Suppressor of fused gene in Carcinogenesis

致癌过程中融合基因的抑制因子

• 批准号: 6859422
• 负责人: Allen Everett Bale
• 金额: $ 26.81万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-27 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6859422
• 关键词: basal cell carcinoma; biological signal transduction; carcinogenesis; clinical research; fusion gene; gene expression; genetic polymorphism; human subject; laboratory mouse; laboratory rabbit; morphology; phenotype; syndrome; tumor suppressor genes

DESCRIPTION (provided by applicant): Developmental pathways first discovered in the fruit fly, Drosophila melanogaster, are conserved in vertebrates, and disruption of these pathways has been associated with a variety of human congenital anomalies. Many developmental genes continue to play a role in regulation of cell growth and differentiation after embryogenesis, and mutations in these genes can result in cancer in children and adults. My laboratory showed that activation of the hedgehog pathway in humans through mutation in the hedgehog receptor "patched' (PTCH) causes Gorlin syndrome, an autosomal dominant disorder characterized by basal cell carcinomas of the skin, medulloblastomas, rhabdomyosarcomas and birth defects. Furthermore, we showed that virtually all sporadic basal cell carcinomas and a minority of other types of tumors have mutations that activate the hedgehog pathway. Activation of this pathway in the mouse results in a phenotype similar to human Gorlin syndrome with exactly the same tumor types. In Drosophila a downstream member of the pathway "suppressor offusecf' (SUFU) has an inhibitory effect on hedgehog signaling. By analogy to other inhibitory members of this pathway, the vertebrate homolog of SUFU should function as a tumor suppressor. This hypothesis is substantiated by the finding of homozygous inactivation of SUFU in human medulloblastomas. Our preliminary data and data from other investigators suggest that SUFU may also play a role in regulation of the WNT pathway. The purpose of this study is to determine the role of SUFU in mammalian cancers that arise with activation of the hedgehog or WNT pathway. The specific aims of this study are to: 1. Characterize the morphologic and cancer phenotypes of an SUFU knockout mouse, 2. Determine the modifying effect of loss of SUFU on the phenotype of PTCH knockout mice, 3. Develop a mouse with inducible expression of SUFU in skin and determine the effect of SUFU overexpression on tumors in PTCH heterozygous mice, 4. Determine the modifying effect of SUFU on the phenotype of APC heterozygous mice, 5. Determine if polymorphisms in human SUFU modify the biologic behavior of basal cell carcinomas and the Gorlin syndrome phenotype.

描述（由申请人提供）：首先在果蝇（Drosophila melanogaster）中发现的发育途径在脊椎动物中是保守的，这些途径的破坏与各种人类先天性异常有关。许多发育基因在胚胎发生后继续在细胞生长和分化的调节中发挥作用，这些基因的突变可能导致儿童和成人的癌症。 我的实验室表明，通过刺猬受体“补丁”（PTCH）突变激活人类的刺猬通路导致戈林综合征，这是一种常染色体显性遗传疾病，其特征是皮肤基底细胞癌、髓母细胞瘤、横纹肌肉瘤和出生缺陷。此外，我们发现几乎所有散发性基底细胞癌和少数其他类型的肿瘤都有激活hedgehog通路的突变。在小鼠中激活这一途径导致与人类Gorlin综合征相似的表型，具有完全相同的肿瘤类型。 在果蝇中，通路的下游成员“抑制剂”（SUFU）对刺猬信号传导具有抑制作用。通过类推到该途径的其他抑制性成员，脊椎动物同源物SUFU应该起肿瘤抑制剂的作用。这一假说被人髓母细胞瘤中SUFU纯合失活的发现所证实。我们的初步数据和其他研究者的数据表明，SUFU也可能在WNT通路的调节中发挥作用。本研究的目的是确定SUFU在哺乳动物癌症中的作用，这些癌症是由刺猬或WNT通路激活引起的。这项研究的具体目标是： 1.表征SUFU敲除小鼠的形态学和癌症表型， 2.确定SUFU缺失对PTCH敲除小鼠表型的修饰作用， 3.开发皮肤中SUFU可诱导表达的小鼠，并确定SUFU过表达对PTCH杂合子小鼠肿瘤的影响， 4.测定SUFU对APC杂合子小鼠表型的修饰作用， 5.确定人SUFU多态性是否改变基底细胞癌的生物学行为和Gorlin综合征表型