RESUMEN
Neurodegenerative diseases (NDDs), which are among the most important aging-related diseases, are typically characterized by neuronal damage and a progressive impairment in neurological function during aging. Few effective therapeutic targets for NDDs have been revealed; thus, an understanding of the pathogenesis of NDDs is important. Forkhead box O (FoxO) transcription factors have been implicated in the mechanisms regulating aging and longevity. The functions of FoxOs are regulated by diverse post-translational modifications (e.g., phosphorylation, acetylation, ubiquitination, methylation and glycosylation). FoxOs exert both detrimental and protective effects on NDDs. Therefore, an understanding of the precise function of FoxOs in NDDs will be helpful for developing appropriate treatment strategies. In this review, we first introduce the post-translational modifications of FoxOs. Next, the regulation of FoxO expression and post-translational modifications in the central nervous system (CNS) is described. Afterwards, we analyze and address the important roles of FoxOs in NDDs. Finally, novel potential directions of future FoxO research in NDDs are discussed. This review recapitulates essential facts and questions about the promise of FoxOs in treating NDDs, and it will likely be important for the design of further basic studies and to realize the potential for FoxOs as therapeutic targets in NDDs.
Asunto(s)
Factores de Transcripción Forkhead/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Animales , HumanosRESUMEN
Forkhead box O (FOXO) family has recently been highlighted as important transcriptional regulators associated with many diverse carcinomas. Although redundant functionality between FOXO family members with cancer is known, regulatory ability of FOXO4 for tumorigenesis and tumor metastasis is still on the way. FOXO4 significantly regulates cell cycle, resists oxidative stress, and responses to hypoxia. FOXO4 alteration is closely linked to the progression of human cancer. In this review, we introduce the regulation of FOXO4 in physiological and pathological conditions. Particularly, the pathophysiological processes and molecular pathways regulated by FOXO4 in the development and progression of cancer are also summarized. Moreover, whether FOXO4 acts as a tumor-suppressor or pro-tumoral factor in tumors and the potential directions of future FOXO4 research are discussed. The information reviewed here may assist in the experimental design and increase the potential of FOXO4 as a therapeutic target for cancer.
Asunto(s)
Carcinogénesis/genética , Neoplasias/genética , Factores de Transcripción/genética , Proteínas de Ciclo Celular , Factores de Transcripción Forkhead , Genes Supresores de Tumor , Humanos , Neoplasias/patología , Estrés Oxidativo/genética , Hipoxia Tumoral/genéticaRESUMEN
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal parenchymal lung disease with limited therapeutic options, with fibroblast-to-myofibroblast transdifferentiation and hyperproliferation playing a major role. Investigating ex vivo-cultured (myo)fibroblasts from human IPF lungs as well as fibroblasts isolated from bleomycin-challenged mice, Forkhead box O3 (FoxO3) transcription factor was found to be less expressed, hyperphosphorylated, and nuclear-excluded relative to non-diseased controls. Downregulation and/or hyperphosphorylation of FoxO3 was reproduced by exposure of normal human lung fibroblasts to various pro-fibrotic growth factors and cytokines (FCS, PDGF, IGF1, TGF-ß1). Moreover, selective knockdown of FoxO3 in the normal human lung fibroblasts reproduced the transdifferentiation and hyperproliferation phenotype. Importantly, mice with global- (Foxo3-/-) or fibroblast-specific (Foxo3f.b-/-) FoxO3 knockout displayed enhanced susceptibility to bleomycin challenge, with augmented fibrosis, loss of lung function, and increased mortality. Activation of FoxO3 with UCN-01, a staurosporine derivative currently investigated in clinical cancer trials, reverted the IPF myofibroblast phenotype in vitro and blocked the bleomycin-induced lung fibrosis in vivo These studies implicate FoxO3 as a critical integrator of pro-fibrotic signaling in lung fibrosis and pharmacological reconstitution of FoxO3 as a novel treatment strategy.
Asunto(s)
Fibroblastos , Proteína Forkhead Box O3/genética , Fibrosis Pulmonar Idiopática/metabolismo , Miofibroblastos , Animales , Proliferación Celular , Transdiferenciación Celular , Células Cultivadas , Citocinas/farmacología , Regulación hacia Abajo , Fibroblastos/metabolismo , Fibroblastos/patología , Proteína Forkhead Box O3/metabolismo , Técnicas de Inactivación de Genes , Humanos , Fibrosis Pulmonar Idiopática/patología , Fibrosis Pulmonar Idiopática/terapia , Modelos Animales , Miofibroblastos/metabolismo , Miofibroblastos/patología , Fosforilación , Estaurosporina/química , Estaurosporina/farmacologíaRESUMEN
Chronic obstructive pulmonary disease (COPD) is a debilitating disease caused by parenchymal damage and irreversible airflow limitation. In addition to lung dysfunction, patients with COPD develop weight loss, malnutrition, poor exercise performance, and skeletal muscle atrophy. The latter has been attributed to an imbalance between muscle protein synthesis and protein degradation. Several reports have confirmed that enhanced protein degradation and atrophy of limb muscles of COPD patient is mediated in part through activation of the ubiquitin-proteasome pathway and that this activation is triggered by enhanced production of reactive oxygen species. Until recently, the importance of the autophagy-lysosome pathway in protein degradation of skeletal muscles has been largely ignored, however, recent evidence suggests that this pathway is actively involved in recycling of cytosolic proteins, organelles, and protein aggregates in normal skeletal muscles. The protective role of autophagy in the regulation of muscle mass has recently been uncovered in mice with muscle-specific suppression of autophagy. These mice develop severe muscle weakness, atrophy, and decreased muscle contractility. No information is yet available about the involvement of the autophagy in the regulation of skeletal muscle mass in COPD patients. Pilot experiments on vastus lateralis muscle samples suggest that the autophagy-lysosome system is induced in COPD patients compared with control subjects. In this review, we summarize recent progress related to molecular structure, regulation, and roles of the autophagy-lysosome pathway in normal and diseased skeletal muscles. We also speculate about regulation and functional importance of this system in skeletal muscle dysfunction in COPD patients.