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ADIPOCYTE GROWTH AND PATHOGENESIS OF LIPOSARCOMA

脂肪细胞的生长和脂肪肉瘤的发病机制

基本信息

批准号：
6376022
负责人：
DAVID RON
金额：
$ 31.07万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-07-15 至 2003-04-30
项目状态：
已结题

项目摘要

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.

描述：该项目探讨了参与的分子机制，通过嵌合转录调节蛋白的细胞转化 TLS-CHOP由t（12：16）染色体重排编码，大多数粘液样和圆细胞脂肪肉瘤。它是假设脂肪肉瘤的转化通过两条平行的途径进行：（1）癌蛋白的CHOP组分将其引导至一组靶基因， TLS组分解除了它们的表达;（2）TLS-CHOP冲击了 RNA结合蛋白TLS的正常功能，干扰了正常的另一组靶基因的表达。第二组分是预测是常见的肉瘤含有TLS（或EWS）成分，它们的致癌蛋白。两组靶基因的成员是被假设为转化过程的效应器。的因此，该项目的目标是鉴定TLS-CHOP靶基因，描述其在脂肪肉瘤中失调的机制，并确定在转型中的作用。这将涉及识别基因接触通过TLS-CHOP和通常由TLS调节的基因，以及识别作为伙伴参与过程的蛋白质， TLS-CHOP履行了其职能。后者包括直接蜂窝 TLS和CHOP的特遣队，以及修改基因的产物，间接转化。 TLS-CHOP和TLS靶标的识别基因将依赖于比较分析的表达模式，细胞中含有或不含有这些调节剂的活性形式的基因。 TLS和CHOP的直接特遣队将通过生物化学和基因手段，而修改过程的基因的鉴定通过TLS-CHOP的转化将通过肿瘤的遗传筛选来实现来自将被开发为动物模型的转基因小鼠癌蛋白引起的肿瘤。