Genomic-scale measurement of mRNA turnover and the mechanisms of action of the anti-cancer drug flavopiridol

Lloyd T Lam¹, Oxana K Pickeral¹, Amy C Peng², Andreas Rosenwald¹, Elaine M Hurt¹, Jena M Giltnane¹, Lauren M Averett¹, Hong Zhao¹, R Eric Davis¹, Mohan Sathyamoorthy¹, Larry M Wahl³, Eric D Harris⁴, Judy A Mikovits⁴, Anne P Monks⁴, Melinda G Hollingshead⁴, Edward A Sausville⁴ and Louis M Staudt¹

¹Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA

²The EMMES Corporation, 401 N Washington Street, Suite 700, Rockville, MD 20850, USA

³National Institute for Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA

⁴Developmental Therapeutics Program, DTP Clinical Trials Unit, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 20892, USA

author email corresponding author email

Genome Biology 2001, 2:research0041.1-0041.11doi:10.1186/gb-2001-2-10-research0041


Published:	13 September 2001

Subject areas: Cell biology, Cancer, Drug discovery

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-β-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 on genes with unstable mRNAs.