Lloyd T. Lam§, Oxana K. Pickeral§, Amy C. Peng*, Andreas Rosenwald§, Elaine M. Hurt§, Jena M. Giltnane§, Lauren Averett§, Hong Zhao§, R. Eric Davis§, Mohan Sathyamoorthy§, Larry M. Wahl#, Eric Harris‡, Judy Mikovits‡, Anne Monks‡, Melinda Hollingshead‡, Edward A. Sausville‡, Louis M. Staudt§
Abstract
Background
Flavopiridol, a flavonoid currently in cancer clinical trials, inhibits cyclin-dependent kinases (CDKs) by competitively blocking their ATP-binding pocket. However, the mechanism of action of flavopiridol as an anti-cancer agent has not been fully elucidated.
Results
Using DNA microarrays, we found that flavopiridol inhibited gene expression broadly, in contrast to two other CDK inhibitors, roscovitine and 9-nitropaullone. The gene expression profile of flavopiridol closely resembled the profiles of two transcription inhibitors, actinomycin D and 5,6-dichloro-1-b-D-ribofuranosyl-benzimidazole (DRB), suggesting that flavopiridol inhibits transcription globally. We were therefore able to use flavopiridol to measure mRNA turnover rates comprehensively and we found that different functional classes of genes had distinct distributions of mRNA turnover rates. In particular, genes encoding apoptosis regulators frequently had very short half-lives as did several genes encoding key cell cycle regulators. Strikingly, genes that were transcriptionally inducible were disproportionately represented in the class of genes with rapid mRNA turnover.
Conclusions
The present genomic-scale measurement of mRNA turnover uncovered a regulatory logic that links gene function with mRNA half-life. The observation that transcriptionally inducible genes often have short mRNA half-lives demonstrates that cells have a coordinated strategy to rapidly modulate the mRNA levels of these genes. In addition, the present results suggest that flavopiridol may be more effective against types of cancer that are highly dependent upon genes with unstable mRNAs.