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Hyperactive HRAS dysregulates energetic metabolism in fibroblasts from patients with Costello syndrome via enhanced production of reactive oxidizing species.
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.
Afiliação
  • Carpentieri G; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome 00146, Italy.
  • Leoni C; Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00161, Italy.
  • Pietraforte D; Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome 00168, Italy.
  • Cecchetti S; Core Facilities, Istituto Superiore di Sanità, Rome 00161, Italy.
  • Iorio E; Core Facilities, Istituto Superiore di Sanità, Rome 00161, Italy.
  • Belardo A; Core Facilities, Istituto Superiore di Sanità, Rome 00161, Italy.
  • Pietrucci D; Department of Ecological and Biological Sciences, Università della Tuscia, Viterbo 01100, Italy.
  • Di Nottia M; Department for Innovation in Biological, Agro-food and Forest Systems, Università della Tuscia, Viterbo 01100, Italy.
  • Pajalunga D; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome 00146, Italy.
  • Megiorni F; Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00161, Italy.
  • Mercurio L; Department of Experimental Medicine, Sapienza University, Rome 00161, Italy.
  • Tatti M; Laboratory of Experimental Immunology and Dermatology Division, IDI-IRCCS, Rome 00167, Italy.
  • Camero S; Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00161, Italy.
  • Marchese C; Department Maternal Infantile and Urological Sciences, SAPIENZA University, Rome 00161, Italy.
  • Rizza T; Department of Experimental Medicine, Sapienza University, Rome 00161, Italy.
  • Tirelli V; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome 00146, Italy.
  • Onesimo R; Core Facilities, Istituto Superiore di Sanità, Rome 00161, Italy.
  • Carrozzo R; Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome 00168, Italy.
  • Rinalducci S; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome 00146, Italy.
  • Chillemi G; Department of Ecological and Biological Sciences, Università della Tuscia, Viterbo 01100, Italy.
  • Zampino G; Department for Innovation in Biological, Agro-food and Forest Systems, Università della Tuscia, Viterbo 01100, Italy.
  • Tartaglia M; Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome 00168, Italy.
  • Flex E; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome 00146, Italy.
Hum Mol Genet ; 31(4): 561-575, 2022 02 21.
Article em En | MEDLINE | ID: mdl-34508588
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Síndrome de Costello Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Síndrome de Costello Idioma: En Ano de publicação: 2022 Tipo de documento: Article