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Ambra1 links autophagy to cell proliferation and tumorigenesis by promoting c-myc dephosphorylation and degradation

Cianfanelli, Valentina
; 
Fuoco, Claudia
; 
Lorente, Mar
; 
Salazar, Maria
; 
Quondamatteo, Fabio
; 
Gherardini, Pier Federico
; 
De Zio, Daniela
; 
Nazio, Francesca
; 
Antonioli, Manuela
; 
D’Orazio, Melania
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Identifiers
http://hdl.handle.net/10379/10785
 https://doi.org/10.13025/28087
Publication Date
2014-12-01
Keywords
protein phosphatase 2a, regulates autophagy, mammalian autophagy, inhibits autophagy, human malignancies, pp2a, growth, cancer, mtor, association
Type
Article
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Citation
Cianfanelli, Valentina; Fuoco, Claudia; Lorente, Mar; Salazar, Maria; 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, Guillermo; Cecconi, Francesco (2014). Ambra1 links autophagy to cell proliferation and tumorigenesis by promoting c-myc dephosphorylation and degradation. Nature Cell Biology 17 (1),
Abstract
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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Publisher
Springer Nature
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Attribution-NonCommercial-NoDerivs 3.0 Ireland
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Externally hosted open access publications with University of Galway authors (2)