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: 6761011
• 负责人: CHIAYENG WANG
• 金额: $ 29.3万
• 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 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6761011
• 关键词: SDS polyacrylamide gel electrophoresis; athymic mouse; cell cycle proteins; cell differentiation; cell growth regulation; chromosome translocation; enzyme inhibitors; genetic markers; genetic regulation; immunoprecipitation; molecular oncology; neoplastic growth; polymerase chain reaction; proteasome; protein kinase; protein sequence; proteolysis; rhabdomyosarcoma; stromelysin; transcription factor; western blottings

DESCRIPTION (provided by applicant): Alveolar rhabdomyosarcoma (aRMS) is a highly malignant tumor and it harbors a unique t (2;13) chromosomal translocation marker that leads to the formation of PAX3-FKHR fusion transcription factor, As the result of fusion process, PAX3-FKHR gains the ability to regulate expression of genes that are not normally regulated by Pax3 and FKHR. This altered gene targeting property is responsible for the oncogenic action of PAX3-FKHR. Therefore, understanding the basis of tumor-specific activation/inactivation pathways will provide useful determinants in therapeutic designs for patient care management.The objective of the current grant proposal is to characterize tumor-specific regulatory mechanisms that contribute to the malignant phenotype in PAX3-FKHR transformed cells. Two lines of evidence from the preliminary study suggest that protein proteolysis plays an important role in PAX3-FKHR mediated oncogenesis. One, PAX3-FKHR aberrantly activates stromelysin-1 1 gene expression. Abnormal expression of stromelysin-1 1 gene is closely associated with tumor invasion and metastatic phenotypes, a characteristic that is found predominantly in the aRMS. Second, PAX3-FKHR accelerates 26Sproteosome dependent degradation of cyclin kinase inhibitor p27Kipl protein, a key regulator involved in cell cycle regulation. Aim 1 of this research is designed to gain a better understanding of regulatory mechanism involved in stromelysin-1 gene activation by PAX3-FKHR and the functional role of stromelysin-1 1 in PAX3-FKHR dependent tumorigenesis. This will provide a mechanistic link between the fusion protein and invasive and metastatic clinical behavior in aRMS tumors. Aim 2 focuses on characterizing the molecular steps involved in PAX3-FKHR down-regulation of p27kipl protein accumulation. Finally, in Aim 3, we will examine the role of deregulation of cell cycle regulatory proteins by PAX3-FKHR in its ability to inhibit myogenic differentiation. Studies outlined in aims 2 and 3 will provide a molecular basis for the uncontrolled growth and differentiation phenotypes in aRMS cells.The proposed studies will further our understanding of mechanistic association between genetic abnormality and pathogenesis of aRMS; they will also expand our ability to use this information for patient diagnosis/or prognosis and to design therapeutic reagents that specifically interrupt tumor function without damaging normal cell function.

描述（由申请人提供）：肺泡横纹肌肉瘤（aRMS）是一种高度恶性肿瘤，其具有独特的t（2;13）染色体易位标记，导致PAX 3-FKHR融合转录因子的形成。作为融合过程的结果，PAX 3-FKHR获得了调节通常不由Pax 3和FKHR调节的基因表达的能力。这种改变的基因靶向特性是PAX 3-FKHR的致癌作用的原因。因此，了解肿瘤特异性激活/失活途径的基础将提供有用的决定因素，在治疗设计的病人护理management.The目前的拨款提案的目的是表征肿瘤特异性的监管机制，有助于PAX 3-FKHR转化细胞的恶性表型。来自初步研究的两条证据表明，蛋白质水解在PAX 3-FKHR介导的肿瘤发生中起重要作用。第一，PAX 3-FKHR异常激活溶基质素-11基因表达。基质溶解素-11基因的异常表达与肿瘤侵袭和转移表型密切相关，这是主要在aRMS中发现的特征。第二，PAX 3-FKHR加速细胞周期蛋白激酶抑制剂p27 Kipl蛋白（参与细胞周期调控的关键调节剂）的26 S蛋白体依赖性降解。本研究的目的1是更好地了解PAX 3-FKHR对基质分解素-1基因激活的调控机制以及基质分解素-11在PAX 3-FKHR依赖的肿瘤发生中的功能作用。这将提供融合蛋白与aRMS肿瘤中的侵袭性和转移性临床行为之间的机制联系。目的2集中于表征参与PAX 3-FKHR下调p27 kipl蛋白积累的分子步骤。最后，在目标3中，我们将研究PAX 3-FKHR对细胞周期调节蛋白的失调在其抑制肌源性分化的能力中的作用。目的2和目的3的研究将为aRMS细胞的生长和分化表型失控提供分子基础，进一步了解遗传异常与aRMS发病机制的关系;它们还将扩大我们使用这些信息进行患者诊断的能力。或预后，并设计特异性中断肿瘤功能而不损害正常细胞功能的治疗试剂。