RESUMO
Whereas it is known that p53 broadly regulates cell metabolism, the specific activities that mediate this regulation remain partially understood. Here, we identified carnitine o-octanoyltransferase (CROT) as a p53 transactivation target that is upregulated by cellular stresses in a p53-dependent manner. CROT is a peroxisomal enzyme catalyzing very long-chain fatty acids conversion to medium chain fatty acids that can be absorbed by mitochondria during ß-oxidation. p53 induces CROT transcription through binding to consensus response elements in the 5'-UTR of CROT mRNA. Overexpression of WT but not enzymatically inactive mutant CROT promotes mitochondrial oxidative respiration, while downregulation of CROT inhibits mitochondrial oxidative respiration. Nutrient depletion induces p53-dependent CROT expression that facilitates cell growth and survival; in contrast, cells deficient in CROT have blunted cell growth and reduced survival during nutrient depletion. Together, these data are consistent with a model where p53-regulated CROT expression allows cells to be more efficiently utilizing stored very long-chain fatty acids to survive nutrient depletion stresses.
Assuntos
Carnitina Aciltransferases , Sobrevivência Celular , Nutrientes , Proteína Supressora de Tumor p53 , Regiões 5' não Traduzidas/genética , Carnitina/metabolismo , Carnitina Aciltransferases/genética , Carnitina Aciltransferases/metabolismo , Processos de Crescimento Celular , Respiração Celular , Ácidos Graxos/química , Ácidos Graxos/metabolismo , Mitocôndrias/metabolismo , Mutação , Nutrientes/deficiência , Nutrientes/metabolismo , Oxirredução , Peroxissomos/enzimologia , Elementos de Resposta/genética , Estresse Fisiológico , Ativação Transcricional , Proteína Supressora de Tumor p53/metabolismoRESUMO
The transcription factor p53 suppresses tumorigenesis via a wide-ranging, concerted set of functions. Although several studies have identified cytoplasmic, transcription-independent functions of p53, the biological relevance of these activities has not been fully elucidated, particularly in vivo. Here, we generated a mouse model with a p53K316P mutation, which mimics a naturally occurring p53 nuclear localization signal (NLS) change observed in bat species. We find that the p53K316P mutation increases cytoplasmic localization of p53 and promotes a pleiotropic metabolic phenotype that includes increased adiposity, increased de novo lipogenesis, and decreased lactate generation. Mechanistic studies show that, independent of its transactivation function, p53K316P interacts with lactate dehydrogenase B (LDHB) and alters the composition and enzymatic activities of LDH complex favoring pyruvate generation and hindering lactate production. Overall, the study identifies a role for cytoplasmic p53 in the regulation of metabolism that favors energy generation and storage.