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

基本信息

批准号：
7390516
负责人：
Elizabeth Moran
金额：
$ 17.55万
依托单位：
UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7390516
关键词：
11p13 ATP phosphohydrolase Attention Biological Biological Assay Blast Cell Cell Cycle Arrest Cell Differentiation process Cell model Cells Central Nervous System Neoplasms Childhood Chromatin Remodeling Factor Chromosomes, Human, Pair 1 Complement Complex Cultured Cells Development Distal Embryo Epithelium Failure Gene Expression Regulation Genes Germ-Line Mutation Histocompatibility Testing Human Individual Kidney Left Link Localized Malignant - descriptor Malignant Neoplasms Malignant neoplasm of kidney Maps Modeling Nephroblastoma Osteoblasts Pediatric Neoplasm Play Predisposition Proliferating Proteins Range 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 role model transcription factor tumor tumorigenic

项目摘要

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 染色质重塑复合物在基本上所有组织的发育和分化过程中的基因表达调节中发挥重要作用。该复合物由八个或更多相关蛋白组成，是调节激活剂和阻遏物对单个基因的访问机制的一部分。该复合物的几种成分中任何一种的缺乏都与肿瘤易感性有关。 ATP 酶本身的缺乏与多种组织类型的癌变有关。非催化亚基对于复合物的抗增殖作用也至关重要，并且非催化亚基INI1/hSNF5已被认为是人类肿瘤易感基因。 INI1 的种系突变已被鉴定，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。这些肿瘤与复合物在终末分化和分化相关的细胞周期停滞中的重要作用一致。大多数细胞中都表达了完整的非催化亚基，但与 INI1 缺陷相关的特定肿瘤范围表明，在某些组织类型中，单个亚基对于控制分化和增殖可能比在其他组织类型中更重要。该复合物中最大的亚基是 ARID1A 基因的 270kDa 蛋白质产物，作为两个密切相关、独立编码的替代蛋白质之一存在于复合物中。我们最近发现，p270/ARID1A 亚基而不是替代的 ARID1B 亚基的存在定义了一种在终末分化过程中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而耗尽p270的细胞无法经历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。这意味着 p270/ARID1A 的缺陷会增加细胞的致瘤潜力。 p270 缺乏可能增加易感性的癌症类型目前尚不清楚。然而，一些有趣的信息表明，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，肾母细胞是导致儿童肾癌（称为肾母细胞瘤）的细胞。我们的假设是，p270/ARID1A 缺陷在功能上与维尔姆斯肿瘤易感基因 1 (WT1) 的缺失相似，并且 ARID1A 本身是维尔姆斯肿瘤的易感基因。我们正在请求初步支持来探索这一新想法，并期望将其发展到其研究值得 R01 支持的程度。