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MDM4 actively restrains cytoplasmic mTORC1 by sensing nutrient availability

Francesca Mancini1,2, Emanuela Teveroni3, Giusy Di Conza4,5

  • 1Institute of Cell Biology and Neurobiology, National Research Council of Italy (CNR), 00143, Rome, Italy. chicca.mancini@tiscali.it.

Molecular Cancer
|March 9, 2017
PubMed
Abstract

Insights

MDM4 acts as a nutrient sensor, inhibiting mTORC1 activity independently of p53. This finding reveals a novel metabolism-related tumor-suppressing function for MDM4 in cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Metabolism

Background:

  • Tumor-related factors significantly influence metabolic pathways, leading to cancer-specific metabolic alterations.
  • MDM4, a p53-inhibitor, exhibits context-dependent oncogenic or anti-survival roles.
  • Understanding MDM4's regulation of cellular metabolism is crucial for cancer research.

Purpose of the Study:

  • To investigate the regulatory relationship between MDM4 and mTORC1.
  • To elucidate the role of MDM4 in cellular metabolism and its implications in cancer.
  • To determine if MDM4's function is dependent on p53.

Main Methods:

  • Overexpression and silencing of MDM4 in cell culture.
  • In vitro kinase assays with purified proteins.
  • In vivo studies using a transgenic mouse model overexpressing MDM4.
  • Analysis of The Cancer Genome Atlas (TCGA) database (N=356) for MDM4 and mTOR correlations.
  • 3D cell cultures to assess p53-independent MDM4 activity.

Main Results:

  • MDM4 inhibits mTORC1 activity upon nutrient deprivation by binding to mTOR, independent of p53.
  • MDM4 reduces the phosphorylation of p70S6K1, a downstream target of mTORC1, in vitro and in vivo.
  • MDM4 diminishes cell size and proliferation, and inhibits mTORC1-mediated mammosphere formation.
  • MDM4 transcript levels are inversely correlated with mTOR levels in breast tumors from TCGA.

Conclusions:

  • MDM4 functions as a nutrient sensor that inhibits mTORC1.
  • MDM4 exhibits a metabolism-related tumor-suppressing function.
  • The p53-independent inhibition of mTORC1 by MDM4 offers new insights into cancer metabolism regulation.
Keywords:
AminoacidMDM4Nutrient deprivationmTORp53

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