ADIPOCYTE GROWTH AND PATHOGENESIS OF LIPOSARCOMA

描述：这个项目探索了涉及到 嵌合转录调节蛋白对细胞的转化 TLS-CHOP，由共同的t(12：16)染色体重排编码 多数为粘液性和圆形细胞脂肪肉瘤。据推测， 脂肪肉瘤的转化通过两条平行的途径进行：(1) 癌蛋白的CHOP组分将其定向到一组靶基因，并且 TLS组件解除对它们的表达的管制；(2)TLS-CHOP冲击 RNA结合蛋白TLS的正常功能，干扰适当的 另一组靶基因的表达。第二个组件是 预测为肉瘤常见的含有TLS(或EWS)成分的肉瘤 它们的致病癌蛋白。这两组靶基因的成员都是 被认为是转变过程的执行者。这个 因此，该项目的目标是识别TLS-CHOP靶基因， 阐明其在脂肪肉瘤中的失控机制，并确定 他们在转型中的作用。这将涉及识别所联系的基因。 通过TLS-CHOP和通常由TLS调控的基因，以及 识别作为合作伙伴参与这一过程的蛋白质 TLS-CHOP实现了它的功能。后者包括直接细胞 TLS和CHOP，以及修饰基因的产物 间接转型。TLS-CHOP和TLS目标的识别 基因将依赖于对基因表达模式的比较分析 细胞中含有和不含有这些调节剂活性形式的基因。 TLS和CHOP的直接特遣队将由生化和 遗传手段，而识别改变这个过程的基因 TLS-CHOP转化的可能性将通过肿瘤的基因筛查实现 来自转基因小鼠，将被开发为动物模型 致癌蛋白的致癌作用。

DESCRIPTION: This project explores the molecular mechanisms involved in cellular transformation by the chimeric transcriptional regulatory protein TLS-CHOP that is encoded by the t(12:16) chromosomal rearrangement common to most myxoid and round cell liposarcomas. It is hypothesized that transformation in liposarcoma proceeds by two parallel pathways: (1) The CHOP component of the oncoprotein directs it to one set of target genes, and the TLS component deregulates their expression; (2) TLS-CHOP impinges on the normal function of the RNA-binding protein TLS, interfering with the proper expression of another set of target genes. The second component is predicted to be common to sarcomas that contain a TLS (or EWS) component in their causative oncoprotein. Members of both sets of target genes are hypothesized to function as effectors of the process of transformation. The goals of this project are, thus, to identify TLS-CHOP target genes, delineate the mechanism of their deregulation in liposarcoma, and determine their role in transformation. This will involve identifying genes contacted by TLS-CHOP and genes that are normally regulated by TLS, as well as identifying proteins that participate as partners in the process by which TLS-CHOP carried out its function. The latter include the direct cellular contingents of TLS and CHOP, as well as the products of genes that modify transformation indirectly. The identification of TLS-CHOP and TLS target genes will rely on the comparative analysis of the expression pattern of genes in cells that do and do not contain active forms of these regulators. The direct contingents of TLS and CHOP will be identified by biochemical and genetic means, whereas the identification of genes that modify the process of transformation by TLS-CHOP will be attained by a genetic screen of tumors derived in genetically-modified mice that will be developed as animal models for tumorigenesis by the oncoprotein.