AMBRA1 links autophagy to cell proliferation and tumorigenesis by promoting c-Myc dephosphorylation and degradation

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...

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Bibliographic Details
Authors: Cianfanelli, Valentina, Fuoco, Claudia, Lorente Pérez, María Del Mar, Salazar Roa, María, Quondamatteo, Fabio, Gherardini, Pier Federico, De Zio, Daniela, Nazio, Francesca, Antonioli, Manuela, D’Orazio, Melania, Skobo, Tatjana, Bordi, Matteo, Rohde, Mikkel, Dalla Valle, Luisa, Helmer-Citterich, Manuela, Gretzmeier, Christine, Dengjel, Joern, Fimia, Gian Maria, Piacentini, Mauro, Di Bartolomeo, Sabrina, Velasco Díez, Guillermo, Cecconi, Francesco
Format: article
Publication Date:2014
Country:España
Institution:Universidad Complutense de Madrid (UCM)
Repository:Docta Complutense
Language:English
OAI Identifier:oai:docta.ucm.es:20.500.14352/97936
Online Access:https://hdl.handle.net/20.500.14352/97936
Access Level:Open access
Keyword:616-006.04
Ambra
Autophagy
Bioquímica (Biología)
Oncología
2403 Bioquímica
3207 Patología
Description
Summary: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.

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