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首页> 外文学位 >Novel regulatory mechanisms of inositol biosynthesis in Saccharomyces cerevisiae and mammalian cells, and implications for the mechanism underlying VPA-induced glucose 6-phosphate depletion.
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Novel regulatory mechanisms of inositol biosynthesis in Saccharomyces cerevisiae and mammalian cells, and implications for the mechanism underlying VPA-induced glucose 6-phosphate depletion.

机译：酿酒酵母和哺乳动物细胞中肌醇生物合成的新型调控机制，以及对VPA诱导的6-磷酸葡萄糖耗竭的潜在机制的影响。

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摘要

Myo-inositol is the precursor of all inositol containing molecules, including inositol phosphates, phosphoinositides and glycosylphosphatidylinositols, which are signaling molecules involved in many critical cellular functions. Perturbation of inositol metabolism has been linked to neurological disorders. Although several widely-used anticonvulsants and mood-stabilizing drugs have been shown to exert inositol depletion effects, the mechanisms of action of the drugs and the role of inositol in these diseases are not understood. Elucidation of the molecular control of inositol synthesis will shed light on the pathologies of inositol related illnesses.;In Saccharomyces cerevisiae, deletion of the four glycogen synthase kinase-3 genes, MCK1, MRK1, MDS1, and YGK3 , resulted in multiple features of inositol depletion. My studies demonstrated that the MCK1 gene is required for normal inositol homeostasis. mck1Delta and gsk3Delta (mck1Deltamrk1Deltamds1Deltaygk3Delta) cells exhibited similar features of inositol depletion. MCK1 ablation led to decreased myo-inositol-3-phosphate synthase (MIPS) activity and a decreased rate of inositol de novo synthesis. This is the first demonstration that Mck1 controls inositol synthesis by regulating MIPS activity.;While elegant studies have revealed several inositol-regulating mechanisms in yeast, very little is known about regulation of inositol synthesis in mammals. My studies discovered that IP6K1, an inositol hexakisphosphate kinase that catalyzes the synthesis of inositol pyrophosphate, negatively regulates inositol synthesis in mammalian cells. Interestingly, IP6K1 preferentially bound to the phospholipid phosphatidic acid, and this binding was required for IP6K1 nuclear localization and the transcriptional regulation of Isyna1 , which encodes mammalian MIPS. This is the first demonstration of the molecular control of de novo synthesis of inositol in mammalian cells.;VPA depletes intracellular glucose 6-phosphate in yeast cells by an unidentified mechanism. My studies discovered that VPA inhibits expression of hexose transporter genes HXT2, HXT4, HXT6, and HXT7. Mig1, a DNA-binding transcription repressor that translocates to the nucleus to repress gene expression under high glucose conditions, is required to inhibit HXT2 and HXT4 expression. Interestingly, VPA triggered Mig1 nuclear localization under non-repressive conditions. Furthermore, ablation of REG1, which regulates Mig1 translocation, reversed VPA-induced inhibition of HXT4 expression. These findings suggest that VPA may inhibit glucose uptake by activating Mig1-mediated repression of hexose transporter genes.
机译：肌醇是所有含肌醇分子的前体，包括肌醇磷酸酯，磷酸肌醇和糖基磷脂酰肌醇，它们是参与许多关键细胞功能的信号分子。肌醇代谢紊乱与神经系统疾病有关。尽管已经显示出几种广泛使用的抗惊厥药和稳定情绪的药物发挥肌醇耗竭作用，但尚不了解药物的作用机理和肌醇在这些疾病中的作用。阐明肌醇合成的分子控制将阐明肌醇相关疾病的病理学。在酿酒酵母中，四个糖原合酶激酶-3基因MCK1，MRK1，MDS1和YGK3的缺失，导致肌醇的多种特征消耗。我的研究表明，正常肌醇稳态需要MCK1基因。 mck1Delta和gsk3Delta（mck1Deltamrk1Deltamds1Deltaygk3Delta）细胞表现出相似的肌醇消耗特征。 MCK1消融导致肌醇-3-磷酸肌醇合成酶（MIPS）活性降低和肌醇从头合成速率降低。这是第一个证明Mck1通过调节MIPS活性来控制肌醇合成的方法。优雅的研究表明，酵母中有几种肌醇调节机制，但对哺乳动物中肌醇合成的调节知之甚少。我的研究发现IP6K1是一种催化六磷酸肌醇合成的肌醇六磷酸激酶，对哺乳动物细胞中肌醇的合成产生负调节作用。有趣的是，IP6K1优先与磷脂磷脂酸结合，而这种结合对于IP6K1核定位和编码哺乳动物MIPS的Isyna1的转录调控是必需的。这是哺乳动物细胞中肌醇从头合成的分子控制的首次证明。VPA通过未知的机制消耗酵母细胞中的细胞内葡萄糖6-磷酸。我的研究发现，VPA抑制己糖转运蛋白基因HXT2，HXT4，HXT6和HXT7的表达。抑制HXT2和HXT4的表达需要Mig1，它是一种DNA结合转录阻遏物，可在高葡萄糖条件下转移到细胞核以抑制基因表达。有趣的是，VPA在非压制条件下触发了Mig1核的定位。此外，调节Mig1易位的REG1消融逆转了VPA诱导的HXT4表达抑制。这些发现表明，VPA可能通过激活Mig1介导的己糖转运蛋白基因的阻遏来抑制葡萄糖的摄取。

著录项

  • 作者

    Yu, Wenxi.;

  • 作者单位

    Wayne State University.;

  • 授予单位 Wayne State University.;
  • 学科 Molecular biology.;Biochemistry.;Genetics.
  • 学位 Ph.D.
  • 年度 2016
  • 页码 137 p.
  • 总页数 137
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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