FOXO介导的氧化应激、代谢和神经元基因转录
中文名称
通路描述
FOXO6作为FOXO家族中研究最少的一员，直接刺激PLXNA4基因转录，该基因编码半胱胺受体SEMA3A的辅因子。FOXO6对PLXNA4表达的调控在皮质发育期间的径向胶质细胞迁移中起重要作用。FOXO介导的参与减少氧化应激负担的基因上调并不局限于神经元，但在神经元存活和神经退行性疾病中起重要作用。FOXO3和FOXO4，以及可能FOXO1，直接刺激SOD2基因转录，该基因编码线粒体锰依赖的超氧化物歧化酶，将超氧化物转化为较不有害的过氧化氢和氧气。FOXO4与ATXN3（一种参与脊髓小脑性共济失调3型蛋白）合作刺激SOD2基因转录。FOXO3和FOXO6，以及可能FOXO1，直接刺激CAT基因转录，该基因编码过氧化氢酶，将过氧化氢转化为水和氧气，从而保护细胞免受氧化应激。FOXO转录因子调节转录的几种基因，其蛋白质产物从下丘脑神经元分泌以控制食欲和食物摄入：NPY基因、AGRP基因和POMC基因。在低胰岛素水平（如饥饿）时，FOXO转录因子结合NPY、AGRP和POMC基因调控区中的胰岛素响应元件（IRES）。FOXO1直接刺激NPY基因转录，编码神经肽Y，以及AGRP基因转录，编码阿格瑞特相关蛋白，两者均刺激食物摄入。同时，FOXO1直接抑制POMC基因转录，编码促黑素细胞激素α，从而抑制食物摄入。当进食后，血液中胰岛素水平升高，胰岛素介导的PI3K/AKT信号通路抑制FOXO转录活性。在肝细胞中，FOXO转录因子调节参与糖异生基因的转录：G6PC基因编码葡萄糖-6-磷酸酶和PCK1基因编码磷酸烯醇丙酮酸羧激酶。G6PC和PCK1的作用使空腹期间血糖水平保持稳定。FOXO1、FOXO3和FOXO4直接刺激PCK1基因转录（Hall et al. 2000, Yang et al. 2002, Puigserver et al. 2003），而FOXO1、FOXO3、FOXO4和FOXO6均直接刺激G6PC基因转录（Yang et al. 2002, Puigserver et al. 2003, Onuma et al. 2006, Kim et al. 2011）。FOXO介导的G6PC和PCK1基因诱导受到胰岛素诱导的PI3K/AKT信号通路的负调节。FOXO1和FOXO3直接刺激IGFBP1基因转录，编码胰岛素生长因子结合蛋白2，增加细胞对胰岛素的敏感性。FOXO1和FOXO3直接刺激ABCA6基因转录，编码一种假想的转运蛋白，被认为与脂质稳态有关。GCK（葡萄糖激酶）基因是脂质稳态中涉及的另一基因，受FOXOs调节。FOXO1与SIN3A:HDAC复合物直接抑制GCK基因转录，从而在胰岛素缺乏时抑制脂合生。SREBF1（SREBP1）基因编码脂质稳态所需的转录激活因子，被FOXO1直接转录抑制（Deng et al. 2012）。RETN基因（编码抵抗素，一种脂肪细胞特异性激素，抑制脂肪细胞对胰岛素介导的葡萄糖摄取）的转录由FOXO1直接刺激。两个编码E3泛素连接酶FBXO32（Atrogin-1）和TRIM63（MURF1）的基因，参与肌肉蛋白降解和饥饿期间的肌肉萎缩，由FOXO转录因子正调节。
英文描述
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes FOXO6, the least studied member of the FOXO family, directly stimulates transcription of PLXNA4 gene, encoding a co-factor for the semaphorin SEMA3A receptor. FOXO6-mediated regulation of PLXNA4 expression plays an important role in radial glia migration during cortical development (Paap et al. 2016).
FOXO-mediated up-regulation of genes involved in reduction of the oxidative stress burden is not specific to neurons, but plays an important role in neuronal survival and neurodegenerative diseases. FOXO3 and FOXO4, and possibly FOXO1, directly stimulate transcription of the SOD2 gene, encoding mitochondrial manganese-dependent superoxide dismutase, which converts superoxide to the less harmful hydrogen peroxide and oxygen (Kops et al. 2002, Hori et al. 2013, Araujo et al. 2011, Guan et al. 2016). FOXO4 stimulates SOD2 gene transcription in collaboration with ATXN3, a protein involved in spinocerebellar ataxia type 3 (SCA3) (Araujo et al. 2011). FOXO3 and FOXO6, and possibly FOXO1, directly stimulate transcription of the CAT gene, encoding catalase, an enzyme that converts hydrogen peroxide to water and oxygen, thus protecting cells from the oxidative stress (Awad et al. 2014, Kim et al. 2014, Rangarajan et al. 2015, Song et al. 2016, Liao et al. 2016, Guo et al. 2016).
FOXO transcription factors regulate transcription of several genes whose protein products are secreted from hypothalamic neurons to control appetite and food intake: NPY gene, AGRP gene and POMC gene. At low insulin levels, characteristic of starvation, FOXO transcription factors bind to insulin responsive elements (IRES) in the regulatory regions of NPY, AGRP and POMC gene. FOXO1 directly stimulates transcription of the NPY gene, encoding neuropeptide-Y (Kim et al. 2006, Hong et al. 2012), and the AGRP gene, encoding Agouti-related protein (Kitamura et al. 2006, Kim et al. 2006), which both stimulate food intake. At the same time, FOXO1 directly represses transcription of the POMC gene, encoding melanocyte stimulating hormone alpha , which suppresses food intake (Kitamura et al. 2006, Kim et al. 2006). When, upon food intake, blood insulin levels rise, insulin-mediated activation of PI3K/AKT signaling inhibits FOXO transcriptional activity.
In liver cells, FOXO transcription factors regulate transcription of genes involved in gluconeogenesis: G6PC gene, encoding glucose-6-phosphatase and PCK1 gene, encoding phosphoenolpyruvate carboxykinase. Actions of G6PC and PCK1 enable steady glucose blood levels during fasting. FOXO1, FOXO3 and FOXO4 directly stimulate PCK1 gene transcription (Hall et al. 2000, Yang et al. 2002, Puigserver et al. 2003), while all four FOXOs, FOXO1, FOXO3, FOXO4 and FOXO6 directly stimulate G6PC gene transcription (Yang et al. 2002, Puigserver et al. 2003, Onuma et al. 2006, Kim et al. 2011). FOXO-mediated induction of G6PC and PCK1 genes is negatively regulated by insulin-induced PI3K/AKT signaling.
FOXO1, FOXO3 and FOXO4 directly stimulate transcription of the IGFBP1 gene, encoding insulin growth factor binding protein 2 (Tang et al. 1999, Kops et al. 1999, Hall et al. 2000, Yang et al. 2002), which increases sensitivity of cells to insulin.
FOXO1 and FOXO3 directly stimulate transcription of the ABCA6 (ATP-binding cassette sub-family A member 6) gene, encoding a putative transporter protein that is thought to be involved in lipid homeostasis (Gai et al. 2013). The GCK (glucokinase) gene is another gene involved in lipid homeostasis that is regulated by FOXOs. FOXO1, acting with the SIN3A:HDAC complex, directly represses the GCK gene transcription, thus repressing lipogenesis in the absence of insulin (Langlet et al. 2017). The SREBF1 (SREBP1) gene, which encodes a transcriptional activator required for lipid homeostasis, is directly transcriptionally repressed by FOXO1 (Deng et al. 2012). Transcription of the RETN gene, encoding resistin, an adipocyte specific hormone that suppresses insulin-mediated uptake of glucose by adipose cells, is directly stimulated by FOXO1 (Liu et al. 2014).
Transcription of two genes encoding E3 ubiquitin ligases FBXO32 (Atrogin-1) and TRIM63 (MURF1), involved in degradation of muscle proteins and muscle wasting during starvation, is positively regulated by FOXO transcription factors (Sandri et al. 2004, Waddell et al. 2008, Raffaello et al. 2010, Senf et al. 2011, Bollinger et al. 2014, Wang et al. 2017).
FOXO-mediated up-regulation of genes involved in reduction of the oxidative stress burden is not specific to neurons, but plays an important role in neuronal survival and neurodegenerative diseases. FOXO3 and FOXO4, and possibly FOXO1, directly stimulate transcription of the SOD2 gene, encoding mitochondrial manganese-dependent superoxide dismutase, which converts superoxide to the less harmful hydrogen peroxide and oxygen (Kops et al. 2002, Hori et al. 2013, Araujo et al. 2011, Guan et al. 2016). FOXO4 stimulates SOD2 gene transcription in collaboration with ATXN3, a protein involved in spinocerebellar ataxia type 3 (SCA3) (Araujo et al. 2011). FOXO3 and FOXO6, and possibly FOXO1, directly stimulate transcription of the CAT gene, encoding catalase, an enzyme that converts hydrogen peroxide to water and oxygen, thus protecting cells from the oxidative stress (Awad et al. 2014, Kim et al. 2014, Rangarajan et al. 2015, Song et al. 2016, Liao et al. 2016, Guo et al. 2016).
FOXO transcription factors regulate transcription of several genes whose protein products are secreted from hypothalamic neurons to control appetite and food intake: NPY gene, AGRP gene and POMC gene. At low insulin levels, characteristic of starvation, FOXO transcription factors bind to insulin responsive elements (IRES) in the regulatory regions of NPY, AGRP and POMC gene. FOXO1 directly stimulates transcription of the NPY gene, encoding neuropeptide-Y (Kim et al. 2006, Hong et al. 2012), and the AGRP gene, encoding Agouti-related protein (Kitamura et al. 2006, Kim et al. 2006), which both stimulate food intake. At the same time, FOXO1 directly represses transcription of the POMC gene, encoding melanocyte stimulating hormone alpha , which suppresses food intake (Kitamura et al. 2006, Kim et al. 2006). When, upon food intake, blood insulin levels rise, insulin-mediated activation of PI3K/AKT signaling inhibits FOXO transcriptional activity.
In liver cells, FOXO transcription factors regulate transcription of genes involved in gluconeogenesis: G6PC gene, encoding glucose-6-phosphatase and PCK1 gene, encoding phosphoenolpyruvate carboxykinase. Actions of G6PC and PCK1 enable steady glucose blood levels during fasting. FOXO1, FOXO3 and FOXO4 directly stimulate PCK1 gene transcription (Hall et al. 2000, Yang et al. 2002, Puigserver et al. 2003), while all four FOXOs, FOXO1, FOXO3, FOXO4 and FOXO6 directly stimulate G6PC gene transcription (Yang et al. 2002, Puigserver et al. 2003, Onuma et al. 2006, Kim et al. 2011). FOXO-mediated induction of G6PC and PCK1 genes is negatively regulated by insulin-induced PI3K/AKT signaling.
FOXO1, FOXO3 and FOXO4 directly stimulate transcription of the IGFBP1 gene, encoding insulin growth factor binding protein 2 (Tang et al. 1999, Kops et al. 1999, Hall et al. 2000, Yang et al. 2002), which increases sensitivity of cells to insulin.
FOXO1 and FOXO3 directly stimulate transcription of the ABCA6 (ATP-binding cassette sub-family A member 6) gene, encoding a putative transporter protein that is thought to be involved in lipid homeostasis (Gai et al. 2013). The GCK (glucokinase) gene is another gene involved in lipid homeostasis that is regulated by FOXOs. FOXO1, acting with the SIN3A:HDAC complex, directly represses the GCK gene transcription, thus repressing lipogenesis in the absence of insulin (Langlet et al. 2017). The SREBF1 (SREBP1) gene, which encodes a transcriptional activator required for lipid homeostasis, is directly transcriptionally repressed by FOXO1 (Deng et al. 2012). Transcription of the RETN gene, encoding resistin, an adipocyte specific hormone that suppresses insulin-mediated uptake of glucose by adipose cells, is directly stimulated by FOXO1 (Liu et al. 2014).
Transcription of two genes encoding E3 ubiquitin ligases FBXO32 (Atrogin-1) and TRIM63 (MURF1), involved in degradation of muscle proteins and muscle wasting during starvation, is positively regulated by FOXO transcription factors (Sandri et al. 2004, Waddell et al. 2008, Raffaello et al. 2010, Senf et al. 2011, Bollinger et al. 2014, Wang et al. 2017).
所含基因
30 个基因