Die Regulation der N-Myc-Stabilität ist eine wichtige Funktion der Aurora-A-Kinase in MYCN- amplifizierten Neuroblastomen

Neuroblastoma is the most common extracranial solid tumor in infancy. It descends from primitive cells of the sympathetic nervous system. The course of the disease varies strongly, ranging from slowly growing tumors, with the potential of spontaneous remission, to progressive disease with metastasis and a five-year survival rate of only 30%. The different biological features are caused by several genetic risk factors. One of these risk factors is the amplification of the MYCN proto-oncogene. The encoded protein N-Myc is a transcription factor that is able to activate other genes and thereby influence cell growth and cell cycle. Although there are several N-Myc target genes known, it has yet not been clarified what the reason for this aggressive growth and the poor outcome in MYCN-amplified Neuroblastoma is. To identify further genes, that are relevant for the growth of MYCN-amplified tumors, a screen was performed. Therefore, 194 genes were depleted separately in a MYCN-amplified and a MYCN-nonamplified cell line. In the screen it was checked, which genes showed an inhibition of cell proliferation in the MYCN-amplified cell line while having no effect on the nonamplified cell line. Seventeen genes were thereby detected. In this dissertation the “knock-down” efficiency of the screen has been proved. This is necessary in order to estimate the number of genes that have been checked in the screen. One of the identified genes is Aurora-A. Depletion of Aurora-A inhibits cell proliferation in the MYCN-amplified cell line. To check whether this observation is a general phenomenon, other Neuroblastoma cell lines were tested. The observation was verified in four MYCN-amplified and four MYCN-nonamplified cell lines. To identify the mechanism of proliferation arrest in Aurora-A depleted cells the eight cell lines were checked for collective protein alterations. The results show, that Aurora-A stabilizes N-Myc and therefore influences cell growth and proliferation. Aurora-A depletion leads to decreased N-Myc levels and promotes proliferation arrest. N-Myc stabilization could be identified as a critical function of Aurora-A in MYCN-amplified Neuroblastoma.