Projektbeschreibung
Funktion und Stabilität von MYC bei Krebs
MYC-Proteine sind an der Zellproliferation, dem Zellwachstum und der Zelldifferenzierung beteiligt. Auch in Tumoren sind sie häufig überexprimiert. Sie fungieren als Transkriptionsfaktoren und regulieren die Expression bestimmter Gene. Im Rahmen des vom Europäischen Forschungsrat finanzierten Projekts AUROMYC wird untersucht, wie MYC-Proteine, die in normalen Zellen schnell abgebaut werden, in Krebszellen stabil werden und die Krebsbildung fördern. Die Forschenden werden verschiedene Verfahren anwenden, um die spezifische Wechselwirkung der Aurora-A-Kinase mit N-MYC in neuroendokrinen Tumoren zu untersuchen und um herauszufinden, wie diese Wechselwirkung durch Inhibitoren gestört werden kann. Die Projektergebnisse werden den Weg für die rationale Entwicklung gezielter Behandlungen gegen N-MYC ebnen.
Ziel
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.
Wissenschaftliches Gebiet
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-ADG - Advanced GrantGastgebende Einrichtung
97070 Wuerzburg
Deutschland