Chromosome translocation-mediated conversion of a tumor suppressor gene into a dominant oncogene: fusion of EWS1 to WT1 in desmoplastic small round cell tumors.
Chromosome translocation-mediated conversion of a tumor suppressor gene into a dominant oncogene: fusion of EWS1 to WT1 in desmoplastic small round cell tumors.
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染色体易位介导的肿瘤抑制基因向显性癌基因的转化：促结缔组织增生性小圆细胞肿瘤中 EWS1 与 WT1 的融合。
DOI：
10.1007/978-3-642-60479-9_10
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发表时间：
1997
影响因子：
--
通讯作者：
Rauscher3rd,FJ
中科院分区：
文献类型：
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作者：
Rauscher3rd,FJ
本卷前面的文章提供了一个独特的遗传和生化机制的概述，这些机制是转录因子功能致癌转换的基础。很明显，许多模型来自儿童和成人白血病的研究。这些研究为实体瘤中涉及转录因子的染色体易位的新兴分析提供了范例。这由巴尔的手稿举例说明，他检查了PAX 3-FKHR融合转录因子，其机制可能涉及正常PAX 3靶基因的激活增加。RonandMay描述的EWS和TLS融合反应了一个类似但可能不完全相同的机械论主题。与PAX 3-FKHR一样，EWS/TLS融合体将一个新的激活结构域赋予一个原本未改变的DNA结合结构域，从而产生一个显性癌基因。最显著的是参与EWS/TLS融合的DNA结合结构域类型的多样性，以及随之而来的疾病过程的多样性。本文将通过描述EWS/TLS癌基因家族的一个新成员，即EWS-WT 1，来扩展这一主题，EWS-WT 1发生在实体瘤促结缔组织增生性小圆细胞肉瘤（DSRCT）中。EWS-WT 1融合体的独特之处在于其DNA结合结构域来源于Wilms肿瘤-1（WT 1）肿瘤抑制蛋白。这是染色体易位介导的原癌基因（EWS）和肿瘤抑制基因（WT 1）融合的第一个例子，它产生了一个显性癌基因。为了理解这些发现的背景，我们将首先简要回顾WT 1、EWS和DSRCT的生物学和遗传学。
The preceding articles in this volume have provided a unique overview of genetic and biochemical mechanisms which underlie oncogenic conversion of transcription factor function. As is evident, many of the models have derived from the study of pediatric and adult leukemias. These studies have provided a paradigm for the emerging analyses of chromosomal translocations involving transcription factors in solid tumors. This is exemplified by the manuscript of Barr who examines the PAX3-FKHR fusion transcription factor whose mechanism likely involves increased activation of normal PAX3 target genes. A similar but probably not identical mechanistic theme is echoed by the EWS and TLS fusions described byRonandMay. Like PAX3-FKHR, the EWS/TLS fusions confer a novel activation domain to an otherwise unaltered DNA binding domain, thereby creating a dominant oncogene. Most remarkable is the diversity of DNA-binding domain types which are involved in EWS/TLS fusions and, concomitantly, the diversity of the disease processes initiated. This article will expand on this theme by describing a new member of the EWS/TLS family of oncogenes, namely EWS-WT1, which occurs in the solid tumor desmoplastic small round cell sarcoma (DSRCT). The EWS-WT1 fusion is unique in that its DNA binding domain is derived from the Wilms’ tumor-1 (WT1) tumor suppressor protein. This is one of the first examples of chromosomal-translocation-mediated fusion of a proto-oncogene (EWS) and a tumor suppressor gene (WT1) which creates a dominant oncogene. In order to understand the context of these findings, we will first provide brief reviews of the biology and genetics of WT1, EWS, and DSRCT.