RESUMO
Protein phosphatase 2A (PP2A) is the major tau phosphatase. Its activity toward tau is regulated by the methylation of PP2A catalytic subunit (PP2Ac) at Leu309. Protein phosphatase methylesterase-1 (PME-1) demethylates PP2Ac and suppresses its activity. We previously found that glycogen synthase kinase-3ß (GSK-3ß) suppresses PME-1 expression. However, the underlying molecular mechanism is unknown. In the present study, we analyzed the promoter of PME-1 gene and found that human PME-1 promoter contains two lymphoid enhancer binding factor-1/T-cell factor (LEF1/TCF) cis-elements in which ß-catenin serves as a co-activator. ß-catenin acted on these two cis-elements and promoted PME-1 expression. GSK-3ß phosphorylated ß-catenin and suppressed its function in promoting PME-1 expression. Inhibition and activation of GSK-3ß by PI3K-AKT pathway promoted and suppressed, respectively, PME-1 expression in primary cultured neurons, SH-SY5Y cells and in the mouse brain. These findings suggest that GSK-3ß phosphorylates ß-catenin and suppresses its function on PME-1 expression, resulting in an increase of PP2Ac methylation.
Assuntos
Hidrolases de Éster Carboxílico/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Tauopatias/etiologia , beta Catenina/metabolismo , Animais , Sequência de Bases , Hidrolases de Éster Carboxílico/genética , Células HEK293 , Humanos , Camundongos Transgênicos , Fosfatidilinositol 3-Quinases/metabolismo , Cultura Primária de Células , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Tauopatias/enzimologiaRESUMO
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and show characteristics of skeletal muscle differentiation. The two major RMS subtypes in children are alveolar (ARMS) and embryonal RMS (ERMS). We demonstrate that approximately 50% of ARMS and ERMS overexpress the LEF1/TCF transcription factor LEF1 when compared to normal skeletal muscle and that LEF1 can restrain aggressiveness especially of ARMS cells. LEF1 knockdown experiments in cell lines reveal that depending on the cellular context, LEF1 can induce pro-apoptotic signals. LEF1 can also suppress proliferation, migration and invasiveness of RMS cells both in vitro and in vivo. Furthermore, LEF1 can induce myodifferentiation of the tumor cells. This may involve regulation of other LEF1/TCF factors i.e. TCF1, whereas ß-catenin activity plays a subordinate role. Together these data suggest that LEF1 rather has tumor suppressive functions and attenuates aggressiveness in a subset of RMS.