title: AMBRA1 links autophagy to cell proliferation and tumorigenesis by promoting c-Myc dephosphorylation and degradation.
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.
authors.affiliation: 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.
authors.forename: Valentina
authors.initials: V
authors.lastname: Cianfanelli
authors.affiliation: Department of Biology, University of Rome 'Tor Vergata', 00133 Rome, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Fuoco
authors.affiliation: 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.
authors.forename: Mar
authors.initials: M
authors.lastname: Lorente
authors.affiliation: 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.
authors.forename: Maria
authors.initials: M
authors.lastname: Salazar
authors.affiliation: Skin and Extracellular Matrix Research Group, Anatomy NUI Galway, Ireland.
authors.forename: Fabio
authors.initials: F
authors.lastname: Quondamatteo
authors.affiliation: Department of Biology, University of Rome 'Tor Vergata', 00133 Rome, Italy.
authors.forename: Pier Federico
authors.initials: PF
authors.lastname: Gherardini
authors.affiliation: Unit of Cell Stress and Survival, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark.
authors.forename: Daniela
authors.initials: D
authors.lastname: De Zio
authors.affiliation: Laboratory of Molecular Neuroembryology, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Nazio
authors.affiliation: 1] Department of Biology, University of Rome 'Tor Vergata', 00133 Rome, Italy [2] National Institute for Infectious Diseases IRCCS 'L. Spallanzani', 00149 Rome, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Antonioli
authors.affiliation: Department of Biology, University of Rome 'Tor Vergata', 00133 Rome, Italy.
authors.forename: Melania
authors.initials: M
authors.lastname: D'Orazio
authors.affiliation: Department of Biology, University of Padua, 35131 Padua, Italy.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Skobo
authors.affiliation: Laboratory of Molecular Neuroembryology, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Bordi
authors.affiliation: Unit of Cell Death and Metabolism, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark.
authors.forename: Mikkel
authors.initials: M
authors.lastname: Rohde
authors.affiliation: Department of Biology, University of Padua, 35131 Padua, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Dalla Valle
authors.affiliation: Department of Biology, University of Rome 'Tor Vergata', 00133 Rome, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Helmer-Citterich
authors.affiliation: 1] Department of Dermatology, University Freiburg Medical Center, 79104 Freiburg, Germany [2] ZBSA Center for Biological Systems Analysis, University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Gretzmeier
authors.affiliation: 1] Department of Dermatology, University Freiburg Medical Center, 79104 Freiburg, Germany [2] ZBSA Center for Biological Systems Analysis, University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Joern
authors.initials: J
authors.lastname: Dengjel
authors.affiliation: 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.
authors.forename: Gian Maria
authors.initials: GM
authors.lastname: Fimia
authors.affiliation: 1] Department of Biology, University of Rome 'Tor Vergata', 00133 Rome, Italy [2] National Institute for Infectious Diseases IRCCS 'L. Spallanzani', 00149 Rome, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Piacentini
authors.affiliation: Department of Biology, University of Rome 'Tor Vergata', 00133 Rome, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Di Bartolomeo
authors.affiliation: 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.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Velasco
authors.affiliation: 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.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cecconi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001343:Autophagy / Q000235:genetics*; D002455:Cell Division / Q000235:genetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D005260:Female; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D057809:HEK293 Cells; D057895:Haploinsufficiency; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D015027:Zebrafish
chemical_list: C553334:AMBRA1 protein, human; D048868:Adaptor Proteins, Signal Transducing; C521754:Ambra1 protein, mouse; C000715470:MAS1 protein, human; C489427:MYC protein, human; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D054648:Protein Phosphatase 2