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Vol. 18, Issue 4, 1179-1186, April 2007

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Retinoblastoma Protein Regulation by the COP9 Signalosome

Zakir Ullah^*,,, Martin S. Buckley^,, David N. Arnosti^*,, and R. William Henry^*,

*Department of Biochemistry and Molecular Biology and Genetics Program, Michigan State University, East Lansing, MI 48824

Submitted September 6, 2006; Revised December 22, 2006; Accepted January 17, 2007
Monitoring Editor: William Tansey

Similar to their human counterparts, the Drosophila Rbf1 and Rbf2 Retinoblastoma family members control cell cycle and developmentally regulated gene expression. Increasing evidence suggests that Rbf proteins rely on multiprotein complexes to control target gene transcription. We show here that the developmentally regulated COP9 signalosome (CSN) physically interacts with Rbf2 during embryogenesis. Furthermore, the CSN4 subunit of the COP9 signalosome co-occupies Rbf target gene promoters with Rbf1 and Rbf2, suggesting an active role for the COP9 signalosome in transcriptional regulation. The targeted knockdown of individual CSN subunits leads to diminished Rbf1 and Rbf2 levels and to altered cell cycle progression. The proteasome-mediated destruction of Rbf1 and Rbf2 is increased in cells and embryos with diminished COP9 activity, suggesting that the COP9 signalosome protects Rbf proteins during embryogenesis. Previous evidence has linked gene activation to protein turnover via the promoter-associated proteasome. Our findings suggest that Rbf repression may similarly involve the proteasome and the promoter-associated COP9 signalosome, serving to extend Rbf protein lifespan and enable appropriate programs of retinoblastoma gene control during development.

These authors contributed equally to this work.

Present address: National Institute of Child Health and Human Development, National Institutes of Health, Building 6/3A-15, 9000 Rockville Pike, Bethesda, MD 20892.

Address correspondence to: R. William Henry (henryrw{at}msu.edu) or David N. Arnosti (arnosti{at}msu.edu)

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