Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2067/47143
Titolo: Hyperactive HRAS dysregulates energetic metabolism in fibroblasts from patients with Costello syndrome via enhanced production of reactive oxidizing species
Autori: Carpentieri Giovanna
Leoni Chiara
Pietraforte Donatella
Cecchetti Serena
Iorio Egidio
Belardo Antonio
Pietrucci Daniele
Di Nottia Michela
Pajalunga Deborah
Megiorni Francesca
Mercurio Laura
Tatti Massimo
Camero Simona
Marchese Cinzia
Rizza Teresa
Tirelli Valentina
Onesimo Roberta
Carrozzo Rosalba
Rinalducci Sara 
Chillemi Giovanni 
Zampino Giuseppe
Tartaglia Marco
Flex Elisabetta
Rivista: HUMAN MOLECULAR GENETICS 
Data pubblicazione: 2022
Abstract: 
Germline-activating mutations in HRAS cause Costello syndrome (CS), a cancer prone multisystem disorder characterized by reduced postnatal growth. In CS, poor weight gain and growth are not caused by low caloric intake. Here, we show that constitutive plasma membrane translocation and activation of the GLUT4 glucose transporter, via reactive oxygen species-dependent AMP-activated protein kinase α and p38 hyperactivation, occurs in primary fibroblasts of CS patients, resulting in accelerated glycolysis and increased fatty acid synthesis and storage as lipid droplets. An accelerated autophagic flux was also identified as contributing to the increased energetic expenditure in CS. Concomitant inhibition of p38 and PI3K signaling by wortmannin was able to rescue both the dysregulated glucose intake and accelerated autophagic flux. Our findings provide a mechanistic link between upregulated HRAS function, defective growth and increased resting energetic expenditure in CS, and document that targeting p38 and PI3K signaling is able to revert this metabolic dysfunction.
URI: http://hdl.handle.net/2067/47143
ISSN: 0964-6906
DOI: 10.1093/hmg/ddab270
Diritti: Attribution-NonCommercial 4.0 International
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