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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adaptor Proteins, Signal Transducing / genetics
-
Adaptor Proteins, Signal Transducing / physiology*
-
Animals
-
Autophagy / genetics*
-
Cell Division / genetics
-
Cell Line, Tumor
-
Cell Transformation, Neoplastic / genetics*
-
Female
-
Genes, Tumor Suppressor / physiology*
-
HEK293 Cells
-
Haploinsufficiency*
-
HeLa Cells
-
Humans
-
Male
-
Mice
-
Mice, Inbred C57BL
-
Mice, Transgenic
-
Phosphorylation
-
Protein Phosphatase 2 / metabolism
-
Proto-Oncogene Mas
-
Proto-Oncogene Proteins c-myc / metabolism*
-
RNA Interference
-
RNA, Small Interfering
-
TOR Serine-Threonine Kinases / antagonists & inhibitors*
-
Zebrafish
Substances
-
AMBRA1 protein, human
-
Adaptor Proteins, Signal Transducing
-
Ambra1 protein, mouse
-
MAS1 protein, human
-
MYC protein, human
-
Proto-Oncogene Mas
-
Proto-Oncogene Proteins c-myc
-
RNA, Small Interfering
-
MTOR protein, human
-
TOR Serine-Threonine Kinases
-
Protein Phosphatase 2