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首页> 外文学位 >cAMP and polyamines overcome inhibition by MAG by activating Cdk5 via increased expression of p35 regulated by activation of eIF5A.
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cAMP and polyamines overcome inhibition by MAG by activating Cdk5 via increased expression of p35 regulated by activation of eIF5A.

机译：cAMP和多胺通过激活ed5A调节的p35表达的增加来激活Cdk5，从而克服了MAG的抑制作用。

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摘要

Damaged axons in adult mammalian central nervous system (CNS) are unable to regenerate after injury although axons in the peripheral nervous system (PNS) or embryonic CNS can. The inhibitory molecules associated with myelin are one of the major obstacles to successful axon regeneration in the adult mammalian CNS. To date, three inhibitors of regeneration have been identified in myelin: NogoA, myelin-associated glycoprotein (MAG), and oligodendrocyte-myelin glycoprotein (OMpg) (Filbin, 2003). Interestingly, all these three ligands bind to the same receptor Nogo receptor (NgR) to mediate the inhibitory effect. p75NTR or TROY and Lingo-1(L&barbelow;RR and I&barbelow;g domain-containing, N&barbelow;ogo Receptor interacting protein) are necessary components of the receptor complex as NgR is glycosyl phosphatidylinositol (GPI)-anchored and lacks a signaling domain (Wang et al., 2002a; Mi et al., 2004; Park et al., 2005; Shao et al., 2005). Activation of the receptor complex by myelin inhibitors activates the small GTPase RhoA resulting in rearrangement of the cytoskeleton and inhibition of axonal outgrowth (Hu and Strittmatter, 2004).;It has been shown in our lab that elevating intracellular levels of cyclic AMP (cAMP), either via application of a cAMP analog or by prior exposure to neurotrophins (NTs) can block the inhibition of axonal regeneration by MAG and myelin (Cai et al., 1999; Cai et al., 2001; Qiu et al., 2002). Elevation of cAMP results in up-regulation of arginase I (ArgI) and subsequent synthesis of polyamines. Up-regulation of ArgI or priming with the polyamine putrescine or spermidine blocks the inhibition of axonal growth by MAG/myelin (Cai et al., 2002; Deng et al., 2009). Polyamines are known to have effects in regulating cytoskeleton organization in both the short term and the long term, but their downstream effectors have yet to be identified. Many studies have shown that Cyclin-dependent kinase 5 (Cdk5) is involved in neurite outgrowth and regulates the neuronal cytosekeleton, which prompted us to hypothesize that Cdk5 may play a role in blocking MAG/myelin-mediated inhibition.;Cdk5 is a multifunctional serine/threonine kinase and its activator, p35, is expressed only in the nervous system (Tsai et al., 1994). It has been shown that activity of Cdk5 is required for neurite elongation (Nikolic et al., 1996; Paglini et al., 1998; Li et al., 2000; Harada et al., 2001). Cdk5 phosphorylates cytoskeleton proteins and regulates the organization of all three cytoskeleton elements microfilaments, microtubules and intermediate filaments (Dhavan and Tsai, 2001). Here we show that Cdk5 is required for db-cAMP and putrescine to overcome inhibition. The effect of db-cAMP and putrescine in overcoming inhibition by MAG is abolished in the presence of a specific inhibitor of Cdk5, Roscovitine. Neurons infected with dominant negative Cdk5 HSV viruses are not able to overcome inhibition by MAG in the presence of db-cAMP or putrescine. Importantly, neurons infected with HSV viruses overexpressing p35, the neuronal specific activator for Cdk5, overcome MAG's inhibition. Moreover, db-cAMP and putrescine increase the expression of p35. This in turn induces the kinase activity of Cdk5. The up-regulation of p35 by putrescine is also reflected in the increased distribution of p35 in neurites and growth cones. Furthermore, we show that putrescine up-regulates p35 protein by hypusine modification of eukaryotic Initiation Factor 5A (eIF5A), and this hypusination is necessary for putrescine to overcome inhibition by MAG. Our findings reveal a previously unknown mechanism by which polyamines encourage regeneration after CNS injury.
机译：尽管周围神经系统（PNS）或胚胎中枢神经系统的轴突可以损伤，但成年哺乳动物中枢神经系统（CNS）中受损的轴突无法再生。与髓磷脂相关的抑制分子是成年哺乳动物中枢神经系统成功轴突再生的主要障碍之一。迄今为止，已经在髓磷脂中鉴定出三种再生抑制剂：NogoA，髓磷脂相关糖蛋白（MAG）和少突胶质细胞髓磷脂糖蛋白（OMpg）（Filbin，2003）。有趣的是，所有这三个配体都与相同的受体Nogo受体（NgR）结合以介导抑制作用。 p75NTR或TROY和Lingo-1（含L和RR结构域，含I和N结构域，N和Ogo受体相互作用蛋白）是受体复合物的必要成分，因为NgR是糖基磷脂酰肌醇（GPI）锚定的，并且缺少信号传导域（Wang等人，2002a； Mi等人，2004； Park等人，2005； Shao等人，2005）。髓磷脂抑制剂激活受体复合物会激活小GTPase RhoA，从而导致细胞骨架重排并抑制轴突生长（Hu and Strittmatter，2004）。；在我们的实验室中已证明，可提高细胞内环状AMP（cAMP）水平通过应用cAMP类似物或事先暴露于神经营养蛋白（NTs）可以阻断MAG和髓磷脂对轴突再生的抑制作用（Cai等，1999; Cai等，2001; Qiu等，2002） 。 cAMP的升高会导致精氨酸酶I（ArgI）的上调并随后合成多胺。 ArgI的上调或多胺腐胺或亚精胺的引发可阻断MAG /髓磷脂对轴突生长的抑制作用（Cai等，2002； Deng等，2009）。已知多胺无论在短期还是长期均具有调节细胞骨架组织的作用，但尚未确定其下游效应物。许多研究表明，细胞周期蛋白依赖性激酶5（Cdk5）参与神经突的生长并调节神经元的细胞骨架，这促使我们推测Cdk5可能在阻断MAG /髓磷脂介导的抑制作用中起作用。Cdk5是一种多功能的丝氨酸。 /苏氨酸激酶及其活化剂p35仅在神经系统中表达（Tsai等，1994）。已经显示出Cdk5的活性对于神经突伸长是必需的（Nikolic等，1996； Paglini等，1998； Li等，2000； Harada等，2001）。 Cdk5磷酸化细胞骨架蛋白并调节所有三个细胞骨架元件的微丝，微管和中间丝的组织（Dhavan和Tsai，2001）。在这里，我们显示Cdk5是db-cAMP和腐胺所必需的，以克服抑制作用。在Cdk5特异性抑制剂Roscovitine的存在下，db-cAMP和腐胺在克服MAG抑制作用中的作用被消除。在存在db-cAMP或腐胺的情况下，感染了显性阴性Cdk5 HSV病毒的神经元无法克服MAG的抑制作用。重要的是，感染过HSV病毒的神经元过表达p35（Cdk5的神经元特异性激活剂）可以克服MAG的抑制作用。此外，db-cAMP和腐胺增加了p35的表达。反过来，这会诱导Cdk5的激酶活性。腐胺对p35的上调也反映在p35在神经突和生长锥中的分布增加。此外，我们表明，腐胺通过对真核生物起始因子5A（eIF5A）的酪氨酸修饰来上调p35蛋白，而这种催眠作用对于腐胺克服MAG的抑制作用是必需的。我们的发现揭示了多胺促进中枢神经系统损伤后再生的先前未知的机制。

著录项

  • 作者

    He, Huifang.;

  • 作者单位

    City University of New York.;

  • 授予单位 City University of New York.;
  • 学科 Biology Molecular.;Biology Neuroscience.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 122 p.
  • 总页数 122
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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