The polycomb group gene BMIl is a target gene of E2F-1: role of Bmi1 in E2F-controlled genetic programs and mode of functional interaction with E2F-1

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E2F transcription factors activate the MYCN gene in a subset of aggressive neuroblastomas. In a search for additional oncogenic target genes of E2F, we have generated neuroblastoma cells that express the 4-hydroxy-tamoxifen regulated E2F-1-ER fusion protein. cDNA-microarray analysis, quantitative RT-PCR, and chromatin immunoprecipitation identified the polycomb group protein BMI1 as a direct target gene of E2F-1 in both human neuroblastoma cells and rat fibroblasts, consistent with the presence of a conserv ed E2F binding site in the BMI1 promoter. The regulatory interaction between E2F-1 and BMI1 raises several questions: 1. Is the activation of BMI1 necessary for the induction of S-phase or apoptosis by E2F-1, or is BMI1 part of a distinct cellular program triggered by E2F-1? 2. How is Bmi1 mechanistically integrated into the response of cells to activated E2F-1? These questions will be addressed with a combination of gain and loss of function approaches and global gene expression analyses.