Basis of PAX3-FKHR oncogenesis in rhabdomyosarcoma

横纹肌肉瘤中 PAX3-FKHR 肿瘤发生的基础

基本信息

批准号：
7846931
负责人：
CHIAYENG WANG
金额：
$ 1.62万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-07-15 至 2009-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7846931
关键词：
26S proteasome Adolescent Affect Alveolar Alveolar Rhabdomyosarcoma Apoptosis Biological Cancerous Candidate Disease Gene Cell Cycle Cell Cycle Regulation Cell Death Cell Differentiation process Cell Nucleus Cell Proliferation Cell physiology Cells Characteristics Child Childhood Chimeric Proteins Chromatin Structure Chromosomal translocation DNA DNA Binding Domain Data Defect Development Diagnosis Differentiation Antigens Differentiation and Growth Enhancers Environmental Risk Factor Event FOXO1A gene Failure Frequencies Funding Gene Expression Gene Targeting Genes Genetic Genetic Transcription Goals Grant Growth Link Malignant Neoplasms Mediating Modification Molecular Muscle Muscle Cells Muscle Fibers Myoblasts Myogenic Regulatory Factors Myogenin Myomatous neoplasm Normal Cell Oncogenic PAX3 gene Parents Pathway interactions Patients Phenotype Process Proteins Proteolysis Recurrence Regulation Research Personnel Rhabdomyosarcoma Role Signal Transduction Skeletal Muscle Soft Tissue Neoplasms Specificity Structure Testing Transcription Coactivator Transcriptional Activation Ubiquitination base cell growth cell transformation chimeric gene design gain of function malignant phenotype mortality myogenesis novel novel strategies novel therapeutics outcome forecast pathogen prevent programs response skeletal muscle differentiation soft tissue tissue/cell culture tool transcription factor tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Rhabdomyosarcoma (RMS), tumor or skeletal muscle, is the most common pediatric soft tissue cancer. RMS development has no known association with environmental factors, thus the key to understanding RMS must come from studying pathogenic changes that are unique to RMS. This application focuses on alveolar RMS (aRMS), the most aggressive RMS form with the highest tumor recurrence and mortality rate. ARMS carries a t2;13 chromosomal translocation that creates a chimeric protein that combines the DNA binding domain of a muscle regulatory factor Pax3 and the activation domain of a ubiquitously expressed FKHR. PAX3-FKHR is a potent transcription factor that causes muscle cells to lose both cell cycle and cell differentiation controls. Obliterating PAX3-FKHR from aRMS cells leads to cell death. These observations support PAX3-FKHR as a critical pathogen in the initiation and progression of aRMS development. Yet, the molecular basis of PAX3-FKHR mediated oncogenesis remains elusive. Data obtained from previous funding periods provided major clues for unveiling the oncogenic basis of the fusion protein. PAX3-FKHR gains novel mechanisms to alter expression of genes that are not normally regulated by the parent proteins. Moreover, the PAX3-FKHR oncogenic effect depends critically on these gains in transcription specificity. We hypothesize that molecular pathways specifically disrupted by PAX3-FKHR represent the most critical events involved in aRMS development. The objective of this grant is to investigate PAX3-FKHR-specific regulatory mechanisms that contribute to the proliferation and differentiation defects in muscle cells. Three specific aims are proposed: Aim 1 is designed to identify and characterize the functional role of genes whose expression is directly targeted by PAX3-FKHR independent of Pax3 and FKHR. This study will define early events in muscle cell transformation by PAX3-FKHR. Aim 2 is designed to define the molecular steps involved in G1 cell cycle defect by PAX3-FKHR, with a specific focus on E2F1-Skp2-p27kip1 regulatory axis. Aim 3 focuses on delineate the molecular events responsible for blockage in muscle differentiation by PAX3-FKHR, with an emphasis on the dysregulated Myogenin/MEF2C activity in promoting muscle specific genes such as Myf6. Studies outlined in Aims 2 and 3 will provide a molecular basis for the uncontrolled growth and differentiation phenotypes in aRMS cells. Results of the proposed studies will fill in the entire pathway in aRMS development, from t2;13 mediated creation of PAX3-FHR to aberrant activation of downstream targets to transformation pathways. Elucidating the basis of tumor-specific activation/inactivation pathways will provide important determinants in patient diagnosis or prognosis and in novel therapeutic design that specifically interrupt tumor function without damaging normal cell function.

描述（由申请人提供）：横纹肌肉瘤（RMS），肿瘤或骨骼肌，是最常见的儿科软组织癌症。 RMS 的发展与环境因素之间没有已知的关联，因此了解 RMS 的关键必须来自于研究 RMS 特有的致病变化。该应用重点关注肺泡 RMS (aRMS)，这是最具侵袭性的 RMS 形式，具有最高的肿瘤复发率和死亡率。 ARMS 携带 t2;13 染色体易位，产生嵌合蛋白，该蛋白结合了肌肉调节因子 Pax3 的 DNA 结合域和普遍表达的 FKHR 的激活域。 PAX3-FKHR 是一种有效的转录因子，可导致肌肉细胞失去细胞周期和细胞分化控制。从 aRMS 细胞中消除 PAX3-FKHR 会导致细胞死亡。这些观察结果支持 PAX3-FKHR 作为 aRMS 发展起始和进展的关键病原体。然而，PAX3-FKHR 介导的肿瘤发生的分子基础仍然难以捉摸。从之前的资助期间获得的数据为揭示融合蛋白的致癌基础提供了主要线索。 PAX3-FKHR 获得了新的机制来改变通常不受亲本蛋白调节的基因的表达。此外，PAX3-FKHR 致癌作用主要取决于转录特异性的这些增益。我们假设 PAX3-FKHR 特异性破坏的分子途径代表了 aRMS 发育中涉及的最关键事件。该资助的目的是研究导致肌肉细胞增殖和分化缺陷的 PAX3-FKHR 特异性调节机制。提出了三个具体目标：目标 1 旨在识别和表征基因的功能作用，这些基因的表达是 PAX3-FKHR 直接靶向的，独立于 Pax3 和 FKHR。这项研究将通过 PAX3-FKHR 定义肌肉细胞转化的早期事件。目标 2 旨在定义 PAX3-FKHR 涉及 G1 细胞周期缺陷的分子步骤，特别关注 E2F1-Skp2-p27kip1 调节轴。目标 3 重点描述导致 PAX3-FKHR 阻断肌肉分化的分子事件，重点是促进肌肉特异性基因（如 Myf6）的肌细胞生成素/MEF2C 活性失调。目标 2 和 3 中概述的研究将为 aRMS 细胞中不受控制的生长和分化表型提供分子基础。拟议研究的结果将填补 aRMS 发展的整个途径，从 t2;13 介导的 PAX3-FHR 的产生到下游靶标的异常激活再到转化途径。阐明肿瘤特异性激活/失活途径的基础将为患者诊断或预后以及特异性中断肿瘤功能而不损害正常细胞功能的新型治疗设计提供重要的决定因素。