In vivo Charakterisierung der Protein Kinase MK2 als potenzielles Zielmolekül für eine neue Chemotherapie-sensitivierende Krebstherapie

为了应对DNA损伤，细胞激活一个复杂的信号网络来阻止细胞周期和修复DNA。在人类癌症中发现该网络的许多组成部分发生突变，许多肿瘤显示出受损的DNA损伤反应。去除剩余的检查点装置与DNA损伤化疗相结合已被提出作为化疗增敏的新治疗概念。我们确定MK2是一种检查点激酶，对DNA损伤后p53缺陷型肿瘤细胞的存活特别重要。该提案旨在了解MK2功能的激活机制和分子细节。我们将使用生物化学和遗传学方法来阐明MK 2对DNA损伤后p53缺陷细胞存活的作用。我们将MK2作为检查点取消治疗与体内化疗联合的靶点。该研究计划旨在实现四个主要目标：表征DNA损伤后MK2激活的机制。鉴定在DNA损伤时被MK2转录后稳定的mRNA，以及参与所鉴定mRNA稳定的RNA结合蛋白。我们将使用肺癌的本地模型来表征MK2作为肿瘤抑制因子的作用。我们将使用适合于特异性MK2抑制的敲入小鼠来表征MK2作为化学增敏治疗的药物靶点的作用。拟议的实验旨在将MK2表征为可能与常规DNA损伤化疗协同作用的药物靶标。

In response to DNA damage cells activate a complex signaling network to arrest the cell cycle and repair DNA. Many components of this network have been found mutated in human cancers and many tumors show an impaired DNA damage response. Abrogation of the remaining checkpoint apparatus in combination with DNA-damaging chemotherapy has been proposed as a new therapeutic concept for chemosensitization. We identified MK2 as a checkpoint kinase specifically critical for the survival of p53-deficient tumor cells after DNA damage. This proposal aims to understand the activation mechanisms and the molecular details of MK2 function. We will use biochemical and genetic approaches to elucidate the role of MK2 for survival of p53-deficient cells after DNA damage. We will characterize MK2 as a target for checkpoint-abrogating therapy in combination with chemotherapy in vivo. The research plan is tailored to achieve four main goals: Characterization of mechanisms that govern MK2 activation after DNA damage. Identification of mRNAs that are posttranscriptionally stabilized by MK2 in response to DNA damage, and RNA-binding proteins involved in the stabilization of the identified mRNAs. We will characterize the role of MK2 as a tumor suppressor using an autochthonous model of lung cancer. We will use a knockin mouse amenable for specific MK2 inhibition to characterize the role of MK2 as a drug target for chemosensitizing therapy. The proposed experiments aim at characterizing MK2 as a drug target that will likely function synergistically with conventional DNAdamaging chemotherapy.