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N-Myc and Aurora A: From Protein Stability to Chromosome Topology N-Myc and Aurora A: From Protein Stability to Chromosome Topology Myc and Aurora A: From Protein Stability to Chromosome Topology

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.

Host institution

JULIUS-MAXIMILIANS-UNIVERSITAT WURZBURG
Net EU contribution
€ 1 891 017,50
Address
Sanderring 2
97070 Wuerzburg
Germany

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Region
Bayern Unterfranken Würzburg, Kreisfreie Stadt
Activity type
Higher or Secondary Education Establishments
Other funding
€ 0,00

Beneficiaries (3)

JULIUS-MAXIMILIANS-UNIVERSITAT WURZBURG
Germany
Net EU contribution
€ 1 891 017,50
Address
Sanderring 2
97070 Wuerzburg

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Region
Bayern Unterfranken Würzburg, Kreisfreie Stadt
Activity type
Higher or Secondary Education Establishments
Other funding
€ 0,00
UNIVERSITY OF LEICESTER

Participation ended

United Kingdom
Net EU contribution
€ 0,00
Address
University Road
LE1 7RH Leicester
Region
East Midlands (England) Leicestershire, Rutland and Northamptonshire Leicester
Activity type
Higher or Secondary Education Establishments
Other funding
€ 0,00
UNIVERSITY OF LEEDS
United Kingdom
Net EU contribution
€ 564 162,50
Address
Woodhouse Lane
LS2 9JT Leeds

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Region
Yorkshire and the Humber West Yorkshire Leeds
Activity type
Higher or Secondary Education Establishments
Other funding
€ 0,00