CHILDHOOD CANCER GENE PROGRAM PROJECT

这个计划项目的长期目标是提高认识 儿童癌症的发病机制和病理生理学， 利用在实验室中获得的分子见解来设计新的 评估预后和改善治疗的手段。 这一广泛目标 正在通过五个协调项目进行， 行政、转基因、分子细胞遗传学和分子生物学 诊断核心 在项目1（M.目的是澄清 CDK 4/CDK 6细胞周期蛋白D依赖性激酶的INK 4抑制剂在 儿童癌症的起源 INK 4家族的每个已知成员 阻止细胞通过第一个间隙（细胞周期的G1期）的进展。 细胞周期，但它们对肿瘤发生的贡献仍有待进一步研究。 定义了 项目2（S. Baker）将讨论EWS-ets的作用 嵌合转录因子家族在异常生长和 尤文肉瘤的分化 EWS相互作用蛋白将是 鉴定的细胞类型和易受融合转化的细胞类型 将在转基因小鼠中定义蛋白质。 的工作假设 项目3（J. Downing）是AML 1融合蛋白有助于 白血病通过干扰正常调节的靶基因， AML 1/CBFbeta复合物。 这个角色将通过定义正常 AML 1基因在胚胎和造血细胞中的功能 发展项目4（D。夏皮罗）是为了确定 PAX 3-FKHR癌蛋白通过明显不同的机制 转化成肌细胞导致腺泡状横纹肌肉瘤。 小说 已经开发了体外模型来评估强制的 PAX 3-FKHR表达的肌源性分化。 项目5（A.T.看） 将依靠荧光原位杂交和其它分子生物学技术 确定和表征推定的 染色体1 p上的神经母细胞瘤抑制基因座。 这个五年计划 旨在整合领先的分子生物学家的努力， 全面的核心服务，以回答有关 导致儿童肿瘤形成的机制 其基本概念是 恶性转化涉及多种信号通路， 在我们知道合法的目标之前， 治疗性或预防性干预。

The long-term goal of this program project is to improve understanding of the pathogenesis and pathophysiology of childhood cancers and to capitalize on molecular insights gained in the laboratory to devise new means of assessing prognosis and improving therapy. This broad objective is being pursued through five coordinated projects supported by administrative, transgenic, molecular cytogenetic and molecular diagnostic cores. In Project 1 (M. Roussel) the aim is to clarify the role of INK4 inhibitors of the CDK4/CDK6 cyclin D-dependent kinases in the genesis of childhood cancers. Each known member of the INK4 family arrests the progression of cells through the first gap (G1 phase of the cell cycle, but their contribution to tumorigenesis remains to be defined. Project 2 (S. Baker) will address the role of the EWS-ets family of chimeric transcription factors in the aberrant growth and differentiation of Ewing's sarcoma. EWS interacting proteins will be identified and cell types susceptible to transformation by the fusion protein will be defined in transgenic mice. The working hypothesis of Project 3 (J. Downing) is that AML1 fusion proteins contribute to leukemia by interfering with target genes normally regulated by the AML1/CBFbeta complex. This role will be clarified by defining the normal function of the AML1 gene in embryologic and hematopoietic cell development. The intent of Project 4 (D. Shapiro) is to identify the apparently diverse mechanisms by which the PAX3-FKHR oncoprotein transforms myogenic cells leading to alveolar rhabdomyosarcoma. Novel in vitro models have been developed to assess the effects of enforced PAX3-FKHR expression of myogenic differentiation. Project 5 (A.T. Look) will rely on fluorescence in situ hybridization and other molecular approaches to identify and characterize the properties of a putative neuroblastoma suppressor locus on chromosome 1p. This 5-year program seeks to integrate the efforts of leading molecular biologists with comprehensive core services to answer pivotal questions about the mechanisms that drive childhood neoplasia. Its underlying concept is that malignant transformation involves diverse signaling pathways that must be identified before we will know the legitimate targets for therapeutic or preventive intervention.