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首页> 外文学位 >Investigating the role of the mamalian ste-20 like kinase 2 (Mst2) in Raf-1-ERK signaling and in neurofibromatosis type 2 (NF2) cancer syndrome.
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Investigating the role of the mamalian ste-20 like kinase 2 (Mst2) in Raf-1-ERK signaling and in neurofibromatosis type 2 (NF2) cancer syndrome.

机译：调查哺乳动物的Ste20样激酶2（Mst2）在Raf-1-ERK信号传导和2型神经纤维瘤病（NF2）癌症综合征中的作用。

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摘要

Many tumor suppressor proteins act to blunt the effects of mitogenic signaling pathways. Loss of function mutations in the Merlin tumor suppressor underlie Neurofibromatosis type 2 (NF2) a familial autosomal dominant cancer syndrome. Studies of Drosophila suggest that Hippo ( Hpo) is required for inhibition of cell proliferation mediated by dMer, the orthologue of human Merlin. Mammalian sterile 20-like kinase-2 (Mst2) is a mammalian Hpo orthologue; and numerous studies implicate Mst2 as a tumor suppressor. Mst2 is negatively regulated by the proto oncoprotein Raf-1 in a manner independent of Raf-1's kinase activity. We sought to determine if, in mammalian cells, Merlin could positively regulate Mst2. We also sought to determine if Mst2, in addition to being negatively regulated by Raf-1, itself might reciprocally regulate Raf-1. In contrast to findings from Drosophila, we find no evidence that mammalian Merlin positively regulates mammalian Mst2. Instead, surprisingly, RNAi silencing of Mst2 leads to elevated inhibitory phosphorylation of Raf-1 at Ser259 and impaired Raf-1 kinase activity. Consequent to this, ERK pathway activation and cell proliferation are attenuated. Phosphatase 2A (PP2A) dephosphorylates Raf-1 Ser259 in response to mitogens. Interestingly RNAi silencing of Mst2 triggers a striking proteasome-dependent decrease in the levels of the catalytic subunit of PP2A (PP2A-C). A similar effect is achieved upon silencing of large tumor suppressor (Lats1/2) direct downstream substrates of Mst2. Our studies reveal a more complex role for Mst2 than previously thought. The Mst2-Lats1/2 pathway, by maintaining PP2A-C levels, may, in some situations, positively affect mitogenic signaling.;Chapter II of this thesis presents unpublished and preliminary data indicating that Merlin may function as a tumor suppressor through negative regulation of mTORC1 complex and promotion of autophagy.
机译：许多肿瘤抑制蛋白的作用是减弱有丝分裂信号通路的作用。 Merlin抑癌药中功能突变的丧失是2型神经纤维瘤病（NF2）的家族性常染色体显性癌症综合征的基础。果蝇的研究表明，河马（Hpo）是抑制人Merlin直系同源基因dMer介导的细胞增殖所必需的。哺乳动物不育20样激酶2（Mst2）是哺乳动物的Hpo直系同源物。许多研究表明Mst2作为肿瘤抑制因子。 Mst2被原癌蛋白Raf-1负调控，其方式独立于Raf-1的激酶活性。我们试图确定在哺乳动物细胞中，Merlin是否可以正调控Mst2。我们还试图确定Mst2除了受Raf-1负调控外，本身是否可以相互调控Raf-1。与果蝇的发现相反，我们没有发现哺乳动物Merlin积极调节哺乳动物Mst2的证据。相反，出人意料的是，Mst2的RNAi沉默导致Ser259上Raf-1的抑制性磷酸化升高，并削弱Raf-1激酶活性。因此，ERK途径激活和细胞增殖被减弱。磷酸酶2A（PP2A）响应有丝分裂原使Raf-1 Ser259去磷酸化。有趣的是，Mst2的RNAi沉默引发了蛋白酶体依赖性的PP2A催化亚基（PP2A-C）水平的显着降低。 Mst2的大型肿瘤抑制因子（Lats1 / 2）直接下游底物沉默后，可获得类似的效果。我们的研究表明Mst2的作用比以前想象的要复杂。在某些情况下，通过维持PP2A-C的水平，Mst2-Lats1 / 2途径可能对促有丝分裂信号产生积极影响。本论文的第二章提供了尚未发表的初步数据，表明Merlin可能通过负调控Merlin而发挥抑癌作用。 mTORC1复合物和促进自噬。

著录项

  • 作者

    Kilili, Geoffrey Kimiti.;

  • 作者单位

    Sackler School of Graduate Biomedical Sciences (Tufts University).;

  • 授予单位 Sackler School of Graduate Biomedical Sciences (Tufts University).;
  • 学科 Biology Molecular.;Health Sciences Oncology.;Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 139 p.
  • 总页数 139
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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