Cellular Consequences of Snf5 Tumor Suppressor Loss

描述（由申请人提供）：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。SNF 5的双等位基因失活是SWI/SNF染色质重塑复合物的核心成分，是一种非常有效的促癌事件，发生在绝大多数恶性横纹肌样瘤（MRT）中，这是一种侵袭性儿童癌症。我们的实验室通过消除SNF 5的两个拷贝开发了MRT的小鼠模型。与儿童一样，小鼠中Snf 5的失活导致100%的小鼠在中位年龄11周时恶性癌症的快速发作。我们现在已经开始研究从这些Snf 5缺陷小鼠分离的细胞中SNF 5损失的分子后果。我们最近已经确定了显着的扰动，细胞周期调控，染色体稳定性和细胞凋亡后的损失Snf 5在原代成纤维细胞。此外，我们已经证明了Snf 5的失活导致p53水平的增加，并且p53的失活导致与Snf 5损失的协同作用，从而在体内形成肿瘤。所提出的实验旨在揭示Snf 5影响细胞周期进程的机制基础，确定Snf 5肿瘤抑制活性的遗传途径，并进一步阐明Snf 5和p53肿瘤抑制因子之间的关系。我们建议利用我们的模型系统，结合数据从损失的Snf 5在原代成纤维细胞，从体内缺失的Snf 5的数据，以评估的Snf 5肿瘤抑制因子的功能，并确定其损失如何导致肿瘤发生。阐明Snf 5肿瘤抑制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.