The p270 SWI/SNF subunit as a potential Wilms' tumor susceptibility gene

描述（由申请人提供）：ATP酶驱动的SWI/SNF染色质重塑复合物在基本上所有组织发育和分化期间的基因表达调控中发挥重要作用。该复合物由八个或更多相关蛋白质组成，并且是调节激活剂和抑制剂进入单个基因的机制的一部分。该复合物的几种组分中的任何一种的缺乏都与肿瘤易感性有关。ATP酶本身的缺陷与几种组织类型的致癌作用有关。非催化亚基也可能是复合物的抗增殖作用所必需的，并且非催化亚基INI 1/hSNF 5已经被认为是人类肿瘤易感基因。已经确定了INI 1的生殖系突变，携带者在儿童期易患恶性横纹肌样瘤和中枢神经系统肿瘤。这些肿瘤与复合物在终末分化和分化相关细胞周期停滞中的重要作用一致。非催化亚基的完整补充在大多数细胞中表达，但与INI 1缺陷相关的肿瘤的特定范围表明，单个亚基对于控制某些组织类型的分化和增殖可能比其他组织类型更重要。复合物中最大的亚基，ARID 1A基因的270 kDa蛋白产物，作为两种替代的、密切相关的、独立编码的蛋白质之一存在于复合物中。我们最近发现，p270/ARID 1A亚基的存在，而不是替代ARID 1B亚基定义了一个复杂的抗增殖功能在终末分化。使用成骨细胞分化的细胞培养模型，我们发现，细胞耗尽的p270表达的适当的siRNA未能进行正常的分化相关的细胞周期停滞，即使SWI/SNF复合物保持完整，否则。这意味着p270/ARID 1A的缺陷会增加细胞的致瘤潜力。p270缺陷可能增加易感性的癌症形式目前尚不清楚。然而，一些有趣的信息提示，p270在SWI/SNF复合物中的作用可能对分化成肾细胞的增殖调节功能至关重要，成肾细胞是引起小儿肾癌的细胞，称为肾母细胞瘤。我们的假设是，p270/ARID 1A的缺陷在功能上与Wilms肿瘤易感基因1（WT 1）的缺失相似，并且ARID 1A本身就是Wilms肿瘤的易感基因。我们正在请求初步支持，以探索这一新想法，并期望将其发展到值得R 01支持的程度。

DESCRIPTION (provided by applicant): The ATPase-powered SWI/SNF chromatin remodeling complex plays an essential role in the regulation of gene expression during development and differentiation in essentially all tissues. The complex consists of eight or more associated proteins, and is part of the mechanism that regulates activator and repressor access to individual genes. Deficiency of any of several components of the complex is linked with tumor susceptibility. Deficiency of the ATPase itself is linked with carcinogenesis in several tissue types. The noncatalytic subunits can also be essential for the anti-proliferative role of the complex, and the noncatalytic subunit INI1/ hSNF5 is already recognized as a human tumor susceptibility gene. Germ-line mutations in INI1 have been identified, and carriers are pre-disposed in childhood to malignant rhabdoid tumors and tumors of the central nervous system. These tumors are consistent with a vital role for the complex in terminal differentiation and differentiation-associated cell cycle arrest. The full complement of noncatalytic subunits is expressed in most cells, but the specific range of tumors linked with INI1 deficiency suggests that individual subunits may be more important for control of differentiation and proliferation in some tissue types than in others. The largest subunit in the complex, the 270kDa protein product of the ARID1A gene, is present in the complex as one of two alternative, closely related, independently encoded proteins. We have recently found that the presence of the p270/ARID1A subunit instead of the alternative ARID1B subunit defines a complex with an anti-proliferative function during terminal differentiation. Using an osteoblast differentiation cell culture model we found that cells depleted of p270 by expression of an appropriate siRNA fail to undergo normal differentiation-associated cell cycle arrest even though the SWI/SNF complexes remain otherwise intact. This implies that deficiency of p270/ARID1A would increase the tumorigenic potential of cells. The forms of cancer to which deficiency of p270 might increase susceptibility are presently unknown. However, several intriguing lines of information suggest that p270, in its role within the SWI/SNF complex, may be critical to the proliferation-regulating functions of differentiating nephroblasts, the cells that give rise to the pediatric kidney cancer known as Wilms' tumor. Our hypothesis is that deficiency of p270/ARID1A is functionally similar to loss of Wilms' tumor susceptibility gene 1 (WT1), and that ARID1A itself is a susceptibility gene for Wilms' tumor. We are requesting preliminary support to explore this new idea with the expectation of developing it to the point that its study will merit R01 support.