Role of PAK1-MORC2 Pathway in Breast Cancer

PAK1-MORC2 通路在乳腺癌中的作用

基本信息

批准号：
7737099
负责人：
Rakesh Kumar
金额：
$ 32.47万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7737099
关键词：
AF2 Accounting Address Affect Alanine Aliquot Amino Acids Area Ataxia-Telangiectasia-Mutated protein kinase BRCA1 gene BRCT Domain Binding Binding Proteins Biochemical Biological Assay Biological Models Breast Breast Cancer Cell CHEK2 gene CHES1 gene Caffeine Cancer Patient Catalytic Domain Cell Cycle Checkpoint Cell Survival Cells Charge Chromatin Chromatin Remodeling Factor Combined Modality Therapy Comet Assay Complex Consensus DNA DNA Damage DNA Repair DNA Synthesis Inhibition DNA biosynthesis DNA lesion DNA-dependent protein kinase Data Defect Dependency Deposition Detergents Diffuse Digestion Dose Electrophoresis Ensure Enzymes Event Exhibits Experimental Designs Exposure to Family Fee-for-Service Plans Figs - dietary Fractionation Funding Gel Genotoxic Stress Goals Growth Histones Hour Human Hypersensitivity Immunoprecipitation In Situ In Vitro Ionizing radiation Kinetics Knowledge Label Laboratories Lasers Learning Length Lesion Life Light Link Lysine MCF7 cell MDA MB 231 Malignant Neoplasms Measures Mediating Metabolic Micrococcal Nuclease Microscope Modification Molecular Monitor Mutate Mutation NBS1 gene Nature Nodule NuRD complex Nuclear Nuclear Protein Nuclear Proteins Nucleosomes Oryctolagus cuniculus Outcome Pathway interactions Pattern Peptides Phase Phosphopeptides Phosphorylation Phosphorylation Site Phosphotransferases Physical condensation Physiologic pulse Physiological Play Positioning Attribute Process Proline Proline-Rich Domain Protein Analysis Protein Tyrosine Phosphatase Proteins Proteomics Quality Control Radiation Radiation Tolerance Radiation therapy Radio Reagent Recombinants Recruitment Activity Regulation Relaxation Repair Complex Research Design Resistance Role SKBR3 Sampling Sequence Analysis Serine Signal Transduction Signaling Protein Site Small Interfering RNA Sodium Chloride Staining method Stains Stress Stretching System TP53 gene Testing Threonine Time Transfection Treatment Protocols Western Blotting Work ataxia telangiectasia mutated protein base cancer cell cancer therapy cancer type chromatin remodeling clinically relevant design experience expression vector human ESR1 protein in vivo inhibitor/antagonist innovation insight interest knock-down laser scissor malignant breast neoplasm methylxanthine migration mutant novel overexpression p21-activated kinase 1 polyclonal antibody polypeptide reconstitution repaired research study response restoration simulation stem three dimensional structure vector wortmannin

项目摘要

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.

P21激活的激酶1（Paki）是一种主要的线索响应信号结节，在人类乳腺癌中被上调。尽管有关PAKL在人类癌症中的作用的信息的显着增长，但尚不清楚Paki还是其直接靶标参与DNA损伤反应途径，因此可能会影响癌细胞对放射治疗的反应性癌细胞 - 一种主要治疗方案一种，目前用于癌症治疗的主要治疗方案是，我们的初步研究是在临床上造成的临床损害刺激型核PAAK PAK的初步研究，并且该研究是在临床上造成的。以Paki磷酸化的方式对γ -H2AX的最佳刺激和乳腺癌细胞的存活。该提案代表了P1的持续兴趣，即定义Paki在人类乳腺癌中的效应子的重要性。在这里，我们建议研究PAKL-MORC途径作为人类乳腺癌细胞中DNA损伤反应机制不断增长的新参与者的作用。我们的初步研究使我们建议PAKL信号在有效的DNA损伤反应性中起固有的作用，并且MORC充当有效激活γ-H2AX的修饰符/信号传导成分。我们可以测试的工作假设是“ DSB刺激核Paki活性，而Paki信号传导通过磷酸化MORC核蛋白有助于DNA损伤反应。” PAKL-MORC途径的调节可能与乳腺癌细胞的敏感性与耐药性有关，可能会产生重大的后果，并有可能被利用以开发新型组合疗法，对Paki和/或Morc的共同靶向。为了解决这些假设，我们的具体目的是确定：（1）DSB损伤刺激Paki刺激的机理基础，Paki在DSB信号中的作用在乳腺癌细胞中；（2）MORC在DNA损伤反应中的贡献的分子基础和意义。我们提案的一个创新方面是关注在癌细胞中既定作用的分子。我们希望从该项目中获得的知识将构成乳腺癌细胞中新生动物反应的新机械进步的基础。