Daisuke Kaida and colleagues investigated the mechanism of FR901464-induced cell death. Initially they found that treatment of HeLa cells with FR901464 resulted in the production of a C-terminally truncated p27 protein, a known inhibitor of the cell cycle. Having ruled out that this was a degradation product, the authors made a biotinylated form of the methylated, active derivative of FR901464; spliceostatin A (SSA). They found that SSA binds to and inhibits the protein complex SF3b, part of the spliceosome machinery that facilitates the removal of intron sequences from pre-mRNAs. Introns contain in-frame stop codons that could potentially result in truncated proteins if they are not removed, therefore it is important for unspliced pre-mRNAs to be retained in the nucleus.

SSA can completely inhibit splicing of in vitro translated pre-mRNAs and, although it can inhibit pre-mRNA processing in cells, this is not as effective because some mature, processed mRNAs are still present even with high concentrations of SSA. However, SSA does induce a build up of pre-mRNAs in the nucleus, and translation of these pre-mRNAs also occurs. Indeed, the C-terminally truncated form of p27 was shown be the product of p27 pre-mRNA translation owing to an in-frame stop codon in intron 1. Importantly, Kaida and colleagues showed that this truncated p27 was still active and could inhibit the cyclin E–cyclin dependent kinase 2 complex, potentially explaining the cell-cycle arrest that is induced by this drug.

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ORIGINAL RESEARCH PAPERS

Kaida, D. et al. Spliceostatin A targets SF3b and inhibits both splicing and nuclear retention of pre-mRNA. Nature Chem. Biol. 22 July 2007 (doi: 10.1038/nchembio.2007.18)
Kotake, Y. et al. Splicing factor SF3b as a target of the antitumour natural product pladienolide. Nature Chem. Biol. 22 July 2007 (doi: 10.1038/nchembio.2007.16)

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