PAX3/FKHR IN ALVEOLAR RHABDOMYOSARCOMA

肺泡型横纹肌肉瘤中的 PAX3/FKHR

• 批准号: 6237715
• 负责人: DAVID N SHAPIRO
• 金额: $ 17.96万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-06-16 至 1998-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6237715
• 关键词: chimeric proteins; gene expression; genetically modified animals; laboratory mouse; laboratory rabbit; molecular cloning; molecular oncology; neoplasm /cancer genetics; neoplastic transformation; oncoproteins; protein structure function; rhabdomyosarcoma; tissue /cell culture; transcription factor; transfection

Rhabdomyosarcoma, a malignant tumor of skeletal muscle, is the most common soft tissue sarcoma of childhood. Approximately 35% of cases have an alveolar histiotype and a (2;13) translocation, which tends to be associated with a more aggressive clinical course. This rearrangement creates a fusion protein involving the developmentally regulated PAX3 transcription factor and a ubiquitously expressed member of the forkhead family of transcription factors, designated FKHR. Preliminary studies have shown that PAX3/FKHR can function both as a transcriptional activator and a potent inhibitor of myogenesis, relying on DNA-binding domains from PAX3 and the novel FKHR activation domain. Cellular transformation by the chimera depends absolutely on the presence of FKHR structural motifs, whereas DNA binding through the PAX3 paired domain appears dispensable, indicating that oncogenesis may not proceed through activation of PAX3 target genes. To precisely understand how the fusion protein contributes to neoplastic transformation of myogenic cells, we propose to define the contribution of each of its distinct domains to the modulation of gene expression. First, the structural components of PAX3/FKHR essential for in vitro cellular transformation will be identified and then tested for their capacity to induce tumors in vivo by targeting their expression to the myogenic precursors of transgenic mice. Second, interacting proteins that associate with these functionally important PAX3/FKHR domains will be evaluated for their capacity to influence the in vitro transforming potential of the fusion protein. A final goal will be to delineate the biologic pathways regulated by PAX3/FKHR through identification of genes that are specifically modulated by enforced expression of the fusion protein and are essential for tumorigenesis. Results of these studies should fill in the entire pathway from t(2;13)-mediated creation of the PAX3/FKHR oncoprotein to its aberrant activation of downstream targets and modulation of biologic pathways, culminating in overt tumor development. Improved understanding of the mechanisms responsible for cellular transformation by PAX3/FKHR will yield important information about the regulatory circuits disrupted by its expression in myogenic cells and may suggest novel approaches for the treatment of this often resistant tumor.

横纹肌肉瘤是骨骼肌的一种恶性肿瘤， 儿童常见的软组织肉瘤。 大约35%的病例 一个肺泡组织型和一个（2;13）易位，这往往是 与更具侵略性的临床过程相关。 这种重排 产生了一种融合蛋白， 转录因子和叉头蛋白的普遍表达成员 转录因子家族，命名为FKHR。初步研究 已经表明PAX 3/FKHR既可以作为转录因子， 激活剂和肌生成的有效抑制剂，依赖于DNA结合 来自PAX 3的结构域和新的FKHR激活结构域。 蜂窝 嵌合体的转化完全取决于FKHR的存在 结构基序，而DNA结合通过PAX 3配对结构域 似乎是不稳定的，表明肿瘤发生可能不会通过 PAX 3靶基因的激活。 为了精确地理解核聚变 蛋白质有助于肌源性细胞的肿瘤转化，我们 建议界定其每一个不同领域对 基因表达的调节。 第一， 对于体外细胞转化必不可少的PAX 3/FKHR将是 鉴定并测试它们在体内诱导肿瘤的能力 通过将它们的表达靶向转基因的肌原性前体， 小鼠 第二，与这些蛋白质相互作用的蛋白质 将评估功能重要的PAX 3/FKHR结构域的 影响融合体体外转化潜力的能力 蛋白 最终的目标将是描绘出 通过鉴定受PAX 3/FKHR调控的基因， 通过融合蛋白的强制表达特异性调节， 对肿瘤的发生至关重要 这些研究的结果应填补 在从t（2;13）介导的PAX 3/FKHR产生的整个途径中， 癌蛋白与其下游靶点的异常激活有关， 调节生物途径，最终导致明显的肿瘤发展。 更好地理解细胞免疫的机制 通过PAX 3/FKHR的转化将产生关于 其在肌原细胞中的表达破坏了调节回路， 提出了治疗这种耐药肿瘤的新方法。