The function of Snf5, an epigenetic tumor suppressor

SNF5基因失活突变导致儿童侵袭性癌症和家族性癌症 易感综合症。作为Swi/Snf ATPase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基因。积累证据 提出了SWI/SNF复合体的扰动可能在糖尿病的发生中起广泛作用的可能性。 多种常见癌症，包括肺癌、乳腺癌和前列腺癌。不同于复杂的 通过染色质的甲基化或乙酰化共价修饰染色质，Swi/SNF复合体不 留下‘印记’，因此它在肿瘤发生中的作用更难检测。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，这 表明Snf5失活后形成了深层次的癌症，证实了Swi/Snf 复合体在调节生长和防止致癌转化方面起着关键作用。由于SnF5是 存在于SWI/SNF复合体的所有变体中，并且它本身是真正的肿瘤抑制物，我们的目标是 评估Snf5的功能并确定其缺失如何导致肿瘤发生。 具体目标： (1)Snf5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)SNF5丢失的细胞后果是什么？这种丢失如何与 已知的肿瘤抑制基因突变？ (3)Snf5的缺失对Swi/Snf复合体的活性有何影响？ 意义：SWI/SNF复合体与多种人类癌症有关。由于SnF5在所有 SWI/SNF复合体的变体和本身是一个真正的肿瘤抑制因子，这些研究-将提供洞察力 这种抑制肿瘤的机制。

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.