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(申请人提供)：ATPase驱动的SWI/SNF染色质重塑复合体在基本上所有组织的发育和分化过程中对基因表达的调节起着至关重要的作用。该复合体由八种或更多相关蛋白组成，是调节激活和抑制因子进入单个基因的机制的一部分。该复合体中任何一种成分的缺乏都与肿瘤易感性有关。在几种组织类型中，ATPase本身的缺乏与癌症的发生有关。非催化亚基对于该复合体的抗增殖作用也是必不可少的，并且非催化亚基INI1/hSNF5已经被认为是人类肿瘤易感基因。已经确定了INI1的胚系突变，携带者在儿童时期就容易患上恶性横纹肌样瘤和中枢神经系统肿瘤。这些肿瘤与该复合体在终末分化和分化相关细胞周期停滞中的重要作用是一致的。大多数细胞都表达完整的非催化亚基，但与INI1缺乏相关的肿瘤的特定范围表明，个别亚基在某些组织类型的分化和增殖控制中可能比在其他组织类型中更重要。该复合体中最大的亚基是ARID1A基因的270 kDa蛋白质产物，作为两种可供选择的密切相关的独立编码蛋白质之一存在于复合体中。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个在末端分化过程中具有抗增殖功能的复合体。利用成骨细胞分化细胞培养模型，我们发现，由于适当的siRNA表达而导致p270缺失的细胞不能经历与正常分化相关的细胞周期停滞，即使SWI/SNF复合体在其他方面保持完整。这意味着p270/ARID1A的缺失会增加细胞的致瘤潜能。P270缺乏可能增加易感性的癌症形式目前尚不清楚。然而，一些耐人寻味的信息表明，p270在SWI/SNF复合体中的作用可能对分化的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的细胞，称为肾母细胞瘤。我们的假设是p270/ARID1A的缺失在功能上类似于Wilms‘s肿瘤易感基因1(WT1)的缺失，并且ARID1A本身是Wilms’s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，并期望将其发展到其研究将值得R01支持的程度。