ADIPOCYTE GROWTH AND PATHOGENESIS OF LIPOSARCOMA

脂肪细胞的生长和脂肪肉瘤的发病机制

• 批准号: 2895058
• 负责人: DAVID RON
• 金额: $ 29.63万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 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 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2895058
• 关键词: RNA binding protein; adipocytes; cell growth regulation; chimeric proteins; chromosome translocation; genetic promoter element; genetic transcription; genetically modified animals; laboratory mouse; liposarcoma; molecular oncology; neoplasm /cancer genetics; neoplastic transformation; oncogenes; oncoproteins; pathologic process; reporter genes; tissue /cell culture; transcription factor; yeast two hybrid system

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：该项目探讨了涉及的分子机制 嵌合转录调节蛋白的细胞转化 TLS-CHOP 由常见的 t(12:16) 染色体重排编码 大多数粘液样和圆形细胞脂肪肉瘤。 假设 脂肪肉瘤的转化通过两条平行途径进行：（1） 癌蛋白的 CHOP 成分将其引导至一组靶基因，并且 TLS 组件放松了它们的表达； (2) TLS-CHOP 影响 RNA 结合蛋白 TLS 的正常功能，干扰正常的功能 另一组靶基因的表达。 第二个组成部分是 预计在包含 TLS（或 EWS）成分的肉瘤中很常见 他们的致病癌蛋白。 两组靶基因的成员是 假设其作为转化过程的效应器。 这 因此，该项目的目标是识别 TLS-CHOP 目标基因， 描述它们在脂肪肉瘤中失调的机制，并确定 他们在转型中的作用。 这将涉及识别接触的基因 由 TLS-CHOP 和通常受 TLS 调控的基因，以及 识别作为伙伴参与该过程的蛋白质 TLS-CHOP 发挥了其作用。 后者包括直接蜂窝 TLS 和 CHOP 的部分，以及修饰基因的产物 间接转化。 TLS-CHOP和TLS目标的识别 基因将依赖于表达模式的比较分析 细胞中含有或不含有这些调节因子活性形式的基因。 TLS和CHOP的直接部分将通过生化和 遗传手段，而修改该过程的基因的识别 TLS-CHOP 的转化将通过肿瘤的遗传筛选来实现 源自将被开发为动物模型的转基因小鼠 通过癌蛋白促进肿瘤发生。