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Regulation of the TSC/mTOR pathway in human disease and cellular stress.

机译：TSC / mTOR途径在人类疾病和细胞应激中的调控。

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摘要

A fundamental question in cell biology is how various extracellular cues can cause changes in translational output and hence the growth of the cell. The mammalian target of rapamycin (mTOR) is a key regulator of translation that acts to stimulate protein synthesis by phosphorylating the ribosomal translation regulators p70 ribosomal S6 kinase (56K) and eukaryote initiation factor 4E binding protein 1 (4EBP1). mTOR is known to receive inputs from multiple signaling pathways and responds by increasing or decreasing protein synthesis appropriately. A prominent example of this phenomenon is how mTOR is stimulated by growth factors and the availability of nutrients, while it is inhibited by conditions such as low ATP levels, the absence of nutrients, or cellular stressors such as DNA damage or hypoxia. Regulation of protein synthesis by mTOR is responsible for controlling cell size and proliferation, and dysregulation of the mTOR pathway in vivo has been implicated in the pathogenesis of several hypertrophic and hamartoma (benign tumor) syndromes, including tuberous sclerosis complex and the pten-hamartoma tumor syndromes. Here we show that LKB1, the gene mutated in another hamartoma syndrome -- the Peutz-Jeghers hamartoma syndrome -- directly affects signaling through mTOR. We show that loss of LKB1 causes increased signaling through mTOR targets S6K and 4EBP1, and LKB1 over-expression causes physiological markers of mTOR signaling to decrease. Our results indicate that LKB1 plays a role in cell growth regulation in response to cellular energy levels; and they also suggest that rapamycin or rapamycin analogs might be of therapeutic benefit in Peutz-Jeghers syndrome. We also propose a provisional system to classify hamartoma and hypertrophic syndromes according to their potential or proven role in the mTOR pathway.; Another area of investigation relates to how mTOR is regulated by stress conditions such as energy starvation, DNA damage, hypoxia, or glucocorticoid treatment. We observed that two stress-induced proteins, RTP801/Redd1 and RTP801L/Redd2, potently inhibit signaling through mTOR. Our data support the hypothesis that RTP801 functions downstream of AKT and upstream of TSC2 -- two known constituents of the mTOR pathway -- to inhibit mTOR functions. RTP801 and RTP801L are homologous, yet show little sequence similarity to known protein domains other than a coiled-coil domain. We also present evidence for a mechanism as to how these proteins may function to regulate the mTOR pathway. Taken together, these results add a new dimension to mTOR pathway regulation and provide a possible molecular mechanism of how cellular stress conditions may regulate mTOR function.
机译：细胞生物学中的一个基本问题是各种细胞外提示如何引起翻译输出的变化以及细胞的生长。雷帕霉素（mTOR）的哺乳动物靶标是翻译的关键调节因子，其通过使核糖体翻译调节因子p70核糖体S6激酶（56K）和真核生物起始因子4E结合蛋白1（4EBP1）磷酸化来刺激蛋白质合成。已知mTOR从多个信号途径接收输入，并通过适当地增加或减少蛋白质合成来作出响应。这种现象的一个突出例子是，生长因子和营养物质的可用性如何刺激mTOR，而ATP水平低，缺乏营养物或DNA损伤或缺氧等细胞应激因素会抑制mTOR。 mTOR对蛋白质合成的调节负责控制细胞的大小和增殖，并且体内mTOR通路的失调与多种肥大性和错构瘤（良性肿瘤）综合征的发病机制有关，包括结节性硬化症和pten-hamartoma肿瘤综合症。在这里，我们显示LKB1是在另一个错构瘤综合征（Peutz-Jeghers错构瘤综合征）中突变的基因，直接影响通过mTOR传递信号。我们表明，LKB1的丢失会导致通过mTOR目标S6K和4EBP1增加信号传递，而LKB1的过表达会导致mTOR信号传递的生理标记降低。我们的结果表明，LKB1在响应细胞能量水平的细胞生长调节中发挥作用。他们还暗示雷帕霉素或雷帕霉素类似物可能对Peutz-Jeghers综合征有治疗作用。我们还提出了一个临时系统，以根据错构瘤和肥大综合症在mTOR途径中的潜在作用或已证实的作用对其进行分类。另一个研究领域涉及如何通过应激条件（例如能量饥饿，DNA损伤，缺氧或糖皮质激素治疗）调节mTOR。我们观察到，两种应激诱导的蛋白RTP801 / Redd1和RTP801L / Redd2有效抑制了通过mTOR发出的信号。我们的数据支持以下假设：RTP801在AKT下游和TSC2上游（mTOR途径的两个已知成分）起作用，以抑制mTOR功能。 RTP801和RTP801L是同源的，但与卷曲螺旋结构域不同，与已知的蛋白质结构域几乎没有序列相似性。我们还提供了有关这些蛋白质如何发挥功能调节mTOR途径的机制的证据。综上所述，这些结果为mTOR途径的调控增加了新的维度，并为细胞应激条件如何调控mTOR功能提供了可能的分子机制。

著录项

  • 作者

    Corradetti, Michael N.;

  • 作者单位

    University of Michigan.;

  • 授予单位 University of Michigan.;
  • 学科 Biology Molecular.; Biology Cell.; Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2008
  • 页码 131 p.
  • 总页数 131
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;细胞生物学;生物化学;
  • 关键词

  • 入库时间 2022-08-17 11:38:49

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