BASIS OF PAX3-FKHR ONCOGENESIS IN RHABDOMYOSARCOMA

描述：（改编自摘要）的长远目标 拟议的研究是了解PAX 3-FKHR在肺泡巨噬细胞中的作用， 横纹肌肉瘤（ARMS），一种胎儿骨骼来源的肿瘤， 常见于儿童。 PAX 3-FKHR是t（2;13）ARMS相关的 染色体易位 这种嵌合转录因子含有 PAX 3 DNA结合结构域和（更强的）FKHR反式激活结构域。 初步研究表明，PAX 3-FKHR异常激活基因， 血小板衍生生长因子α受体（PDGFaR）。 这是第一 受PAX 3-FKHR特异性影响的细胞靶基因的实例 而不是PAX 3。 第一个具体目标是描述PAX 3-FKHR应答 PDGFaR基因侧翼的元件。 第二个目标是绘制蛋白质图谱 在PAX 3-FKHR中的一个或多个基序，使其能够激活PDGFaR基因。 的 第三个目的是检查PDGFaR功能如何有助于ARMS肿瘤细胞 增长 由于PDGF是一种有效的有丝分裂生长因子， 它的受体可能在细胞转化中起关键作用。

DESCRIPTION: (Adapted from the abstract.) The long range goal of the proposed research is to understand the role of PAX3-FKHR in alveolar rhabdomyosarcoma (ARMS), a tumor of fetal skeletal origin that is most common in children. PAX3-FKHR is a product of t(2;13) ARMS-associated chromosomal translocations. This chimeric transcription factor contains the PAX3 DNA binding domain and the (stronger) FKHR transactivation domain. Preliminary studies show that PAX3-FKHR aberantly activates the gene for the platelet derived growth factor alpha receptor (PDGFaR). This is the first example of a cellular target gene that is specifically affected by PAX3-FKHR and not PAX3. The first specific aim is to delineate the PAX3-FKHR response element that flanks the PDGFaR gene. The second aim is to map the protein motif(s) in PAX3-FKHR that enables it to activate the PDGFaR gene. The third aim is to examine how PDGFaR function contributes to ARMS tumor cell growth. Since PDGF is a potent mitotic growth factor, aberrant expression of its receptor is likely to play a crucial role in cell transformation.