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

p270 SWI/SNF 亚基作为潜在的维尔姆斯肿瘤易感基因

• 批准号: 7637741
• 负责人: Elizabeth Moran
• 金额: $ 21.06万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7637741
• 关键词: 11p13; ATP phosphohydrolase; Attention; Biological; Biological Assay; Blast Cell; Cell Culture Techniques; Cell Cycle Arrest; Cell model; Cells; Central Nervous System Neoplasms; Childhood; Chromatin Remodeling Factor; Chromosomes, Human, Pair 1; Complement; Complex; Development; Distal; Embryo; Epithelium; Failure; Gene Expression Regulation; Genes; Germ-Line Mutation; Histocompatibility Testing; Human; Individual; Kidney; Left; Link; Malignant - descriptor; Malignant Neoplasms; Maps; Modeling; Nephroblastoma; Osteoblasts; Pediatric Neoplasm; Play; Predisposition; Proliferating; Proteins; Rattus; Renal Tissue; Renal carcinoma; Rhabdoid Tumor; Role; SMARCB1 gene; Small Interfering RNA; Staging; Susceptibility Gene; Testing; Tissue Sample; Tissues; Tumor Suppression; Tumor Tissue; Upper arm; Wilms Tumor Genes; Zinc Fingers; cancer type; carcinogenesis; cell type; expectation; integrase interactor 1; kidney cell; osteoblast differentiation; role model; transcription factor; tumor; tumorigenic

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.

描述（由申请人提供）：ATPase驱动的SWI/SNF染色质重塑络合物在基本所有组织的发育和分化过程中的基因表达和分化过程中起着至关重要的作用。该复合物由八种或多种相关的蛋白质组成，是调节激活因子和阻遏物访问各个基因的机制的一部分。该络合物的几个组成部分中的任何一个都与肿瘤敏感性有关。 ATPase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复合物的抗增殖作用至关重要，而非催化亚基INI1/ HSNF5已经被认为是人类肿瘤易感基因。已经鉴定出INI1中的种系突变，并且在儿童期预先将载体预先鉴定为中枢神经系统的恶性胸腺肿瘤和肿瘤。这些肿瘤与该复合物在末端分化和与分化相关的细胞周期停滞中的重要作用一致。非催化亚基的完整补体在大多数细胞中表达，但是与INI1缺乏症相关的特定肿瘤表明，与某些组织类型的分化和增殖相比，单个亚基可能更重要。复合物中最大的亚基是ARID1A基因的270KDA蛋白产物，作为两个替代性，密切相关，独立编码的蛋白质之一。我们最近发现，P270/ARID1A亚基的存在，而不是替代ARID1B亚基在末端分化过程中定义具有抗增殖功能的复合物。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耗尽p270的细胞未能经历正常分化相关的细胞周期停滞，即使SWI/SNF复合物仍然完好无损。这意味着p270/arid1a的缺乏会增加细胞的致瘤潜力。目前尚不清楚p270缺乏症的癌症形式。然而，几条有趣的信息线表明，p270在SWI/SNF复合物中的作用可能对分化肾细胞的增殖调节功能至关重要，肾细胞的细胞会导致所谓的小儿肾癌被称为Wilms肿瘤。我们的假设是，p270/arid1a的缺乏在功能上类似于Wilms肿瘤易感性基因1（WT1）的丧失，并且ARID1A本身是Wilms肿瘤的易感基因。我们要求初步支持以探索这一新想法，并希望开发它，以至于其研究值得R01支持。