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首页> 外文学位 >Investigation of Inducible Mitogen and Stress Activated Protein Kinase 1 (MSK1) and Histone H3 Phosphorylation by the RAS-MAPK Pathway in Cancer Cells.
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Investigation of Inducible Mitogen and Stress Activated Protein Kinase 1 (MSK1) and Histone H3 Phosphorylation by the RAS-MAPK Pathway in Cancer Cells.

机译：通过癌细胞中的RAS-MAPK途径研究诱导型丝裂原和应激激活的蛋白激酶1（MSK1）和组蛋白H3磷酸化。

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摘要

The RAS-mitogen-activated protein kinase (MAPK) pathway is an essential signaling mechanism that regulates numerous cellular processes and culminates in the activation of specific gene expression programs. Alterations in the RAS-MAPK pathway by receptor over-expression or gain of function gene mutations can modify epigenetic programs and confer cell growth and/or transformation advantages. In fact, deregulation of the RAS-MAPK signaling cascade is a key event in tumour development and about 30% of human cancers contain RAS mutations. In breast and pancreatic epithelial cancers, characterization of an aberrant RAS-MAPK signaling pathway has focused on upstream mediators such as receptors and oncogenic RAS molecules. However, the impact of downstream targets has not been fully explored.;Our studies focused on MSK-mediated H3 phosphorylation under the frame of inducible and constitutively activated RAS-MAPK signaling. As model cell systems, we used Ras-transformed mouse fibroblasts, human breast cancer cell lines with over-expressed receptors and human pancreatic cancer cell lines with activating K-RAS mutations. We present evidence for the critical involvement of MSK1 and H3 phosphorylation as mediators that bridge the aberrant signals driven by the RAS-MAPK pathway with nucleosomal modifications, chromatin remodeling, IEG expression and malignant transformation in mouse fibroblasts. In order to verify our observations from murine cell model systems, we examined if activation of RAS-MAPK signaling in breast cancer cells elicits similar molecular events. We firstly demonstrate that the RAS-MAPK pathway is induced and consequently enhances the association of MSK1 and H3 phosphorylation on the IEG Trefoil Factor 1 resulting in transcriptional activation. Secondly, we observed that mutated K-RAS expression did not correlate with genomic instability or altered signaling in pancreatic cancer cell lines in comparison to overexpressed HER2 and EGFR breast cancer cell lines which generally exhibit upregulated ERK1/2 and H3 phosphorylation levels.;Taken together, MSK-regulated gene expression may potentially be exploited by epithelial cancerous cells with abnormal MAPK signaling to acquire further growth/transformation advantages. Our studies also contribute to the further understanding of MSK-mediated transcriptional activation in response to RAS-MAPK signaling in oncogenetransformed and cancer cell lines. As such, inhibition of MSK activity may be an unexplored avenue for combination cancer therapy with abnormal RAS-MAPK signaling pathways.;Stimulation of the RAS-MAPK pathway leads to downstream activation of mitogen- and stress-activated protein kinases 1 and 2 (MSK1/2) which are responsible for the phosphorylation of histone H3 on S10 and S28. Herein, we postulate that the deregulation of the RAS-MAPK pathway produced by mitogen stimulation, or that the constitutive activation and/or over-expression of upstream components consequently leads to enhanced MSK1 activity and elevated histone H3 phosphorylation levels. We further hypothesize that MSK1-mediated H3 phosphorylation is critical for immediate early gene (IEG) expression, Ras-driven transformation and associates with regulatory regions upon gene transcription.
机译：RAS促分裂原激活的蛋白激酶（MAPK）通路是一种重要的信号传导机制，可调节众多细胞过程并最终激活特定的基因表达程序。通过受体过表达或功能基因突变的获得而引起的RAS-MAPK途径的改变可以修饰表观遗传程序并赋予细胞生长和/或转化优势。实际上，RAS-MAPK信号级联的失调是肿瘤发展中的关键事件，大约30％的人类癌症包含RAS突变。在乳腺癌和胰腺上皮癌中，异常RAS-MAPK信号通路的特征集中于上游介质，例如受体和致癌RAS分子。然而，下游靶标的影响尚未得到充分探索。我们的研究集中在可诱导和组成性激活的RAS-MAPK信号传导框架下的MSK介导的H3磷酸化。作为模型细胞系统，我们使用了Ras转化的小鼠成纤维细胞，受体过度表达的人乳腺癌细胞系和激活K-RAS突变的人胰腺癌细胞系。我们目前的证据表明，MSK1和H3磷酸化的关键参与作为桥梁介导由RAS-MAPK途径驱动的异常信号与核小体修饰，染色质重塑，IEG表达和恶性转化在小鼠成纤维细胞中的介导。为了验证我们从鼠细胞模型系统得到的观察结果，我们检查了乳腺癌细胞中RAS-MAPK信号传导的激活是否引起相似的分子事件。我们首先证明，RAS-MAPK途径被诱导，因此增强了IEK三叶因子1上MSK1和H3磷酸化的缔合，从而导致转录激活。其次，与通常过度表达ERK1 / 2和H3磷酸化水平的过表达的HER2和EGFR乳腺癌细胞系相比，突变的K-RAS表达与胰腺癌细胞系中的基因组不稳定性或信号传导改变无关。 ，具有异常MAPK信号传导的上皮癌细胞可能利用MSK调控的基因表达来获得进一步的生长/转化优势。我们的研究也有助于进一步理解癌基因转化和癌细胞系中响应RAS-MAPK信号的MSK介导的转录激活。因此，抑制MSK活性可能是用于具有异常RAS-MAPK信号通路的联合癌症治疗的未开发途径。;刺激RAS-MAPK通路会导致下游的丝裂原活化和应激活化蛋白激酶1和2（MSK1 / 2）负责组蛋白H3在S10和S28上的磷酸化。在本文中，我们假设有丝分裂原刺激产生的RAS-MAPK通路失控，或者上游成分的组成型激活和/或过度表达导致MSK1活性增强和组蛋白H3磷酸化水平升高。我们进一步假设，MSK1介导的H3磷酸化对于立即早期基因（IEG）表达，Ras驱动的转化以及基因转录后与调控区相关联至关重要。

著录项

  • 作者

    Espino, Paula.;

  • 作者单位

    University of Manitoba (Canada).;

  • 授予单位 University of Manitoba (Canada).;
  • 学科 Biology Cell.;Biology Molecular.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 235 p.
  • 总页数 235
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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