The function of Snf5, an epigenetic tumor suppressor

SNF 5基因失活突变导致儿童侵袭性癌症和家族性癌症 易感综合征作为Swi/Snf ATP酶染色质重塑复合物的核心成员，Snf 5 (lni1/Baf 47/SmarcB 1）是一种新发现的肿瘤抑制基因。越来越多的证据 提出的可能性，扰动的Swi/Snf复合物可能有一个广泛的作用，在成因 许多类型的常见癌症，包括肺癌、乳腺癌和前列腺癌。不像那些 虽然Swi/Snf复合物通过染色质的甲基化或乙酰化共价修饰染色质，但Swi/Snf复合物不 因此它在肿瘤发生中作用更难检测。然而，最近的研究表明， Swi/Snf亚基对特定癌症的失活以及小鼠模型实验， 证实了Snf 5失活后的深刻的癌症形成，已经确定Swi/Snf 复合体在调节生长和预防致癌转化方面发挥着关键作用。由于SnF 5是 存在于Swi/Snf复合物的所有变体中，并且它本身是真正的肿瘤抑制因子，我们的目标是 评估Snf 5的功能并确定其缺失如何导致肿瘤发生。 具体目标： (1)Snf 5在T细胞分化中的作用是什么？为什么它的缺失会导致T细胞淋巴瘤？ (2)Snf 5缺失的细胞后果是什么，这种缺失如何与细胞因子相互作用。 已知肿瘤抑制基因的突变 (3)Snf 5的丢失对Swi/Snf复合物的活性有什么影响？ 意义：Swi/Snf复合物与多种人类癌症有关。由于SnF 5存在于所有 Swi/Snf复合物的变体，本身就是一种真正的肿瘤抑制因子，这些研究将提供深入了解 肿瘤抑制的机制。

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.