The function of Snf5, an epigenetic tumor suppressor

描述（由申请人提供）：SNF5基因失活突变导致儿童侵袭性癌症和家族性癌症易感性综合征。作为Swi/Snf atp酶染色质重塑复合体的核心成员，Snf5 （lni1/Baf47/SmarcB1）是一种新发现的肿瘤抑制因子。越来越多的证据表明，Swi/Snf复合物的扰动可能在包括肺癌、乳腺癌和前列腺癌在内的多种常见癌症的发生中起着广泛的作用。与通过染色质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”，因此其在肿瘤发生中的作用更难检测。然而，最近的研究将Swi/Snf亚基的失活与特定的癌症以及小鼠模型实验联系起来，这些实验表明Snf5失活后癌症的形成是深刻的，已经确定Swi/Snf复合物在调节生长和防止致癌转化中起着关键作用。由于Snf5存在于Swi/Snf复合物的所有变体中，而且它本身是一种真正的肿瘤抑制因子，我们的目标是评估Snf5的功能，并确定它的缺失是如何导致肿瘤发生的。具体目的：(1)Snf5在T细胞分化中的作用是什么？为什么Snf5缺失会导致T细胞淋巴瘤？(2) Snf5缺失的细胞后果是什么？这种缺失如何与已知肿瘤抑制基因的突变相互作用？(3) Snf5的损失对Swi/Snf复合物活性的影响是什么？意义：Swi/Snf复合物与多种人类癌症有关。由于Snf5存在于Swi/Snf复合物的所有变体中，并且本身是一种真正的肿瘤抑制因子，因此这些研究将有助于深入了解这种肿瘤抑制机制。

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.