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

Nat Cell Biol. 2015 Jan;17(1):20-30. doi: 10.1038/ncb3072.

Valentina Cianfanelli ¹, Claudia Fuoco ², Mar Lorente ³, Maria Salazar ³, Fabio Quondamatteo ⁴, Pier Federico Gherardini ², Daniela De Zio ⁵, Francesca Nazio ⁶, Manuela Antonioli ⁷, Melania D'Orazio ², Tatjana Skobo ⁸, Matteo Bordi ⁶, Mikkel Rohde ⁹, Luisa Dalla Valle ⁸, Manuela Helmer-Citterich ², Christine Gretzmeier ¹⁰, Joern Dengjel ¹⁰, Gian Maria Fimia ¹¹, Mauro Piacentini ⁷, Sabrina Di Bartolomeo ², Guillermo Velasco ³, Francesco Cecconi ¹²

Affiliations

1 1] Unit of Cell Stress and Survival, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark [2] Laboratory of Molecular Neuroembryology, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy.
2 Department of Biology, University of Rome 'Tor Vergata', 00133 Rome, Italy.
3 1] Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040 Madrid, Spain [2] Instituto de Investigaciones Sanitarias San Carlos (IdISSC), 28040 Madrid, Spain.
4 Skin and Extracellular Matrix Research Group, Anatomy NUI Galway, Ireland.
5 Unit of Cell Stress and Survival, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark.
6 Laboratory of Molecular Neuroembryology, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy.
7 1] Department of Biology, University of Rome 'Tor Vergata', 00133 Rome, Italy [2] National Institute for Infectious Diseases IRCCS 'L. Spallanzani', 00149 Rome, Italy.
8 Department of Biology, University of Padua, 35131 Padua, Italy.
9 Unit of Cell Death and Metabolism, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark.
10 1] Department of Dermatology, University Freiburg Medical Center, 79104 Freiburg, Germany [2] ZBSA Center for Biological Systems Analysis, University of Freiburg, 79104 Freiburg, Germany.
11 1] National Institute for Infectious Diseases IRCCS 'L. Spallanzani', 00149 Rome, Italy [2] Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Lecce 73100, Italy.
12 1] Unit of Cell Stress and Survival, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark [2] Laboratory of Molecular Neuroembryology, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy [3] Department of Biology, University of Rome 'Tor Vergata', 00133 Rome, Italy.

PMID: 25438055 DOI: 10.1038/ncb3072

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.

Name
Email *

	Sorry, but the email address you supplied was invalid.