• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Nature >Cyclin D1-Cdk4 controls glucose metabolism independently of cell cycle progression
【24h】

Cyclin D1-Cdk4 controls glucose metabolism independently of cell cycle progression

机译：细胞周期蛋白D1-Cdk4独立于细胞周期进程控制葡萄糖代谢

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Insulin constitutes a principal evolutionarily conserved hormonal axis for maintaining glucose homeostasis; dysregulation of this axis causes diabetes. PGC-1α (peroxisome-proliferator-activated receptor-γ coactivator-1α) links insulin signalling to the expression of glucose and lipid metabolic genes. The histone acetyltransferase GCN5 (general control non-repressed protein 5) acetylates PGC-1α and suppresses its transcriptional activity, whereas sirtuin 1 deacetylates and activates PGC-1α. Although insulin is a mitogenic signal in pro-liferative cells, whether components of the cell cycle machinery contribute to its metabolic action is poorly understood. Here we report that in mice insulin activates cyclin D1-cyclin-dependent kinase 4 (Cdk4), which, in turn, increases GCN5 acetyltransferase activity and suppresses hepatic glucose production independently of cell cycle progression. Through a cell-based high-throughput chemical screen, we identify a Cdk4 inhibitor that potently decreases PGC-1α acet-ylation. Insulin/GSK-3β (glycogen synthase kinase 3-beta) signalling induces cyclin D1 protein stability by sequestering cyclin D1 in the nucleus. In parallel, dietary amino acids increase hepatic cyclin D1 messenger RNA transcripts. Activated cyclin D1-Cdk4 kinase phosphorylates and activates GCN5, which then acetylates and inhibits PGC-1α activity on gluconeogenic genes. Loss of hepatic cyclin D1 results in increased gluconeogenesis and hyperglycaemia. In diabetic models, cyclin D1 -Cdk4 is chronically elevated and refractory to fasting/feeding transitions; nevertheless further activation of this kinase normalizes glycaemia. Our findings show that insulin uses components of the cell cycle machinery in post-mitotic cells to control glucose homeostasis independently of cell division.
机译：胰岛素构成维持葡萄糖稳态的主要进化保守激素轴。该轴失调会导致糖尿病。 PGC-1α（过氧化物酶体增殖物激活的受体-γ共激活剂-1α）将胰岛素信号传导与葡萄糖和脂质代谢基因的表达联系起来。组蛋白乙酰基转移酶GCN5（非控制性非抑制蛋白5）乙酰化PGC-1α，抑制其转录活性，而瑟土因1脱乙酰基并激活PGC-1α。尽管胰岛素是增生细胞中的促有丝分裂信号，但人们对细胞周期机制的组成部分是否对其代谢作用没有了解。在这里，我们报告说，在小鼠体内，胰岛素激活细胞周期蛋白D1-细胞周期蛋白依赖性激酶4（Cdk4），进而增加GCN5乙酰转移酶的活性，并抑制肝葡萄糖生成，与细胞周期进程无关。通过基于细胞的高通量化学筛选，我们确定了一种Cdk4抑制剂，该抑制剂可有效降低PGC-1α的乙酰化程度。胰岛素/GSK-3β（糖原合酶激酶3-β）信号传导通过将细胞周期蛋白D1隔离在细胞核中来诱导细胞周期蛋白D1蛋白的稳定性。同时，饮食中的氨基酸会增加肝细胞周期蛋白D1信使RNA转录本。激活的细胞周期蛋白D1-Cdk4激酶磷酸化并激活GCN5，然后将其乙酰化并抑制糖异生基因上的PGC-1α活性。肝细胞周期蛋白D1的丢失导致糖异生和高血糖增加。在糖尿病模型中，细胞周期蛋白D1-Cdk4长期升高，对禁食/进食过渡无反应。然而，该激酶的进一步激活使血糖正常化。我们的发现表明，胰岛素利用有丝分裂后细胞中细胞周期机制的成分来独立于细胞分裂来控制葡萄糖稳态。

著录项

  • 来源
    《Nature》 |2014年第7506期|547-551|共5页
  • 作者

    Yoonjin Lee; John E. Dominy; Yoon Jong Choi; Michael Jurczak; Nicola Tolliday; Joao Paulo Camporez; Helen Chim; Ji-Hong Lim; Hai-Bin Ruan; Xiaoyong Yang; Francisca Vazquez; Piotr Sicinski; Gerald I. Shulman; Pere Puigserver;

  • 作者单位

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA,Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA,Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA;

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA,Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA,Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Yale's Mouse Metabolic Phenotyping Center and Departments of Internal Medicine and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA;

    Chemical Biology Platform, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, Massachusetts 02141, USA;

    Yale's Mouse Metabolic Phenotyping Center and Departments of Internal Medicine and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA;

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA,Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA,Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Yale's Mouse Metabolic Phenotyping Center and Departments of Internal Medicine and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA;

    Yale's Mouse Metabolic Phenotyping Center and Departments of Internal Medicine and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA;

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA,Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA,Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Yale's Mouse Metabolic Phenotyping Center and Departments of Internal Medicine and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA;

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA,Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号