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FoxO1转录因子及其翻译后修饰的生物学意义 总被引:1,自引:0,他引:1
FoxO1转录因子属于Fox家族成员,主要参与细胞凋亡、应激、DNA损伤/修复、肿瘤发生、血管生成和糖代谢等生命过程.PI-3K和Akt信号通路可磷酸化FoxO1,使其由胞核转运至胞质,导致转录活性灭活,从而抑制FoxO1所调控的下游基因表达.FoxO1的乙酰化可削弱FoxO1结合同源DNA序列的能力,同时加强FoxO1的磷酸化,进一步降低其转录活性.正是由于FoxO1本身的翻译后修饰可调节FoxO1的功能,使得其在肿瘤发生、免疫反应、细胞周期、分化、代谢、应激和凋亡中都起着重要的作用.本文对FoxO1及其翻译后修饰的生物学意义进行综述. 相似文献
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Protein kinase B (PKB) is a member of the second-messenger regulated subfamily of protein kinases implicated in signalling downstream of growth factor and insulin receptor tyrosine kinases and phosphatidylinositol 3-kinase (PI 3-kinase). PKB is activated by phosphorylation in response to mitogens and survival factors. Membrane recruitment driven by lipid second-messengers derived from PI 3-kinase leads to PKB phosphorylation and activation by upstream kinases (PDK1 and an as yet identified protein kinase). Prolonged stimulation with growth factors results in nuclear translocation, providing evidence that PKB activation at the plasma membrane precedes its nuclear translocation and supporting a role for PKB in signalling from receptor tyrosine kinases to the nucleus. 相似文献
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Meur G Qian Q da Silva Xavier G Pullen TJ Tsuboi T McKinnon C Fletcher L Tavaré JM Hughes S Johnson P Rutter GA 《The Journal of biological chemistry》2011,286(15):13647-13656
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Chen H Lin AS Li Y Reiter CE Ver MR Quon MJ 《The Journal of biological chemistry》2008,283(43):29228-29238
Dehydroepiandrosterone (DHEA) is an endogenous adrenal steroid hormone with controversial actions in humans. We previously reported that DHEA has opposing actions in endothelial cells to stimulate phosphatidylinositol (PI) 3-kinase/Akt/endothelial nitric-oxide synthase leading to increased production of nitric oxide while simultaneously stimulating MAPK-dependent secretion of the vasoconstrictor ET-1. In the present study we hypothesized that DHEA may stimulate PI 3-kinase-dependent phosphorylation of FoxO1 in endothelial cells to help regulate endothelial function. In bovine or human aortic endothelial cells (BAEC and HAEC), treatment with DHEA (100 nM) acutely enhanced phosphorylation of FoxO1. DHEA-stimulated phosphorylation of FoxO1 was inhibited by pretreatment of cells with wortmannin (PI 3-kinase inhibitor) or H89 (protein kinase A (PKA) inhibitor) but not ICI182780 (estrogen receptor blocker), or PD98059 (MEK (MAPK/extracellular signal-regulated kinase kinase) inhibitor). Small interfering RNA knockdown of PKA inhibited DHEA-stimulated phosphorylation of FoxO1. DHEA promoted nuclear exclusion of FoxO1 that was blocked by pretreatment of cells with wortmannin, H89, or by small interfering RNA knockdown of PKA. DHEA treatment of endothelial cells increased PKA activity and intracellular cAMP concentrations. Transfection of BAEC with a constitutively nuclear FoxO1 mutant transactivated a co-transfected ET-1 promoter luciferase reporter. Treatment of BAEC with DHEA inhibited transactivation of the ET-1 promoter reporter in cells overexpressing FoxO1. ET-1 promoter activity and secretion in response to DHEA treatment was augmented by PI 3-kinase blockade and inhibited by MAPK blockade. We conclude that DHEA stimulates phosphorylation of FoxO1 via PI 3-kinase- and PKA-dependent pathways in endothelial cells that negatively regulates ET-1 promoter activity and secretion. Balance between PI 3-kinase-dependent inhibition and MAPK-dependent stimulation of ET-1 secretion in response to DHEA may determine whether DHEA supplementation improves or worsens cardiovascular and metabolic function. 相似文献
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Yun SJ Kim EK Tucker DF Kim CD Birnbaum MJ Bae SS 《Biochemical and biophysical research communications》2008,371(1):138-143
The phosphatidylinositol 3-kinase (PI3K)/Akt pathway tightly regulates adipose cell differentiation. Here we show that loss of Akt1/PKBα in primary mouse embryo fibroblast (MEF) cells results in a defect of adipocyte differentiation. Adipocyte differentiation in vitro and ex vivo was restored in cells lacking both Akt1/PKBα and Akt2/PKBβ by ectopic expression of Akt1/PKBα but not Akt2/PKBβ. Akt1/PKBα was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation. Differentiation-induced cell division was significantly abrogated in Akt1/PKBα-deficient cells, but was restored after forced expression of Akt1/PKBα. Moreover, expression of p27Kip1, an inhibitor of the cell cycle, was down regulated in an Akt1/PKBα-specific manner during adipocyte differentiation. Based on these data, we suggest that the Akt1/PKBα isoform plays a major role in adipocyte differentiation by regulating FoxO1 and p27Kip1. 相似文献