Regulation of aurora B expression by the bromodomain protein Brd4.
The bromodomain protein Brd4 plays critical roles in cellular proliferation and cell cycle progression. In this study, we investigated the involvement of Brd4 in cell cycle regulation and observed aberrant chromosome segregation and failures in cytokinesis in cancer cells as well as in primary keratinocytes in which Brd4 has been knocked down by RNA interference. Suppression of Brd4 protein levels in proliferating cells decreased Aurora B protein and transcript levels and abolished its chromosomal distribution. In contrast, exogenous Brd4 expression stimulated Aurora B promoter reporter activity and upregulated endogenous Aurora B expression. Aurora B kinase is a chromosomal passenger protein that is essential for chromosome segregation and cytokinesis. Either overexpression of Aurora B or its inactivation can induce defects in centrosome function, spindle assembly, chromosome alignment, and cytokinesis in various cancer cells. The impaired regulation of Aurora B expression in human cells by Brd4 knockdown or overexpression coincided with mitotic catastrophe and multinucleation that are typically observed when Aurora B is inactivated or overexpressed. Overall, our data suggest that Brd4 is essential for the maintenance of the cell cycle progression mediated at least in part through the control of transcription of the Aurora B kinase cell cycle regulatory gene.
You
Jianxin
J
Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Li
Qing
Q
Wu
Chong
C
Kim
Jina
J
Ottinger
Matthias
M
Howley
Peter M
PM
D000818:Animals; D064107:Aurora Kinase B; D064127:Aurora Kinases; D018797:Cell Cycle Proteins; D002460:Cell Line; D049109:Cell Proliferation; D002843:Chromatin / Q000378:metabolism; D020090:Chromosome Segregation; D015536:Down-Regulation / Q000235:genetics; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D051379:Mice; D008938:Mitosis; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000378:metabolism; D013489:Suppression, Genetic; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D000092468:Bromodomain Containing Proteins
D064107:Aurora Kinase B; D064127:Aurora Kinases; D018797:Cell Cycle Proteins; D002843:Chromatin; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C576921:AURKB protein, human; C576924:Aurkb protein, mouse