BMI1 is a target gene of E2F-1 and is strongly expressed in primary neuroblastomas.
The oncogene BMI1 encodes a polycomb group transcription factor that is required for embryonic development and self-renewal of stem cells. Despite these important functions little is known about the regulation of BMI1 expression. A cDNA microarray based search for target genes of E2F-1 in neuroblastoma cells expressing a 4-OHT-regulated E2F-1-ER fusion protein identified many hitherto unknown E2F-1 regulated genes. A total of 10% of these genes, including BMI1, encode proteins that function primarily in the regulation of gene expression. The BMI1 promoter contains a putative E2F binding site that was required for the activation of a BMI1 promoter-dependent reporter construct by E2F-1. Chromatin immunoprecipitation revealed 4-OHT-dependent binding of E2F-1-ER and binding of endogenous E2F-1 to the BMI1 promoter in tumor cells. We have previously shown activation of the oncogene MYCN by E2F. Thus, in neuroblastomas deregulated E2F-1 can activate two oncogenes, MYCN and BMI1 that are known to co-operate in tumor formation. Consistent with a role of Bmi1 in neuroblastoma tumorigenesis we found strong Bmi1 expression in primary neuroblastomas. Our results reveal a novel link between E2F and polycomb transcription factors and suggest a role of Bmi1 in neuroblastomas.
Nowak
Katrin
K
Institute of Molecular Biology and Tumor Research (IMT), Emil-Mannkopff-Strasse 2, 35033 Marburg, Germany.
Kerl
Kornelius
K
Fehr
Daniel
D
Kramps
Christoph
C
Gessner
Christine
C
Killmer
Katrin
K
Samans
Birgit
B
Berwanger
Bernd
B
Christiansen
Holger
H
Lutz
Werner
W
D000818:Animals; D001665:Binding Sites; D002453:Cell Cycle; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D009423:Nervous System Neoplasms / Q000235:genetics* / Q000378:metabolism; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D063150:Polycomb Repressive Complex 1; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
C069077:BMI1 protein, human; D002843:Chromatin; D050687:E2F1 Transcription Factor; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D063150:Polycomb Repressive Complex 1