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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - AUROMYC (N-Myc and Aurora A: From Protein Stability to Chromosome TopologyN-Myc and Aurora A: From Protein Stability to Chromosome TopologyMyc and Aurora A: From Protein Stability to Chromosome Topology)

Teaser

Summary

The question that is being addressed is to understand the function of a complex of the MYCN protein with the Aurora-A kinase. The MYCN protein is a critical oncoprotein that drives the development of many, mainly neuroendocrine tumours. Understanding the function of this protein and finding ways to target it for the therapy of tumours is therefore of significant theoretical and medical benefit. Our previous work had shown that MYCN forms a complex with the Aurora-A kinase that stabilises the MYCN protein in human tumours. We and others have also provided evidence that targeting the complex via small molecule ligands of Aurora-A achieves considerable therapeutic benefit in mouse models of MYCN and also in several models of tumours driven by the closely related MYC oncoprotein. Initial data in human trails of one such ligand had shown some efficacy but also pointed very clearly to the need for further improvement.

Work performed

The work program comprises a biochemical and structural analysis of complexes of the N-MYC protein; initially, the work started from a proteomic analysis of N-MYC complexes. Two major results are completed: first, the team in Leeds has resolved the structure of the Aurora-A/N-MYC complex, providing a firm basis for understanding its effects on N-MYC stability and the effects of different Aurora-A inhibitors. Second, the team in WÃ¼rzburg has shown that the association with Aurora-A regulates N-MYCÂ´s global transcriptional function in a cell cycle-dependent manner and provided evidence that the complex co-ordinates transcriptional elongation with DNA replication.

Final results

We expect that the project will yield a largely complete biochemical model and structural insights into how N-MYC co-ordinates transcription with DNA replication and provide strategies how to target this process for tumor therapy.