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Molecular and Cellular Biology, October 2004, p. 9059-9069, Vol. 24, No. 20
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.20.9059-9069.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Bromodomain Protein Brd4 Binds to GTPase-Activating SPA-1, Modulating Its Activity and Subcellular Localization

Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland,¹ Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan,² Department of Biochemistry and Cell Biology, Baylor College of Medicine, Houston, Texas,³ Dana-Farber Cancer Institute, Boston, Massachusetts⁴

Received 25 February 2004/ Returned for modification 26 April 2004/ Accepted 27 July 2004

Brd4 is a mammalian protein that contains a double bromodomain. It binds to chromatin and regulates cell cycle progression at multiple stages. By immunopurification and mass spectrometry, we identified a Rap GTPase-activating protein (GAP), signal-induced proliferation-associated protein 1 (SPA-1), as a factor that interacts with Brd4. SPA-1 localizes to the cytoplasm and to a lesser degree in the nucleus, while Brd4 resides in the nucleus. Bifluorescence complementation revealed that Brd4 and SPA-1 interact with each other in the nucleus of living cells. Supporting the functional importance of the interaction, Brd4 enhanced Rap GAP activity of SPA-1. Furthermore ectopic expression of SPA-1 and Brd4 redirected subcellular localization of the partner and disrupted normal cell cycle progression. These effects were, however, reversed by coexpression of the two proteins, indicating that a proper balance between Brd4 and SPA-1 in G₂ is required for cell division. This work reveals a novel link between Brd4 and a GTPase-dependent mitogenic signaling pathway.

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