Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Más filtros

Bases de datos
Tipo del documento
Asunto de la revista
País de afiliación
Intervalo de año de publicación
1.
Nat Metab ; 4(2): 225-238, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-35228743

RESUMEN

Many types of cancer feature TP53 mutations with oncogenic properties. However, whether the oncogenic activity of mutant p53 is affected by the cellular metabolic state is unknown. Here we show that cancer-associated mutant p53 protein is stabilized by 2-hydroxyglutarate generated by malic enzyme 2. Mechanistically, malic enzyme 2 promotes the production of 2-hydroxyglutarate by adjusting glutaminolysis, as well as through a reaction that requires pyruvate and NADPH. Malic enzyme 2 depletion decreases cellular 2-hydroxyglutarate levels in vitro and in vivo, whereas elevated malic enzyme 2 expression increases 2-hydroxyglutarate production. We further show that 2-hydroxyglutarate binds directly to mutant p53, which reduces Mdm2-mediated mutant p53 ubiquitination and degradation. 2-Hydroxyglutarate supplementation is sufficient for maintaining mutant p53 protein stability in malic enzyme 2-depleted cells, and restores tumour growth of malic enzyme 2-ablated cells, but not of cells that lack mutant p53. Our findings reveal the previously unrecognized versatility of malic enzyme 2 catalytic functions, and uncover a role for mutant p53 in sensing cellular 2-hydroxyglutarate levels, which contribute to the stabilization of mutant p53 and tumour growth.


Asunto(s)
Neoplasias , Proteína p53 Supresora de Tumor , Carcinogénesis , Glutaratos , Humanos , Malato Deshidrogenasa , Neoplasias/genética , Neoplasias/metabolismo , Estabilidad Proteica , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo
2.
Ageing Res Rev ; 62: 101116, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32554058

RESUMEN

Neurodegenerative diseases (NDDs), which contribute to progressive and irreversible impairments of both the structure and function of the nervous system, pose a substantial socioeconomic burden on society. Mitochondrial dysfunction, oxidative stress, membrane damage, DNA damage, and abnormal protein degradation pathways play pivotal roles in the etiology of NDDs. Recently, growing evidence has demonstrated that caveolins are important in the pathology of NDDs due to their cellular functions in signal transduction, endocytosis, transcytosis, cholesterol transport, and lipid homeostasis. Given the significance of caveolins, here we review the literature to clarify their molecular mechanisms and roles in NDDs. We first briefly introduce the general background on caveolins. Next, we focus on the various important functions of caveolins in the brain. Finally, we emphasize recent progress regarding caveolins, especially Cav-1, which exert both benefit and unfavorable effects in NDDs such as AD and PD. Collectively, the data presented here should advance the investigation of caveolins for the future development of innovative strategies for the treatment of NDDs.


Asunto(s)
Enfermedades Neurodegenerativas , Caveolina 1/metabolismo , Homeostasis , Humanos , Estrés Oxidativo , Transducción de Señal
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA