Descrizione del progetto
Funzione e stabilità del gene Myc nel cancro
Le proteine Myc sono coinvolte nella proliferazione, nella crescita e nella differenziazione cellulare, e sono anche spesso sovraespresse nei tumori. Funzionano come fattori di trascrizione, regolando l’espressione di geni specifici. Il progetto AUROMYC, finanziato dal Consiglio europeo della ricerca, è interessato a capire come le proteine Myc, che vengono rapidamente degradate nelle cellule normali, diventino stabili nelle cellule tumorali e promuovano la formazione del cancro. I ricercatori utilizzeranno varie tecniche per studiare l’interazione specifica della chinasi Aurora-A con N-myc nei tumori neuroendocrini, approfondendo inoltre come questa interazione possa essere interrotta utilizzando degli inibitori. I risultati del progetto apriranno la strada allo sviluppo razionale di trattamenti mirati contro N-myc.
Obiettivo
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.
Campo scientifico
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-ADG - Advanced GrantIstituzione ospitante
97070 Wuerzburg
Germania