首页> 外文OA文献 >Modeling and targeting signal transduction pathways governing cell migration
【2h】

Modeling and targeting signal transduction pathways governing cell migration

机译:建模和靶向控制细胞迁移的信号转导途径

代理获取
本网站仅为用户提供外文OA文献查询和代理获取服务,本网站没有原文。下单后我们将采用程序或人工为您竭诚获取高质量的原文,但由于OA文献来源多样且变更频繁,仍可能出现获取不到、文献不完整或与标题不符等情况,如果获取不到我们将提供退款服务。请知悉。

摘要

Cell migration is a complex biophysical event that is dysregulated in a variety of human diseases including cancer. The ability of tumor cells to migrate enables cancer dissemination causing significant mortality thus making it an important therapeutic target. Motility is exhibited epigenetically by activation of numerous signaling pathways that transmit extracellular cues to the final effectors of cell movement. Such signaling switches are a part of larger and highly complex signaling (proteomic) networks that are under the control of numerous activators or inhibitors. Although majority of the proteins that are 'required' during cell motility have been identified, it is yet unclear wherein they fit within the signaling network to govern motility. Thus, a 'systems biology' approach is needed to understand the complex interplay of signaling cascades in mediating cell motility so that better therapeutic targets can be defined. We utilized a mathematical modeling approach, called decision tree analysis to map the interplay between five key signaling proteins known to regulate vital biophysical processes of fibroblast motility downstream of EGF receptor activation. Interestingly, our model identified myosin light chain (MLC) mediated cell contractility as a crucial node for maximal motility. Even more non-intuitively the decision tree model predicted that subtotal inhibition of MLC can actually increase motility. Confirmatory experiments with fibroblasts and cancer cells have shown that to be the case. Since the model proposed that total abrogation of contractility can limit cell migration, we asked if such an intervention can limit tumor invasion. Since PKCδ is implicated in EGF receptor mediated transcellular contractility, we abrogated PKCδ using pharmacological (Rottlerin) and molecular (RNAi) interventions. Such depletion of PKCδ reduced migration as well as invasiveness of prostate carcinoma cells predominantly by decreasing their contractility through myosin light chain (MLC). Additionally, activation of PKCδ correlated with human prostate cancer progression as assessed by immunohistochemistry of prostate tissue sections. In summation our studies illustrate the importance of quantitative (total versus subtotal) disruption of key signaling nodes in mediating a desired cell response. Novel computational modeling approaches are needed to identify newer molecular switches from existing proteomic networks that can be explored, using classical experimental methods, as therapeutic targets.
机译:细胞迁移是一个复杂的生物物理事件,在包括癌症在内的各种人类疾病中均失调。肿瘤细胞迁移的能力使癌症得以传播,从而导致明显的死亡率,从而使其成为重要的治疗靶标。通过大量信号传递途径的活化,表观遗传上的运动性将细胞外信号传递到细胞运动的最终效应器。此类信号交换是较大的且高度复杂的信号(蛋白质组学)网络的一部分,该网络在众多激活剂或抑制剂的控制下。尽管已经鉴定了在细胞运动过程中“必需”的大多数蛋白质,但是还不清楚它们在信号传导网络中的哪一部分适合控制运动性。因此,需要一种“系统生物学”方法来理解信号级联在介导细胞运动中的复杂相互作用,以便可以定义更好的治疗靶标。我们利用一种称为决策树分析的数学建模方法来绘制五种关键信号蛋白之间的相互作用,这些信号蛋白已知可调节EGF受体激活下游成纤维细胞运动的重要生物物理过程。有趣的是,我们的模型将肌球蛋白轻链(MLC)介导的细胞收缩性确定为最大运动性的关键节点。甚至更不直观地,决策树模型预测,对MLC的小计抑制实际上可以提高运动能力。用成纤维细胞和癌细胞进行的验证性实验表明情况确实如此。由于该模型提出完全消除收缩性可以限制细胞迁移,因此我们询问这种干预是否可以限制肿瘤的侵袭。由于PKCδ与EGF受体介导的跨细胞收缩有关,因此我们使用药理学(Rottlerin)和分子(RNAi)干预措施来废除PKCδ。 PKCδ的这种耗竭主要是通过降低其通过肌球蛋白轻链(MLC)的收缩力来减少前列腺癌细胞的迁移以及侵袭性。另外,通过前列腺组织切片的免疫组织化学评估,PKCδ的活化与人前列腺癌的进展有关。总而言之,我们的研究说明了在介导所需细胞反应中关键信号传导节点的定量破坏(总数与小计)的重要性。需要新颖的计算建模方法来从现有的蛋白质组学网络中识别出较新的分子开关,可以使用经典的实验方法将其探索为治疗目标。

著录项

  • 作者

    Kharait Sourabh Prakash;

  • 作者单位
  • 年度 2006
  • 总页数
  • 原文格式 PDF
  • 正文语种 en
  • 中图分类

相似文献

  • 外文文献
  • 中文文献
  • 专利

客服邮箱:kefu@zhangqiaokeyan.com

京公网安备:11010802029741号 ICP备案号:京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有
  • 客服微信

  • 服务号