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01.12.2017 | Research | Ausgabe 1/2017 Open Access

Molecular Cancer 1/2017

MDM4 actively restrains cytoplasmic mTORC1 by sensing nutrient availability

Zeitschrift:
Molecular Cancer > Ausgabe 1/2017
Autoren:
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
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​s12943-017-0626-7) contains supplementary material, which is available to authorized users.

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.
Zusatzmaterial
Additional file 1: Figure S1. MDM4 inhibits S6K1 phosphorylation. Figure S2. MDM4 depletion leads to mTORC1 relocalization. Figure S3 MDM4 affects cell size. (PDF 428 kb)
12943_2017_626_MOESM1_ESM.pdf
Literatur
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