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Molecular Cancer
Published in: Molecular Cancer 1/2017

Open Access 01-12-2017 | Research

MDM4 actively restrains cytoplasmic mTORC1 by sensing nutrient availability

Authors: Francesca Mancini, Emanuela Teveroni, Giusy Di Conza, Valentina Monteleone, Ivan Arisi, Marsha Pellegrino, Marianna Buttarelli, Luisa Pieroni, Mara D’Onofrio, Andrea Urbani, Alfredo Pontecorvi, Massimiliano Mazzone, Fabiola Moretti

Published in: Molecular Cancer | Issue 1/2017

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Abstract

Background

Many tumor-related factors have shown the ability to affect metabolic pathways by paving the way for cancer-specific metabolic features. Here, we investigate the regulation of mTORC1 by MDM4, a p53-inhibitor with oncogenic or anti-survival activities depending on cell growth conditions.

Method

MDM4-mTOR relationship was analysed through experiments of overexpression or silencing of endogenous proteins in cell culture and using purified proteins in vitro. Data were further confirmed in vivo using a transgenic mouse model overexpressing MDM4. Additionally, the Cancer Genome Atlas (TCGA) database (N = 356) was adopted to analyze the correlation between MDM4 and mTOR levels and 3D cultures were used to analyse the p53-independent activity of MDM4.

Results

Following nutrient deprivation, MDM4 impairs mTORC1 activity by binding and inhibiting the kinase mTOR, and contributing to maintain the cytosolic inactive pool of mTORC1. This function is independent of p53. Inhibition of mTORC1 by MDM4 results in reduced phosphorylation of the mTOR downstream target p70S6K1 both in vitro and in vivo in a MDM4-transgenic mouse. Consistently, MDM4 reduces cell size and proliferation, two features controlled by p70S6K1, and, importantly, inhibits mTORC1-mediated mammosphere formation. Noteworthy, MDM4 transcript levels are significantly reduced in breast tumors characterized by high mTOR levels.

Conclusion

Overall, these data identify MDM4 as a nutrient-sensor able to inhibit mTORC1 and highlight its metabolism-related tumor-suppressing function.
Appendix
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Metadata
Title
MDM4 actively restrains cytoplasmic mTORC1 by sensing nutrient availability
Authors
Francesca Mancini
Emanuela Teveroni
Giusy Di Conza
Valentina Monteleone
Ivan Arisi
Marsha Pellegrino
Marianna Buttarelli
Luisa Pieroni
Mara D’Onofrio
Andrea Urbani
Alfredo Pontecorvi
Massimiliano Mazzone
Fabiola Moretti
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2017
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-017-0626-7

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