Basis of PAX3-FKHR oncogenesis in rhabdomyosarcoma

横纹肌肉瘤中 PAX3-FKHR 肿瘤发生的基础

• 批准号: 7625068
• 负责人: CHIAYENG WANG
• 金额: $ 30.11万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-15 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7625068
• 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

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的发展与环境因素没有已知的联系，因此理解RMS的关键必须来自研究RMS特有的致病变化。该应用程序的重点是牙槽型RMS（aRMS），最具侵略性的RMS形式与最高的肿瘤复发率和死亡率。武器系统携带一个t2; 13染色体易位，其产生结合肌肉调节因子Pax 3的DNA结合结构域和广泛表达的FKHR的活化结构域的嵌合蛋白。PAX 3-FKHR是一种有效的转录因子，导致肌肉细胞失去细胞周期和细胞分化控制。从aRMS细胞中清除PAX 3-FKHR导致细胞死亡。这些观察结果支持PAX 3-FKHR作为aRMS发展的起始和进展中的关键病原体。然而，PAX 3-FKHR介导的肿瘤发生的分子基础仍然难以捉摸。从以前的资助期获得的数据提供了揭示融合蛋白致癌基础的主要线索。PAX 3-FKHR获得了改变通常不受亲本蛋白调控的基因表达的新机制。此外，PAX 3-FKHR致癌作用关键取决于转录特异性的这些增益。我们假设PAX 3-FKHR特异性破坏的分子途径代表了aRMS发展中涉及的最关键事件。该基金的目的是研究PAX 3-FKHR特异性调节机制，这些机制有助于肌肉细胞的增殖和分化缺陷。提出了三个具体目标：目标1旨在鉴定和表征其表达被PAX 3-FKHR直接靶向的基因的功能作用，而不依赖于Pax 3和FKHR。本研究将确定PAX 3-FKHR肌细胞转化的早期事件。目的二是明确PAX 3-FKHR介导的G1期细胞周期缺陷的分子机制，特别是E2 F1-Skp 2-p27 kip 1调控轴。目的3重点描述PAX 3-FKHR阻断肌肉分化的分子事件，重点是肌细胞生成素/MEF 2C活性在促进肌肉特异性基因如Myf 6中的失调。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发展中的整个途径，从t2;13介导的PAX 3-FHR的产生到下游靶点的异常激活到转化途径。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决定因素。