RESUMO
Valproic acid (VPA) has been shown to increase the reprogramming efficiency of induced pluripotent stem cells (iPSC) from somatic cells, but the mechanism by which VPA enhances iPSC induction has not been defined. Here we demonstrated that VPA directly activated Oct4 promoter activity through activation of the PI3K/Akt/mTOR signaling pathway that targeted the proximal hormone response element (HRE, -41â¼-22) in this promoter. The activating effect of VPA is highly specific as similar compounds or constitutional isomers failed to instigate Oct4 promoter activity. We further demonstrated that the upstream 2 half-sites in this HRE were essential to the activating effect of VPA and they were targeted by a subset of nuclear receptors, such as COUP-TFII and TR2. These findings show the first time that NRs are implicated in the VPA stimulated expression of stem cell-specific factors and should invite more investigation on the cooperation between VPA and NRs on iPSC induction.
Assuntos
Fator II de Transcrição COUP/genética , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células Musculares/efeitos dos fármacos , Membro 1 do Grupo C da Subfamília 2 de Receptores Nucleares/genética , Fator 3 de Transcrição de Octâmero/genética , Ácido Valproico/farmacologia , Animais , Sequência de Bases , Fator II de Transcrição COUP/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral , Reprogramação Celular , Regulação da Expressão Gênica , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos , Dados de Sequência Molecular , Células Musculares/citologia , Células Musculares/metabolismo , Membro 1 do Grupo C da Subfamília 2 de Receptores Nucleares/metabolismo , Fator 3 de Transcrição de Octâmero/agonistas , Fator 3 de Transcrição de Octâmero/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Regiões Promotoras Genéticas , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Ácido Valproico/análogos & derivadosRESUMO
The formation of tetrahydrofurans from 2-hydroxyalkyl-oxirane or aziridine is reported. The 5-endo-tet cyclization/ring opening of aziridine proceeded smoothly to give tetrahydrofurans (THFs) under mild conditions. In contrast, the corresponding process of oxirane was unsuccessful and a sequence of SN2 substitution/cyclization was required to form THFs. The application of the process to prepare ent-(-)-pachastrissamine is described.
