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The Journal of Neuroscience, June 1, 2005, 25(22):5430-5437; doi:10.1523/JNEUROSCI.0263-05.2005

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Cellular/Molecular
The Double-Time Protein Kinase Regulates the Subcellular Localization of the Drosophila Clock Protein Period

Shawn A. Cyran,¹ Georgia Yiannoulos,¹ Anna M. Buchsbaum,¹ Lino Saez,² Michael W. Young,² and Justin Blau¹

¹Department of Biology, New York University, New York, New York 10003, and ²The Rockefeller University, New York, New York 10021

The Period (PER), Timeless (TIM), and Double-Time (DBT) proteins are essential components of one feedback loop in the Drosophila circadian molecular clock. PER and TIM physically interact. Coexpression of PER and TIM promotes their nuclear accumulation and influences the activity of DBT: although DBT phosphorylates and destabilizes PER, this is suppressed by TIM. Experiments using Drosophila cells in culture have indicated that PER can translocate to the nucleus without TIM and will repress transcription in a DBT-potentiated manner. In this study, we examined the control of PER subcellular localization in Drosophila clock cells in vivo.We found that PER can translocate to the nucleus in tim⁰¹ null mutants but only if DBT kinase activity is inhibited. We also found that nuclear PER is a potent transcriptional repressor in dbt mutants in vivo without TIM. Thus, in vivo, DBT regulates PER subcellular localization, in addition to its previously documented role as a mediator of PER stability. However, DBT does not seem essential for transcriptional repression by PER. It was reported previously that overexpression of a second kinase, Shaggy (SGG)/Glycogen Synthase Kinase 3, accelerates PER nuclear accumulation. Here, we show that these effects of SGG on PER nuclear accumulation require TIM. We propose a revised clock model that incorporates this tight kinase regulation of PER and TIM nuclear entry.

Key words: circadian; Period; Double-Time; Timeless; nuclear entry; Drosophila

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Received Jan 19, 2005; revised April 25, 2005; accepted April 28, 2005.

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