Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Mais filtros

Base de dados
Tipo de documento
País de afiliação
Intervalo de ano de publicação
1.
Annu Rev Physiol ; 83: 381-403, 2021 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-33113341

RESUMO

Sestrins are a family of proteins that respond to a variety of environmental stresses, including genotoxic, oxidative, and nutritional stresses. Sestrins affect multiple signaling pathways: AMP-activated protein kinase, mammalian target of rapamycin complexes, insulin-AKT, and redox signaling pathways. By regulating these pathways, Sestrins are thought to help adapt to stressful environments and subsequently restore cell and tissue homeostasis. In this review, we describe how Sestrins mediate physiological stress responses in the context of nutritional and chemical stresses (liver), physical movement and exercise (skeletal muscle), and chemical, physical, and inflammatory injuries (heart). These findings also support the idea that Sestrins are a molecular mediator of hormesis, a paradoxical beneficial effect of low- or moderate-level stresses in living organisms.


Assuntos
Sestrinas/metabolismo , Estresse Fisiológico/fisiologia , Animais , Exercício Físico/fisiologia , Homeostase/fisiologia , Humanos , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiologia , Transdução de Sinais/fisiologia
2.
Gastroenterology ; 164(3): 376-391.e13, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36410445

RESUMO

BACKGROUND & AIMS: Colorectal cancer (CRC) is a devastating disease that is highly modulated by dietary nutrients. Mechanistic target of rapamycin complex 1 (mTORC1) contributes to tumor growth and limits therapy responses. Growth factor signaling is a major mechanism of mTORC1 activation. However, compensatory pathways exist to sustain mTORC1 activity after therapies that target oncogenic growth factor signaling. Amino acids potently activate mTORC1 via amino acid-sensing GTPase activity towards Rags (GATOR). The role of amino acid-sensing pathways in CRC is unclear. METHODS: Human colon cancer cell lines, preclinical intestinal epithelial-specific GATOR1 and GATOR2 knockout mice subjected to colitis-induced or sporadic colon tumor models, small interfering RNA screening targeting regulators of mTORC1, and tissues of patients with CRC were used to assess the role of amino acid sensing in CRC. RESULTS: We identified loss-of-function mutations of the GATOR1 complex in CRC and showed that altered expression of amino acid-sensing pathways predicted poor patient outcomes. We showed that dysregulated amino acid-sensing induced mTORC1 activation drives colon tumorigenesis in multiple mouse models. We found amino acid-sensing pathways to be essential in the cellular reprogramming of chemoresistance, and chemotherapeutic-resistant patients with colon cancer exhibited de-regulated amino acid sensing. Limiting amino acids in in vitro and in vivo models (low-protein diet) reverted drug resistance, revealing a metabolic vulnerability. CONCLUSIONS: Our findings suggest a critical role for amino acid-sensing pathways in driving CRC and highlight the translational implications of dietary protein intervention in CRC.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Animais , Camundongos , Humanos , Aminoácidos/metabolismo , Resistencia a Medicamentos Antineoplásicos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo
3.
Nat Commun ; 11(1): 190, 2020 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-31929512

RESUMO

Exercise is among the most effective interventions for age-associated mobility decline and metabolic dysregulation. Although long-term endurance exercise promotes insulin sensitivity and expands respiratory capacity, genetic components and pathways mediating the metabolic benefits of exercise have remained elusive. Here, we show that Sestrins, a family of evolutionarily conserved exercise-inducible proteins, are critical mediators of exercise benefits. In both fly and mouse models, genetic ablation of Sestrins prevents organisms from acquiring metabolic benefits of exercise and improving their endurance through training. Conversely, Sestrin upregulation mimics both molecular and physiological effects of exercise, suggesting that it could be a major effector of exercise metabolism. Among the various targets modulated by Sestrin in response to exercise, AKT and PGC1α are critical for the Sestrin effects in extending endurance. These results indicate that Sestrin is a key integrating factor that drives the benefits of chronic exercise to metabolism and physical endurance.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteínas de Drosophila/metabolismo , Exercício Físico/fisiologia , Proteínas de Choque Térmico/metabolismo , Oxirredutases/metabolismo , Peroxidases/metabolismo , Animais , Proteínas de Ciclo Celular/genética , Diferenciação Celular , Drosophila , Proteínas de Drosophila/genética , Metabolismo Energético , Expressão Gênica , Proteínas de Choque Térmico/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fibras Musculares Esqueléticas/citologia , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiologia , Biogênese de Organelas , Oxirredutases/genética , Peroxidases/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Resistência Física/genética , Resistência Física/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
4.
Cell Discov ; 5: 60, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31754457

RESUMO

mTORC1 is a protein kinase important for metabolism and is regulated by growth factor and nutrient signaling pathways, mediated by the Rheb and Rag GTPases, respectively. Here we provide the first animal model in which both pathways were upregulated through concurrent mutations in their GTPase-activating proteins, Tsc1 and Depdc5. Unlike former models that induced limited mTORC1 upregulation, hepatic deletion of both Tsc1 and Depdc5 (DKO) produced strong, synergistic activation of the mTORC1 pathway and provoked pronounced and widespread hepatocyte damage, leading to externally visible liver failure phenotypes, such as jaundice and systemic growth defects. The transcriptome profile of DKO was different from single knockout mutants but similar to those of diseased human livers with severe hepatitis and mouse livers challenged with oxidative stress-inducing chemicals. In addition, DKO liver cells exhibited prominent molecular pathologies associated with excessive endoplasmic reticulum (ER) stress, oxidative stress, DNA damage and inflammation. Although DKO liver pathologies were ameliorated by mTORC1 inhibition, ER stress suppression unexpectedly aggravated them, suggesting that ER stress signaling is not the major conduit of how hyperactive mTORC1 produces liver damage. Interestingly, superoxide scavengers N-acetylcysteine (NAC) and Tempol, chemicals that reduce oxidative stress, were able to recover liver phenotypes, indicating that mTORC1 hyperactivation induced liver damage mainly through oxidative stress pathways. Our study provides a new model of unregulated mTORC1 activation through concomitant upregulation of growth factor and nutrient signaling axes and shows that mTORC1 hyperactivation alone can provoke oxidative tissue injury.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA