Role of PAK1-MORC2 Pathway in Breast Cancer

p21活化激酶1 （Paki）是一种主要的丝分裂细胞应答信号结节，在人类乳腺癌中表达上调。尽管关于Pakl在人类癌症中的作用的信息显著增长，但仍然不清楚Pakl或其直接靶点是否参与DNA损伤反应途径，因此，我们的初步研究首次发现，临床相关剂量的DNA损伤刺激核Pakl活性，并且需要一种新的Pakl底物MORC，以Paki磷酸化依赖的方式对γ - h2ax进行最佳刺激和乳腺癌细胞的存活。这一提议代表了P1对确定Paki效应物在人类乳腺癌中的重要性的持续兴趣。在这里，我们建议研究Pakl-MORC通路在人类乳腺癌细胞DNA损伤反应机制网络中作为一个新的参与者的作用。我们的初步研究表明，Pakl信号在有效的DNA损伤反应中起着固有的作用，MORC作为有效激活γ - h2ax的修饰剂/信号成分。我们可测试的工作假设是“DSB刺激核巴基活性，巴基信号通过磷酸化MORC核蛋白促进DNA损伤反应。”Pakl-MORC通路的调控可能会对乳腺癌细胞的敏感性和耐药性产生重大影响，并可能被用于开发新的联合疗法，共同靶向Paki和/或MORC。为了解决这些假设，我们的具体目标是确定：(1)DSB损伤刺激Paki的机制基础以及Paki在乳腺癌细胞DSB信号传导中的作用；(2) MORC在DNA损伤应答中的分子基础及意义。我们的提议的一个创新方面是关注在癌细胞中具有既定作用的分子。我们希望从这个项目中获得的知识将为乳腺癌细胞中dna损伤反应的新机制进展奠定基础。

P21-activated kinase 1 (Paki), a major mitocen-responsive signaling nodule, is upregulated in human breast cancer. Despite the remarkable growth of information about the role of Pakl in human cancer, remains unknown whether Paki or its direct targets participate in the DNA damage response pathway and thus, could influence the responsiveness cancer cells to radiation therapy - one the major treatment regimens currently used for cancer treatment Our preliminary studies have discovered for the first time that clinically relevant dose of DNA damage stimulates the nuclear Pakl activity and that a novel Pakl substrate MORC, is required for optimal stimulation of gamma-H2AX and survival of breast cancer cells in a Paki -phosphorylation dependent manner. This proposal represents a continuing interest of the P1 to define the significance of Paki its effectors in human breast cancer. Here we propose to investigate the role of the Pakl-MORC pathway as a new player to the growing network of DNA damage response mechanisms in human breast cancer cells. Our preliminary studies have allowed us to suggest that Pakl signaling plays an inherent role in efficient DNA damage responsiveness and that MORC acts as a modifier/signaling component for efficient activation of gamma-H2AX. Our testable working hypothesize is that "DSB stimulates nuclear Paki activity and that Paki signaling contributes to DNA damage response via phosphorylating MORC nuclear protein." Regulation of Pakl-MORC pathway may have significant consequences relating to the sensitivity versus resistance of breast cancer cells and could be potentially exploited to develop novel combination therapies, co-targeting of Paki and/or MORC. To address these hypotheses, our Specific Aims are to determine: (1) The mechanistic basis of Paki stimulation by DSB damage and role of Paki in DSB signaling in breast cancer cells; (2) The molecular basis and significance of MORC's contribution in DNA damage response. An innovative aspect of our proposal is the focus on molecules with established roles in cancer cells. It is our hope that the knowledge gained from this project will form the basis for new mechanistic advances in DNAdamage response in breast cancer cells.