Die Regulation von BMI1, FOXO1 und FOXO3a durch den Transkriptionsfaktor E2F-1

The transcription factor BMI1 belongs to the polycomb proteins and is necessary for the embryonal development. Furthermore it is important for the maintenance of the self-renewal of stem cells. FOXO1 and FOXO3a are members of the sub-group O of the forkhead transcription factors. They are involved in many cellular processes like apoptosis, cell cycle arrest and glucose metabolism. So far the transcriptional regulation of BMI1 and the FOXOs was not further analyzed although changes of their amount and functionality occur in several tumor types. In previous experiments my working group were able to show that BMI1, FOXO1 and FOXO3a are direct target genes of the transcription factor E2F-1. In this work I could show that E2F-1-induced BMI1 is localized in the nucleus and chromatin-associated. Therefore basic requisites for the functionality of BMI1 are established. The activation of BMI1 by E2F-1 in cells of different species suggest a conserved regulation. In contrast to other E2F-1 target genes BMI1 is not strongly expressed in late G1 phase. This leads to the conclusion that the regulation of BMI1 by E2F-1 is not important for the cell cycle control. I determined the BMI1 levels of primary neuroblastomas whose initiation from stem cells of the neural crest is not further analyzed. Over 90% of these tumors displayed high BMI1 levels. Therefore BMI1 may play a role for the tumorigenesis of neuroblastomas. In contrast to BMI1 the regulation of FOXO1 and FOXO3a by E2F-1 is presumably tissue-specific. Furthermore I was able to prove that BMI1, FOXO1 and FOXO3a are already induced by nearly physiological E2F-1 activity. In different models I analyzed the role of the FOXOs for E2F-1-induced apoptosis. During the induction of neuronal apoptosis I could show that the FOXOs are not activated by E2F-1. Due to this observation a general role of FOXO1 and FOXO3a for the E2F-1-dependent apoptosis can not be excluded.