RESUMO
Kinase suppressors of Ras 1 and 2 (KSR1 and KSR2) function as molecular scaffolds to potently regulate the MAP kinases ERK1/2 and affect multiple cell fates. Here we show that KSR2 interacts with and modulates the activity of AMPK. KSR2 regulates AMPK-dependent glucose uptake and fatty acid oxidation in mouse embryonic fibroblasts and glycolysis in a neuronal cell line. Disruption of KSR2 in vivo impairs AMPK-regulated processes affecting fatty acid oxidation and thermogenesis to cause obesity. Despite their increased adiposity, ksr2(-/-) mice are hypophagic and hyperactive but expend less energy than wild-type mice. In addition, hyperinsulinemic-euglycemic clamp studies reveal that ksr2(-/-) mice are profoundly insulin resistant. The expression of genes mediating oxidative phosphorylation is also downregulated in the adipose tissue of ksr2(-/-) mice. These data demonstrate that ksr2(-/-) mice are highly efficient in conserving energy, revealing a novel role for KSR2 in AMPK-mediated regulation of energy metabolism.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Metabolismo Energético , Resistência à Insulina , Proteínas Serina-Treonina Quinases/metabolismo , Tecido Adiposo/metabolismo , Animais , Células COS , Células Cultivadas , Chlorocebus aethiops , Metabolismo Energético/fisiologia , Ácidos Graxos/metabolismo , Glucose/metabolismo , Glicólise/fisiologia , Resistência à Insulina/fisiologia , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos , Camundongos Knockout , Obesidade/etiologia , Obesidade/metabolismo , Oxirredução , Fosforilação Oxidativa , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Termogênese/fisiologiaRESUMO
This article presents an overview of medical management of persistent or recurrent differentiated thyroid cancer, in particular focusing on monitoring strategy and treatment plans. Most patients with differentiated thyroid carcinoma can be successfully rendered to be free of disease with initial treatments, and those with persistent or recurrent disease can still expect long-term survival when they are monitored properly and treated accordingly. Along with serum thyroglobulin, neck ultrasonography, and radioactive iodine whole-body scans, the use of cross-sectional imaging studies and (18F) fluoro-2-deoxy-D-glucose-positron emission tomography have facilitated the effort in localizing lesions and traditional treatments can be implemented effectively. For disease resistant to conventional therapies, there are new treatment modalities emerging and being tested, including several agents targeting specific signaling pathways, each of which may offer the potential remedy.