Project description
Myc function and stability in cancer
Myc proteins are involved in cell proliferation, growth, and differentiation. They are also frequently overexpressed in tumours. They function as transcription factors, regulating expression of specific genes. Funded by the European Research Council, the AUROMYC project is interested in understanding how Myc proteins, which are rapidly degraded in normal cells, become stable in cancer cells and promote cancer formation. Researchers will employ various techniques to investigate the specific interaction of Aurora-A kinase with N-myc in neuroendocrine tumours and how this interaction can be disrupted using inhibitors. Project findings will pave the way for the rational development of targeted treatments against N-myc.
Objective
There is an intense interest in the function of human Myc proteins that stems from their pervasive role in the genesis of human tumors. A large body of evidence has established that expression levels of one of three closely related Myc proteins are enhanced in the majority of all human tumors and that multiple tumor entities depend on elevated Myc function, arguing that targeting Myc will have significant therapeutic efficacy. This hope awaits clinical confirmation, since the strategies that are currently under investigation to target Myc function or expression have yet to enter the clinic. Myc proteins are global regulators of transcription, but their mechanism of action is poorly understood.
Myc proteins are highly unstable in normal cells and rapidly turned over by the ubiquitin/proteasome system. In contrast, they are stabilized in tumor cells. Work by us and by others has shown that stabilization of Myc is required for tumorigenesis and has identified strategies to destabilize Myc for tumor therapy. This work has also led to the surprising observation that the N-Myc protein, which drives neuroendocrine tumorigenesis, is stabilized by association with the Aurora-A kinase and that clinically available Aurora-A inhibitors can dissociate the complex and destabilize N-Myc. Aurora-A has not previously been implicated in transcription, prompting us to use protein crystallography, proteomics and shRNA screening to understand its interaction with N-Myc. We have now identified a novel protein complex of N-Myc and Aurora-A that provides an unexpected and potentially groundbreaking insight into Myc function. We have also solved the crystal structure of the N-Myc/Aurora-A complex. Collectively, both findings open new strategies to target Myc function for tumor therapy.
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Funding Scheme
ERC-ADG - Advanced GrantHost institution
97070 Wuerzburg
Germany