Suppressor of fused gene in Carcinogenesis

致癌过程中融合基因的抑制因子

• 批准号: 7009950
• 负责人: Allen Everett Bale
• 金额: $ 26.18万
• 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/7009950
• 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(申请人提供)：最早在果蝇中发现的发育途径在脊椎动物中是保守的，这些途径的中断与各种人类先天异常有关。胚胎发生后，许多发育基因继续在调节细胞生长和分化方面发挥作用，这些基因的突变可能导致儿童和成人患癌症。 我的实验室显示，在人类中，通过Hedgehog受体“Patted‘(PTCH)突变激活Hedgehog途径会导致Gorlin综合征，这是一种常染色体显性遗传病，以皮肤基底细胞癌、髓母细胞瘤、横纹肌肉瘤和出生缺陷为特征。此外，我们还发现，几乎所有散发性的基底细胞癌和少数其他类型的肿瘤都有激活Hedgehog途径的突变。在小鼠身上激活这条途径会导致与人类Gorlin综合征的表型相似，肿瘤类型完全相同。 在果蝇中，“suppressor offusecf‘(SUFU)途径的下游成员对Hedgehog信号具有抑制作用。与该途径的其他抑制成员类似，脊椎动物中的SUFU同源基因应该具有肿瘤抑制作用。在人类髓母细胞瘤中发现SUFU纯合失活，证实了这一假说。我们的初步数据和来自其他研究人员的数据表明，SUFU也可能在WNT途径的调节中发挥作用。本研究的目的是确定SUFU在由于Hedgehog或WNT途径激活而引起的哺乳动物癌症中的作用。本研究的具体目的是： 1.鉴定SUFU基因敲除小鼠的形态和肿瘤表型， 2.测定苏云金对PTCH基因敲除小鼠表型的修饰作用。 3.建立皮肤可诱导表达SUFU的小鼠模型，检测SUFU过表达对PTCH杂合子小鼠肿瘤的影响。 4.测定苏肤灵对APC杂合子小鼠表型的修饰作用， 5.确定人类SUFU基因的多态性是否改变了基底细胞癌的生物学行为和Gorlin综合征的表型。