REGULATION OF PAX3/PAX7 EXPRESSION IN RHABDOMYOSARCOMA

描述：(改编自调查人员摘要)PAX3和PAX7是 转录因子的配对BOX家族中密切相关的成员。 基因产物以重叠但不同的模式表达 在骨骼肌谱系的形成过程中，并在 调节生长、分化和运动。小儿科的研究 癌症肺泡型横纹肌肉瘤(ARMS)已经证明PAX3和PAX7 在涉及骨骼肌的肿瘤发展中发挥重要作用 血统。在ARM中，PAX 3或PAX7基因与FKHR基因通过 T(2；13)或t(1；13)染色体易位创造有效 具有假定致癌活性的转录激活物。此外 对于这些功能改变，初步实验表明 改变ARM中PAX3和PAX7表达的不同机制； T(1；13)易位与重排的扩增有关 PAX7基因，而t(2；13)易位与 重组的PAX3基因在未扩增的情况下过表达。研究 胚胎性横纹肌肉瘤(ERMS)是第二种与儿童癌症有关的癌症 肌源性血统，显示了野生型PAX7表达的差异 ERMS和ARM之间的差异，因此表明在ERMS和ARM中存在肿瘤特异性差异 各自的转录环境。要定义PAX3的模式和 PAX7在ARM和ERMS中的表达，并阐明它们之间的差异或 表达、RNA和蛋白质表达的变化将在 肿瘤株和标本。作为阐明基因的起点-和 肿瘤的特异性表达特征，将进行实验以 确定染色质特征在长程基因组图谱上的位置 PAX3和PAX7基因座。然后，这些资源将用于 报告基因转染法用于鉴定调控顺式作用元件 Pax3和PAX7在这些肿瘤中的表达。对于那些顺式作用的元素 它们负责改变重排基因的表达或 ERMS和ARM之间的差异表达，相应的 反式作用因子将通过DNA结合和转录来研究 化验。因此，这些研究将结合mRNA检测、基因组学 作图和转录方法来定义模式和分子 为控制PAX3和PAX7在这些肿瘤中的表达提供了依据 理解它们在正常骨骼肌中表达的模型 发展，并最终使战略的设计能够操纵 这些基因的表达。

DESCRIPTION: (adapted from the investigator's abstract) PAX3 and PAX7 are closely related members of the paired box family of transcription factors. The gene products are expressed with overlapping yet distinct patterns during formation of the skeletal muscle lineage and have important roles in regulating growth, differentiation, and motility. Studies of the pediatric cancer alveolar rhabdomyosarcoma (ARMS) have demonstrated that PAX3 and PAX7 play important roles in neoplastic develpment involving the skeletal muscle lineage. In ARMS, the PAX 3 or PAX7 gene is fused to the FKHR gene by the t(2;13) or t(1;13) chromosomal translocation to created potent transcriptional activators with postulated oncogenic activity. In addition to these functional alterations, preliminary experiments have revealed distinct mechanisms for altering PAX3 and PAX7 expression in ARMS; the t(1;13) translocation is associated with amplification of the rearranged PAX7 gene, whereas the t(2;13) translocation is associated with overexpression of the rearranged PAX3 gene without amplification. Studies of embryonal rhabdomyosarcoma (ERMS), a second pediatric cancer related to the myogenic lineage, have revealed differences in wild-type PAX7 expression between ERMS and ARMS, and thus suggest tumor-specific differences in the respective transcriptional environments. To define the patterns of PAX3 and PAX7 expression in ARMS and ERMS, and elucidate the differences or alterations in expression, RNA and protein expression will be assaysed in tumor lines and specimens. As a starting-point for elucidating gene-and tumor-specific expression features, experiments will be conducted to determine the location of chromatin features on long-range genomic maps of the PAX3 and PAX7 loci. These resources will then be utilized in reporter-transfection assays to identify cis-acting elements that regulate PAX3 and PAX7 expression in these tumors. For those cis-acting elements which are responsible for altered expression of the rearranged genes or differential expression between ERMS and ARMS, the corresponding trans-acting factors will be studies by DNA binding and transcriptional assays. These studies will therefore combine mRNA detection, genomic mapping, and transcriptional approaches to define the pattern and molecular basis for control of PAX3 and PAX7 expression in these tumors, provide models for understanding their expression during normal skeletal muscle development, and ultimately enable the design of strategies to manipulate expression of these genes.