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Molecular and Cellular Biology, November 2000, p. 8220-8229, Vol. 20, No. 21
0270-7306/00/$04.00+0

Roughex Mediates G1 Arrest through a Physical Association with Cyclin A

Sergei N. Avedisov, Irina Krasnoselskaya,dagger Mark Mortin, and Barbara J. Thomas*

Laboratory of Biochemistry, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4255

Received 15 February 2000/Returned for modification 21 March 2000/Accepted 31 July 2000

Differentiation in the developing Drosophila eye requires synchronization of cells in the G1 phase of the cell cycle. The roughex gene product plays a key role in this synchronization by negatively regulating cyclin A protein levels in G1. We show here that coexpressed Roughex and cyclin A physically interact in vivo. Roughex is a nuclear protein, while cyclin A was previously shown to be exclusively cytoplasmic during interphase in the embryo. In contrast, we demonstrate that in interphase cells in the eye imaginal disk cyclin A is present in both the nucleus and the cytoplasm. In the presence of ectopic Roughex, cyclin A becomes strictly nuclear and is later degraded. Nuclear targeting of both Roughex and cyclin A under these conditions is dependent on a C-terminal nuclear localization signal in Roughex. Disruption of this signal results in cytoplasmic localization of both Roughex and cyclin A, confirming a physical interaction between these molecules. Cyclin A interacts with both Cdc2 and Cdc2c, the Drosophila Cdk2 homolog, and Roughex inhibits the histone H1 kinase activities of both cyclin A-Cdc2 and cyclin A-Cdc2c complexes in whole-cell extracts. Two-hybrid experiments suggested that the inhibition of kinase activity by Roughex results from competition with the cyclin-dependent kinase subunit for binding to cyclin A. These findings suggest that Roughex can influence the intracellular distribution of cyclin A and define Roughex as a distinct and specialized cell cycle inhibitor for cyclin A-dependent kinase activity.

* Corresponding author. Mailing address: National Cancer Institute, NIH, Bldg. 37, Room 4C10, 37 Convent Dr., MSC 4255, Bethesda, MD 20892-4255. Phone: (301) 435-2814. Fax: (301) 402-3095. E-mail: bthomas{at}sunspot.nci.nih.gov.

dagger Present address: Department of Biochemistry, George Washington University Medical Center, Washington, D.C. 20037.

Molecular and Cellular Biology, November 2000, p. 8220-8229, Vol. 20, No. 21
0270-7306/00/$04.00+0


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