AMBRA1: when autophagy meets cell proliferationby Valentina Cianfanelli, Francesco Cecconi

Autophagy

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Year
2015
DOI
10.1080/15548627.2015.1053681
Subject
Cell Biology / Molecular Biology

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AMBRA1: when autophagy meets cell proliferation

Valentina Cianfanelliab & Francesco Cecconiabc a Unit of Cell Stress and Survival, Danish Cancer Society Research Center, 2100

Copenhagen, Denmark b IRCCS Fondazione Santa Lucia, 00143 Rome, Italy c Department of Biology, University of Rome ‘Tor Vergata’, 00133 Rome, Italy

Accepted author version posted online: 23 Jun 2015.

To cite this article: Valentina Cianfanelli & Francesco Cecconi (2015): AMBRA1: when autophagy meets cell proliferation,

Autophagy, DOI: 10.1080/15548627.2015.1053681

To link to this article: http://dx.doi.org/10.1080/15548627.2015.1053681

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AMBRA1: when autophagy meets cell proliferation

Valentina Cianfanellia,b & Francesco Cecconia,b,c,* aUnit of Cell Stress and Survival, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark; bIRCCS Fondazione Santa Lucia, 00143 Rome, Italy; cDepartment of Biology, University of Rome „Tor Vergata‟, 00133 Rome, Italy; *Correspondence to: Francesco Cecconi; Email: cecconi@cancer.dk

Keywords: cancer, MYC, MTORC1, PPP2/PP2A.

Punctum to:

Cianfanelli V, Fuoco C, Lorente M, Salazar M, Quondamatteo F, Gherardini

PF, De Zio D, Nazio F, Antonioli M, D'Orazio M, et al. AMBRA1 links autophagy to cell proliferation and tumorigenesis by promoting c-Myc dephosphorylation and degradation. Nature cell biology 2015; 17:20-30.

Cianfanelli V, D'Orazio M, and Cecconi F. AMBRA1 and BECLIN 1 interplay in the crosstalk between autophagy and cell proliferation. Cell cycle 2015; 14:959-963.

Abstract

A growing amount of evidence reported in the literature in recent years strongly support the relevance of the interplay between autophagy and other pathways. In this context, the study of the link between autophagy and cell proliferation regulation has been among the most challenging. In our recent publications, we finely characterize a role for the pro-autophagic protein

AMBRA1 in the regulation of cell proliferation. AMBRA1 modulates autophagy and interacts with PPP2/PP2A (protein phosphatase 2), thus also modulating

MYC protein levels and the cell proliferation rate. Interestingly, this pathway of regulation is controlled by the master regulator of autophagy and cell growth,

MTORC1. Notably, in our study we demonstrate the relevance of the

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AMBRA1-mediated regulation of MYC in tumorigenesis, also identifying

AMBRA1 as a tumor suppressor gene.

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Environmental restrictions, such as nutrient shortage and cellular stressors, trigger a cell response consisting of autophagy induction and simultaneous inhibition of cell proliferation. The conservation among species of this metabolic reprogramming also suggests a reciprocal regulation of autophagy and cell proliferation, although our understanding of the molecular mechanism(s) linking these 2 pathways is far from being conclusive. In this context, the mechanistic target of rapamycin complex 1 (MTORC1) is an exception, since it has been long known to regulate both autophagy and cell growth, although distinct MTORC1 substrates play independent roles in the 2 pathways. The depletion of some upstream regulators of autophagy, AMBRA1 among them, has been as well associated with increased proliferation.

AMBRA1 has emerged as a scaffold protein regulating autophagy in multiple ways. In “fed” conditions, AMBRA1 tethers the class III PtdIns3K complex at the cytoskeleton, negatively regulating autophagy; however, this inhibitory mechanism is lost upon starvation, when the ULK1 kinase phosphorylates AMBRA1. In a positive feedback control, AMBRA1 activates

ULK1, an event that is prevented by the MTORC1-mediated phosphorylation of AMBRA1, thereby inhibiting autophagy. Finally, Antonioli and co-authors recently showed that AMBRA1 also establishes a feedback loop on the kinase