Direct regulation of an oncogenic micro-RNA cluster by E2F transcription factors.
Micro-RNAs (miRNAs) are a class of non-coding RNAs that post-transcriptionally regulate gene expression via the RNA interference pathway. In addition to roles in normal development, miRNAs have recently been implicated in a range of human diseases, including cancer. We recently demonstrated that a polycistronic cluster of miRNAs, miR-17-92, is oncogenic in a mouse model for Burkitt's lymphoma. This is due, in part, to a reduced apoptotic program. In an effort to understand the regulation of miR-17-92, we have studied the promoter structure of this miRNA cluster. The primary transcript initiates from a consensus initiator sequence downstream of a nonconsensus TATA box. The core promoter region contains two functional E2F transcription factor binding sites. Chromatin immunoprecipitation demonstrates that E2F3 is the primary E2F family member that occupies the promoter. These data place miR-17-92 in a regulatory loop between E2F3 and the miR-17 target E2F1. We propose a model whereby miR-17-92 promotes cell proliferation by shifting the E2F transcriptional balance away from the pro-apoptotic E2F1 and toward the proliferative E2F3 transcriptional network.
Woods
Keith
K
Department of Cell and Developmental Biology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Thomson
J Michael
JM
Hammond
Scott M
SM
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D050684:E2F Transcription Factors / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008957:Models, Genetic; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic
D050684:E2F Transcription Factors; D035683:MicroRNAs