Cellular Consequences of Snf5 Tumor Suppressor Loss

描述(申请人提供)：调节生长和分化的基因的异常表达是致癌转化的关键组成部分。SNF5是SWI/SNF染色质重塑复合体的核心成分，它的双等位基因失活是一种极其有效的促癌事件，发生在绝大多数恶性横纹肌瘤(MRT)中，MRT是一种儿童侵袭性癌症。我们实验室通过消除SNF5的两个副本，开发了一种MRT的小鼠模型。与儿童一样，小鼠体内Snf5的失活会导致100%的小鼠在平均年龄为11周时极快地患上恶性肿瘤。我们现在已经开始研究SNF5缺失在从这些SnF5缺陷小鼠分离的细胞中的分子后果。我们最近发现在原代成纤维细胞中丢失Snf5后，细胞周期调节、染色体稳定性和凋亡发生了戏剧性的扰动。此外，我们已经证明了Snf5的失活会导致P53水平的增加，而P53的失活会导致与Snf5的缺失在体内形成肿瘤的协同作用。这些实验旨在揭示Snf5影响细胞周期进程的机制基础，确定Snf5抑癌活性的遗传途径，并进一步阐明Snf5与P53抑癌基因的关系。我们建议利用我们的模型系统，结合来自原代成纤维细胞Snf5缺失的数据和来自体内Snf5缺失的数据，来评估Snf5肿瘤抑制因子的功能，并确定其缺失如何导致肿瘤发生。阐明Snf5抑癌活性的基础可能最终导致新的治疗方法。

DESCRIPTION (provided by applicant): Aberrant expression of genes that regulate growth and differentiation is a critical component of oncogenic transformation. Biallelic inactivation of SNF5, a core component of the SWI/SNF chromatin remodeling complex, is an extremely potent, cancer-promoting event that occurs in the large majority of malignant rhabdoid tumors (MRT), an aggressive cancer of childhood. Our laboratory has developed a mouse model of MRT by eliminating both copies of SNF5. As in children, inactivation of Snf5 in mice leads to the extremely rapid onset of malignant cancers in 100% of mice at a median age of 11 weeks. We have now begun studying the molecular consequences of SNF5 loss in cells isolated from these Snf5 deficient mice. We have recently identified dramatic perturbations of cell cycle regulation, chromosomal stability and apoptosis following loss of Snf5 in primary fibroblasts. Further, we have demonstrated that inactivation of Snf5 leads to increased levels of p53, and that inactivation of p53 results in synergy with Snf5 loss for tumor formation in vivo. The proposed experiments are designed to reveal the mechanistic basis by which Snf5 affects cell cycle progression, determine the genetic pathways that underlie the tumor suppressor activity of Snf5, and to further elucidate the relationship between Snf5 and p53 tumor suppressors. We propose to utilize our model systems, combining data from loss of Snf5 in primary fibroblasts, with data from in vivo deletion of Snf5, to evaluate the function of the Snf5 tumor suppressor and determine how its loss leads to oncogenesis. Elucidating the basis for Snf5 tumor suppressor activity may ultimately lead to novel therapeutic treatments.