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:
    7840454
  • 负责人:
  • 金额:
    $ 30.11万
  • 依托单位:
  • 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 2012-05-31
  • 项目状态:
    已结题

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(申请人提供):横纹肌肉瘤(RMS),肿瘤或骨骼肌,是最常见的儿童软组织癌。RMS的发生发展与环境因素没有已知的联系,因此理解RMS的关键必须来自于研究RMS特有的致病变化。这项应用主要针对肺泡型RMS(ARMS),这是一种最具侵袭性的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,产生一种融合了肌肉调节因子Pax3的DNA结合域和普遍表达的FKHR的激活域的嵌合蛋白。Pax3-FKHR是一种强大的转录因子,可导致肌肉细胞失去对细胞周期和细胞分化的控制。从手臂细胞中清除PAX3-FKHR会导致细胞死亡。这些观察结果支持PAX3-FKHR在武器发展的启动和进展中是一个关键病原体。然而,PAX3-FKHR介导的肿瘤发生的分子基础仍然不清楚。从以前的资助时期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获得了改变通常不受亲本蛋白调控的基因表达的新机制。此外,PAX3-FKHR的致癌作用关键依赖于这些转录特异性的获得。我们假设,被PAX3-FKHR特异性干扰的分子通路代表了武器发展中最关键的事件。这项资助的目的是研究PAX3-FKHR特定的调控机制,这些机制有助于肌肉细胞的增殖和分化缺陷。我们提出了三个特定的目标:Aim 1旨在识别和表征PAX3-FKHR直接靶向其表达的基因的功能作用,而不依赖于Pax3和FKHR。这项研究将确定PAX3-FKHR转化肌肉细胞的早期事件。AIM 2旨在明确PAX3-FKHR参与G1期细胞周期缺陷的分子步骤,特别关注E2F1-Skp2-p27kip1调节轴。目的3重点描述PAX3-FKHR阻断肌肉分化的分子事件,重点是在促进Myf6等肌肉特异性基因的表达中,Mygenin/MEF2C活性异常。AIMS 2和AIMS 3中概述的研究将为武器细胞的不受控制的生长和分化表型提供分子基础。拟议的研究结果将填补整个手臂发育的途径,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的诊断或预后以及在不损害正常细胞功能的情况下特异性阻断肿瘤功能的新的治疗设计提供重要的决定因素。

项目成果

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CHIAYENG WANG其他文献

CHIAYENG WANG的其他文献

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{{ truncateString('CHIAYENG WANG', 18)}}的其他基金

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:
    6542330
  • 财政年份:
    1997
  • 资助金额:
    $ 30.11万
  • 项目类别:
BASIS OF PAX3-FKHR ONCOGENESIS IN RHABDOMYOSARCOMA
横纹肌肉瘤中 PAX3-FKHR 致癌的基础
  • 批准号:
    2896046
  • 财政年份:
    1997
  • 资助金额:
    $ 30.11万
  • 项目类别:
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:
    7846931
  • 财政年份:
    1997
  • 资助金额:
    $ 30.11万
  • 项目类别:
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
  • 财政年份:
    1997
  • 资助金额:
    $ 30.11万
  • 项目类别:
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:
    8076908
  • 财政年份:
    1997
  • 资助金额:
    $ 30.11万
  • 项目类别:
BASIS OF PAX3-FKHR ONCOGENESIS IN RHABDOMYOSARCOMA
横纹肌肉瘤中 PAX3-FKHR 致癌的基础
  • 批准号:
    2733361
  • 财政年份:
    1997
  • 资助金额:
    $ 30.11万
  • 项目类别:
BASIS OF PAX3-FKHR ONCOGENESIS IN RHABDOMYOSARCOMA
横纹肌肉瘤中 PAX3-FKHR 致癌的基础
  • 批准号:
    6376454
  • 财政年份:
    1997
  • 资助金额:
    $ 30.11万
  • 项目类别:
PDGF RECEPTOR EXPRESSION IN GLIAL CELLS
胶质细胞中的 PDGF 受体表达
  • 批准号:
    2039081
  • 财政年份:
    1997
  • 资助金额:
    $ 30.11万
  • 项目类别:
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:
    6909865
  • 财政年份:
    1997
  • 资助金额:
    $ 30.11万
  • 项目类别:
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:
    7314279
  • 财政年份:
    1997
  • 资助金额:
    $ 30.11万
  • 项目类别:

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