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

作为对DNA损伤的反应，细胞激活一个复杂的信号网络来阻止细胞周期并修复DNA。这个网络的许多组成部分在人类癌症中被发现发生了突变，许多肿瘤显示出DNA损伤反应受损。取消剩余的检查点装置，结合DNA损伤化疗，已被提出为化疗增敏的新的治疗概念。我们发现MK2是一种检查点蛋白，对于DNA损伤后p53基因缺陷的肿瘤细胞的存活至关重要。这一建议旨在了解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的方法来阐明MK2在DNA损伤后P53缺陷细胞存活中的作用。我们将在体内将MK2描述为联合使用检查点清除治疗和化疗的靶点。这项研究计划是为实现四个主要目标而量身定做的：描述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mRNAs，以及参与稳定已鉴定mRNAs的RNA结合蛋白。我们将使用一种原生的肺癌模型来表征MK2作为肿瘤抑制因子的作用。我们将使用一只对MK2具有特异性抑制作用的敲打小鼠来表征MK2作为化疗增敏治疗药物靶点的作用。拟议的实验旨在将MK2表征为一种药物靶点，可能与传统的DNAdamage化疗具有协同作用。

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.