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. Epub 2014 Dec 1.

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 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
  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • RNA, Small Interfering
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Protein Phosphatase 2