Identifizierung von Aurora-A als essentielles Protein im MYCN-amplifizierten Neuroblastom und Relevanz der c-Myc/Miz1-Interaktion für die MYC-induzierte Tumorgenese in vivo

Myc-Onkoproteine (c-Myc, N-Myc und L-Myc) sind in einer Vielzahl humaner maligner Tumore in erhöhten Mengen nachgewiesen worden und in der Lage, in verschiedenen Mausmodellen maligne Tumore zu induzieren. Dabei wurden die onkogenen Funktionen von Myc bisher größtenteils einer transkriptionellen Akti...

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Bibliographic Details
Main Author: Otto, Tobias
Contributors: Renkawitz-Pohl, Renate (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2008
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Myc oncoproteins (c-Myc, N-Myc and L-Myc) were detected in elevated amounts in several human malignant tumours and are capable of inducing malignant tumours in a variety of mouse models. So far, the oncogenic function of Myc has been ascribed mainly to the transcriptional activation of specific target genes. Furthermore, the relevance of transcriptional repression by binding to the transcription factor Miz1 has been shown for several biological functions of Myc within the last ten years. Moreover, inhibition of Myc function can cause regression of established tumours in different mouse models. However, direct inhibition of Myc function has not been successful yet. Therefore, identification of proteins that are essential for Myc-induced tumours provides a therapeutic alternative. In neuroblastoma, amplification of MYCN correlates with poor prognosis. In this thesis, Aurora-A has been identified as an essential protein for proliferation of MYCN-amplified neuroblastoma cells. Aurora-A is required for continuously high levels of N-Myc throughout the cell cycle by inhibition of the phosphorylation-dependent, mitotic degradation of N-Myc. Aurora-A directly interacts with phosphorylated N-Myc and impairs the proteasomal degradation of N-Myc induced by the ubiquitin ligase SCF(Fbxw7α) in a kinase activity independent manner, presumably by altering the ubiquitin linkages of poly-ubiquitinated N-Myc. This demonstrates, in addition to the already described centrosome amplification, a novel kinase-independent oncogenic function of Aurora-A that is probably also essential for tumour cell proliferation in other tumours with high levels of Aurora-A. The importance of the repressive function of c-Myc was analysed in a mouse model by the use of a mutation of c-Myc (V394D) that interferes with the binding to Miz1 and therefore blocks repression of target genes. This leads to a delay in the development of c-Myc induced T cell lymphomas. In this process, Myc-wt repressed the TGFβ-induced expression of p15Ink4b as well as cellular senescence as a tumour-protective mechanism. In contrast, the Miz1 binding-deficient mutant c-Myc-V394D is not able to accomplish this. Therefore, additional mutations are presumably necessary whose acquisition causes the delay in tumorigenesis.