Effects of cyclin-dependent kinase inhibitors on transcription and ocular circadian rhythm of Aplysia.

Abstract

Cyclin-dependent kinases (CDKs) mediate cell-cycle phase transitions. Recently, CDKs have been associated with non-cell-cycle roles such as DNA repair, transcription, and phosphate metabolism in yeast. The cyclical processes, circadian rhythms and the eukaryotic cell cycle, are similar in many respects. It is possible that a kinase like CDK is involved in the control of circadian rhythms. In this study, the effects of CDK inhibitors (olomoucine, roscovitine, and butyrolactone I) on the Aplysia ocular circadian rhythm were investigated. Continuous treatments with olomoucine (10 microM) lengthened the free-running period of the rhythm, and pulse treatments of olomoucine (6 h, 100 microM) delayed the rhythm. The effects of olomoucine on the rhythm were qualitatively similar to those of a reversible inhibitor of transcription, 5,6-dichloro-beta-1-ribobenzimidazole. Subsequently, olomoucine was found to inhibit RNA synthesis in the eye of Aplysia and Bulla. All of the other CDK inhibitors used in this study also inhibited transcription in the eye of Aplysia, and their effects on transcription correlated with their effects on the circadian rhythm. This study adds substantial evidence to that previously obtained by using 5,6-dichloro-beta-1-ribobenzimidazole for a role of transcription in the mechanism responsible for circadian rhythmicity in the eye of Aplysia. Also, these results indicate that caution is warranted in interpreting results obtained by using CDK inhibitors, because these drugs appear to inhibit transcription as well as CDKs.