YY1 and NF-Y binding sites regulate the transcriptional activity of the dek and dek-can promoter.
The mammalian protein DEK has been implicated in multiple cellular processes, including transcriptional regulation, mRNA processing, and chromatin remodeling, and is associated with a number of clinical autoimmune and neoplastic conditions. The connection between DEK and cancer exists at multiple levels: (a) the t(6;9) chromosomal translocation that characterizes a subtype of acute myelogenous leukemia cases results in the formation of a DEK-CAN fusion oncoprotein; (b) a fragment of dek cDNA is capable of partially reversing the radiation-sensitive phenotype of fibroblasts cultured from ataxia-telangiectasia patients; and (c) increased levels of dek mRNA have been found to be associated with hepatocellular carcinoma, glioblastoma, and melanoma. Despite the growing list of cancer subtypes with a connection to DEK, the factors that mediate its expression have yet to be characterized. Here we undertake the analysis of DEK regulation by mapping the discrete elements within the proximal promoter that are responsible for constitutive transcription of dek in transformed cells. We find that functional elements include an inverted CCAAT box and a YY1 consensus binding site, and the introduction of point mutations into these sites markedly diminishes transcriptional activity. In addition, we identify the transcriptional activator NF-Y as a member of the CCAAT-binding complex, and verify binding of the transcription factor YY1 at its consensus site in the dek promoter. The discovery of NF-Y and YY1 as regulatory determinants of DEK expression is consistent with the well-documented roles of these two factors in cellular proliferation and transformation.
Sitwala
Kajal V
KV
Department of Internal Medicine and Program in Cellular and Molecular Biology, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, Michigan, MI 48109-0640, USA.
Adams
Kristine
K
Markovitz
David M
DM
D001483:Base Sequence; D001665:Binding Sites; D023081:CCAAT-Binding Factor / Q000378:metabolism*; D018076:DNA, Complementary; D050981:Erythroid-Specific DNA-Binding Factors; D006801:Humans; D019169:Jurkat Cells; D015513:Oncogene Proteins / Q000235:genetics*; D015514:Oncogene Proteins, Fusion; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D050986:YY1 Transcription Factor
D023081:CCAAT-Binding Factor; C104001:DEK-CAN fusion protein, recombinant; D018076:DNA, Complementary; D050981:Erythroid-Specific DNA-Binding Factors; D015513:Oncogene Proteins; D015514:Oncogene Proteins, Fusion; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D050986:YY1 Transcription Factor; C494698:YY1 protein, human