AMBRA1 links autophagy to cell proliferation and tumorigenesis by promoting c-Myc dephosphorylation and degradation PMID: 25438055

ADC Targets in Oncology

2026-04-10

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.

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.