Rolle des Onkoproteins Bmi-1 im Neuroblastom

Der Transkriptionsfaktor Bmi-1 ist Bestandteil des Polycomb-Proteinkomplexes PRC1 und wird beim Menschen in verschiedenen Karzinomen überexprimiert. Das kodierende Onkogen BMI1 ist ein direktes Zielgen des Transkriptionsfaktors E2F-1, der eine zentrale Rolle in der Regulation von Zellzyklus und prog...

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Bibliographic Details
Main Author: Fehr, Daniel
Contributors: Lutz, Werner (Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2007
Online Access:PDF Full Text
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The transcription factor Bmi-1 is part of the polycomb protein complex PRC1 and is found overexpressed in several human carcinomas. The accordant oncogene BMI1 is a direct target gene of the transcription factor E2F-1, that plays a crucial role in regulation of cell cycle progression and apoptosis. Based on human neuroblastoma cells in which the expression of BMI1 could be reversibly induced, a cellular system was established to respond to the question if Bmi-1 is involved in effects of E2F-1. The prognosis of neuroblastomas, a common tumour of the nerval system in childhood, correlates with overexpression of several E2F target genes like MYCN and MAD2 amongst others. In neuroblastoma cells a up to tenfold increase of Bmi-1 expression could be detected after induction. As opposed to cells in which E2F-1 was activated, no change of cell cycle progression or apotosis rate was observed. This argues against the ability of overexpressed Bmi-1 to activate genetic programs regulated by E2F-1 in neuroblastoma cells. Otherwise the amount of endogenous Bmi-1 within the cells could have been already sufficient to perform its task. Therefore prospective experiments should also make use of loss of function approaches. Bmi-1 promotes cell cycle progression by inhibiting p16Ink4a and p19Arf. But in contrast to many other genes regulated by E2F-1, BMI1 is being expressed equally during G1-, G0- and S-phase of the cell cycle. This was demonstrated by a synchronized population of neuroblastoma cells. The polycomb proteins Bmi-1, Ring1 and Hpc2 interact but fulfill different or even opposed tasks. Ring1 and Hpc2 were not or only transient increased after induction of E2F-1. Therefore BMI1 is the only gene of a member of the polycomb protein complex PRC1 that is being regulated by E2F-1. The biological function of a polycomb protein complex seems to be determined by its composition. Since E2F-1 determines the relative amount of different proteins in the complex and not its total volume this finding might explain the promotion of cell proliferation by E2F-1.