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

描述（由申请人提供）：atpase驱动的SWI/SNF染色质重塑复合体在几乎所有组织的发育和分化过程中对基因表达的调控起着至关重要的作用。该复合物由8个或更多的相关蛋白组成，是调节激活因子和抑制因子进入单个基因的机制的一部分。这种复合物的任何一种成分的缺乏都与肿瘤易感性有关。atp酶本身的缺乏与几种组织类型的癌变有关。非催化亚基也可能对该复合物的抗增殖作用至关重要，非催化亚基INI1/ hSNF5已经被认为是人类肿瘤易感基因。已经确定了INI1的种系突变，并且携带者在儿童时期易患恶性横纹肌瘤和中枢神经系统肿瘤。这些肿瘤与复合体在终末分化和分化相关的细胞周期阻滞中的重要作用是一致的。非催化亚基的完整补体在大多数细胞中表达，但与INI1缺乏相关的肿瘤的特定范围表明，在某些组织类型中，个体亚基可能比其他组织类型更重要地控制分化和增殖。该复合体中最大的亚基，ARID1A基因的270kDa蛋白产物，作为两种密切相关的独立编码蛋白之一存在于该复合体中。我们最近发现p270/ARID1A亚基取代ARID1B亚基的存在定义了在终末分化过程中具有抗增殖功能的复合体。使用成骨细胞分化细胞培养模型，我们发现通过表达适当的siRNA来减少p270的细胞不能经历正常分化相关的细胞周期阻滞，即使SWI/SNF复合物在其他方面保持完整。这表明p270/ARID1A的缺失会增加细胞的致瘤潜能。缺乏p270可能增加易感性的癌症类型目前尚不清楚。然而，一些有趣的信息提示p270在SWI/SNF复合体中的作用可能对分化肾母细胞的增殖调节功能至关重要，肾母细胞是引起儿童肾癌Wilms肿瘤的细胞。我们的假设是p270/ARID1A的缺失在功能上类似于Wilms的肿瘤易感基因1 （WT1）的缺失，并且ARID1A本身就是Wilms肿瘤的易感基因。我们正在请求初步支持，以探索这个新想法，并期望将其发展到值得R01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.