The function of Snf5, an epigenetic tumor suppressor

表观遗传肿瘤抑制因子 Snf5 的功能

• 批准号: 7086815
• 负责人: CHARLES ROBERTS
• 金额: $ 32.93万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7086815
• 关键词: T cell receptor; carcinogenesis; cell differentiation; cytotoxic T lymphocyte; flow cytometry; gene expression; genetically modified animals; helper T lymphocyte; laboratory mouse; lymphoma; neoplasm /cancer genetics; polymerase chain reaction; tumor suppressor genes

DESCRIPTION (provided by applicant): Inactivating mutations in the SNF5 gene result in aggressive cancers in children and a familial cancer predisposition syndrome. As a core member of the Swi/Snf ATPase chromatin-remodeling complex, Snf5 (lni1/Baf47/SmarcB1) represents a newly recognized type of tumor suppressor. Accumulating evidence raises the possibility that perturbation of the Swi/Snf complex may have a widespread role in the genesis of numerous types of common cancers including those of lung, breast and prostate. Unlike complexes that covalently modify chromatin through methylation or acetylation of chromatin, the Swi/Snf complex does not leave a 'mark' and thus its role in oncogenesis is more difficult to detect. However, recent studies linking inactivation of Swi/Snf subunits to specific cancers as well as mouse modeling experiments, which demonstrate profound cancer formation following inactivation of Snf5, have established that the Swi/Snf complex serves a critical role in regulating growth and preventing oncogenic transformation. Since Snf5 is present in all variants of the Swi/Snf complex and it itself a bona fide tumor suppressor, our goal is to evaluate the function of Snf5 and determine how its loss leads to oncogenesis. Specific Aims: (1) What is the role of Snf5 in T cell differentiation and why does its loss lead to T cell lymphoma? (2) What are the cellular consequences of Snf5 loss and how does this loss interact with mutations in known tumor suppressor genes? (3) What are the effects of Snf5 loss upon the activity of the Swi/Snf complex? Significance: The Swi/Snf complex is implicated in a variety of human cancers. Since Snf5 is present in all variants of the Swi/Snf complex and is itself a bona fide tumor suppressor, these studies will provide insight into this mechanism of tumor suppression.

描述（由申请人提供）：SNF5基因的灭活突变导致儿童的侵略性癌症和家族性癌症易感综合征。作为SWI/SNF ATPase染色质复合物复合物的核心成员，SNF5（LNI1/BAF47/SMARCB1）代表了一种新认识的肿瘤抑制类型。积累的证据增加了SWI/SNF复合物的扰动可能在包括肺，乳腺癌和前列腺的多种类型的常见癌症的起源中具有广泛作用的可能性。与通过染色质的甲基化或乙酰化共价修饰染色质的复合物不同，SWI/SNF复合物不会留下“标记”，因此更难检测其在肿瘤发生中的作用。但是，将SWI/SNF亚基灭活与特定癌症的失活以及小鼠建模实验的最新研究表明，在SNF5失活后，癌症形成了深刻的癌症形成，已经确定SWI/SNF复合物在调节生长和防止癌症转化方面发挥着关键作用。由于SNF5存在于SWI/SNF复合物的所有变体中，并且本身是真正的肿瘤抑制剂，因此我们的目标是评估SNF5的功能并确定其损失如何导致肿瘤发生。具体目的：（1）SNF5在T细胞分化中的作用是什么，为什么其损失会导致T细胞淋巴瘤？ （2）SNF5丢失的细胞后果是什么？这种损失与已知肿瘤抑制基因的突变有何相互作用？ （3）SNF5损失对SWI/SNF复合物的活性有什么影响？意义：SWI/SNF复合体与各种人类癌症有关。由于SNF5存在于SWI/SNF复合物的所有变体中，并且本身就是真正的肿瘤抑制剂，因此这些研究将提供对这种抑制肿瘤机制的见解。