Regulation der Genexpression von MYCN in humanen Neuoblastomzellen durch Transkriptionsfaktoren der E2F-Familie

Seit fast 30 Jahren ist bekannt, dass die Amplifikation und Expression des Onkogens MYCN in Neuroblastomen mit einer sehr ungünstigen Prognose für die Patienten einhergeht. Dennoch liegen die Mechanismen der Genregulation von MYCN weiterhin größtenteils im Dunkeln. Die Präsenz potentieller Bindung...

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Bibliographic Details
Main Author: Kneppe, Verena
Contributors: Eilers, Martin (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2005
Online Access:PDF Full Text
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It is known for more then 30 years that amplification and overexpression of the N-myc oncogene in neuroblastoma tumours correlates with a very bad prognosis for the patients, but still the mechanisms of gene regulation of MYCN remain largely unclear. The presence of potential binding sites for e2f proteins in the MYCN promoter as well as cell culture experiments pointed to a role of transcription factors of the e2f family in the regulation of MYCN expression. To find the answers to the questions whether e2f proteins are necessary to maintain the primarily high expression of N-myc in neuroblastoma cells with ampification of the oncogene, and whether they are sufficient to induce the transcription of MYCN in cells without endogenous expression of MYCN was the goal of this work. The amount of MYCN mRNA declined clearly in neuroblastoma cells through overexpression of the tumour suppressor protein p16 which leads to an inactivation of endogenous e2f proteins. Comparable results were achieved through overexpression of dominant negative e2f-1. Since some studies demonstrated that myc proteins can activate e2f genes we assume that a loop of positive feedback between e2f on the one hand and N-myc on the other hand maintains the high level of MYCN expression. Stably transfected e2f-er-fusion proteins were not able to switch on the endogenous MYCN gene in neuroblastoma cells without epxression of N-myc. Thus, e2f proteins are necessary to maintain the high level of MYCN expression in neuroblastoma but are not sufficient to activate the oncogene MYCN in cells without endogenous N-myc. Prevention of binding of e2f proteins to their target sequence in the promoter or gentherapeutic strategies that reconstruct the signaling pathway between p16 and e2f for example by viral infection, could lower the expression of N-myc in neuoblastomas in the future so that the aggressiveness of the tumours could be reduced and the individual prognosis of the patients would be improved.