Description du projet
Fonction et stabilité des protéines MYC dans le cancer
Les protéines MYC sont impliquées dans la prolifération, la croissance et la différenciation des cellules. Elles sont également fréquemment surexprimées dans les tumeurs. Ces éléments fonctionnent comme des facteurs de transcription, régulant l’expression de gènes spécifiques. Financé par le Conseil européen de la recherche, le projet AUROMYC cherche à comprendre comment les protéines MYC, qui sont rapidement dégradées dans les cellules normales, deviennent stables dans les cellules cancéreuses et favorisent la formation du cancer. Les chercheurs utiliseront différentes techniques pour étudier l’interaction spécifique de la kinase Aurora-A avec N-Myc dans les tumeurs neuroendocrines et la manière dont cette interaction peut être perturbée à l’aide d’inhibiteurs. Les résultats du projet ouvriront la voie au développement rationnel de traitements ciblés contre N-Myc.
Objectif
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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ERC-ADG - Advanced GrantInstitution d’accueil
97070 Wuerzburg
Allemagne