RT Journal Article
T1 AMBRA1 links autophagy to cell proliferation and tumorigenesis by promoting c-Myc dephosphorylation and degradation
A1 Cianfanelli, Valentina
A1 Fuoco, Claudia
A1 Lorente Pérez, María Del Mar
A1 Salazar Roa, María
A1 Quondamatteo, Fabio
A1 Gherardini, Pier Federico
A1 De Zio, Daniela
A1 Nazio, Francesca
A1 Antonioli, Manuela
A1 D’Orazio, Melania
A1 Skobo, Tatjana
A1 Bordi, Matteo
A1 Rohde, Mikkel
A1 Dalla Valle, Luisa
A1 Helmer-Citterich, Manuela
A1 Gretzmeier, Christine
A1 Dengjel, Joern
A1 Fimia, Gian Maria
A1 Piacentini, Mauro
A1 Di Bartolomeo, Sabrina
A1 Velasco Díez, Guillermo
A1 Cecconi, Francesco
AB Inhibition of a main regulator of cell metabolism, the protein kinase mTOR, induces autophagy and inhibits cell proliferation. However, the molecular pathways involved in the cross-talk between these two mTOR-dependent cell processes are largely unknown. Here we show that the scaffold protein AMBRA1, a member of the autophagy signalling network and a downstream target of mTOR, regulates cell proliferation by facilitating the dephosphorylation and degradation of the proto-oncogene c-Myc. We found that AMBRA1 favours the interaction between c-Myc and its phosphatase PP2A and that, when mTOR is inhibited, it enhances PP2A activity on this specific target, thereby reducing the cell division rate. As expected, such a de-regulation of c-Myc correlates with increased tumorigenesis in AMBRA1-defective systems, thus supporting a role for AMBRA1 as a haploinsufficient tumour suppressor gene.
PB Nature Research
SN 1465-7392
YR 2014
FD 2014
LK https://hdl.handle.net/20.500.14352/97936
UL https://hdl.handle.net/20.500.14352/97936
LA eng
NO Cianfanelli, V., Fuoco, C., Lorente, M. et al. AMBRA1 links autophagy to cell proliferation and tumorigenesis by promoting c-Myc dephosphorylation and degradation. Nat Cell Biol 17, 20–30 (2015). https://doi.org/10.1038/ncb3072
NO AcknowledgementsWe wish to thank M. Canney, V. Unterkircher, R. Laricchia and M. Salomé for excellent technical assistance, and M. Acuña Villa and M. W. Bennett for editorial and secretarial work. We also thank S. Campello for critical reading of the manuscript. We are indebted to R. Sears (Portland, Oregon, USA), A. C. Gingras (Toronto, Canada) and A. Teleman and K. Dimitriadis (Heidelberg, Germany) for providing us with V5–Flag–c-Myc and Flag–PR65A constructs and Tsc2 MEFs, respectively, and to S. Cannata (Rome) for his advice on histopathology. This work was supported by grants from KBVU (R72-A4408), Lundbeck Foundation (R167-2013-16100), Novo Nordisk Foundation (7559), The Bjarne Saxhof Foundation, AIRC (IG2010 and IG2012 to both F.C. and M.P.), and in part from FISM (2009), the Telethon Foundation (GGP10225), the Italian Ministry of University and Research (PRIN 2009 and FIRB Accordi di Programma 2011) and the Italian Ministry of Health (RF 2009). V.C. is supported by the Lundbeck Foundation (R165-2013-15982). Also, we are grateful to the Spanish Ministry of Economy and Competitiveness (MINECO) (PS09/01401; PI12/02248, FR2009-0052 and IT2009-0053) and to Fundación Mutua Madrileña (AP101042012) for funding the laboratory of G.V.
NO Lundbeck Foundation
NO Novo Nordisk Foundation
NO The Bjarne Saxhof Foundation
NO Research Foundation on Cancer (Italy)
NO Telethon Foundation (Italy)
NO Ministry of University and Research (Italy)
NO Ministry of Health (Italy)
NO Fundación Mutua Madrileña
NO Ministerio de Economía y Competitividad (España)
DS Docta Complutense
RD 18 abr 2025