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

Nature cell biology (2014-12-02)
Valentina Cianfanelli, Claudia Fuoco, Mar Lorente, Maria Salazar, Fabio Quondamatteo, Pier Federico Gherardini, Daniela De Zio, Francesca Nazio, Manuela Antonioli, Melania D'Orazio, Tatjana Skobo, Matteo Bordi, Mikkel Rohde, Luisa Dalla Valle, Manuela Helmer-Citterich, Christine Gretzmeier, Joern Dengjel, Gian Maria Fimia, Mauro Piacentini, Sabrina Di Bartolomeo, Guillermo Velasco, Francesco Cecconi
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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