Role of hsnf5/BAF47 Loss in Human Cancer Development

肿瘤抑制基因的识别使人们对人类癌症的机制有了新的认识 发展。这些基因的正常功能往往在于对基因表达的控制，尤其是在 细胞周期控制和细胞分化的领域。最近的几项研究表明， 染色质重塑复合体在人类癌症发生发展中的活性。基因突变 INI1/SNF5/BAF47基因是SWI/SNF染色质重塑复合体的一个组成部分，几乎在所有 恶性横纹肌肉瘤(MRT)。SWI/SNF复合体作为全球转录激活因子发挥作用 通过能量依赖机制改变核小体在DNA上的定位。在之前的资助期间 期间，我们已经确定SNF5表达的缺失会影响细胞周期调节和复制 通过改变P21WAF1/CIP1和p16INK4A的表达来实现衰老。然而，我们也发现， SNF5没有在全球范围内灭活MRT中的DNA损伤检查点。我们还从基因上开发了一种 用于MRT开发的工程化小鼠模型，表明SNF5丢失不会使 PRB家族在捷运发展中的活动。我们的研究还表明，MRT可能源于 神经前体细胞群。基于这些研究，我们假设SNF5控制正常 通过将特定的转录因子招募到特定细胞周期的启动子来阻止细胞周期 调控基因。我们进一步假设SNF5表达的丧失及其伴随的 在神经细胞发育的狭窄窗口期间扰乱正常生长调节促进 横纹肌样肿瘤的发生。为了验证这一假设，我们提出了三个具体目标。首先，我们将调查 用RT-PCR芯片研究SNF5诱导MRT细胞生长停滞的机制 模特。第二个具体目标是确定与捷运发展相关的SNF5下游目标 使用ChlP-chjp和基因表达阵列分析的组合。在第三个具体目标中，我们将 确定Snf5失活在神经细胞发育和恶性横纹肌样肿瘤发生中的作用 使用新的基因工程小鼠模型。SNF5在捷运中的作用剖析 发展将拓宽我们对其正常生物和生化活动的认识，提供新的 SWI/SNF复合体在细胞周期调控和正常发育中的作用 寻找治疗这种高度侵袭性肿瘤的新途径。

The identification of tumor suppressor genes has led to new insights into the mechanisms of human cancer development. The normal functions of these genes often lie in the control of gene expression, especially in the realm of cell cycle control and cellular differentiation. Several recent studies have implicated aberrant activity of chromatin remodeling complexes in the development of human cancer. Mutations in the INI1/SNF5/BAF47 gene, a component of the SWI/SNF chromatin remodeling complex, occur in virtually all malignant rhabdoid tumors (MRTs). The SWI/SNF complex acts as a global transcriptional activator that alters nucleosome positioning on DMAvia an energy-dependent mechanism. During the previous funding period, we have determined that loss of SNF5 expression affects cell cycle regulation and replicative senescence through changes in P21WAF1/CIP1 and p16INK4A expression. However, we also found the loss of SNF5 did not globally inactivate DNA damage checkpoints in MRTs. We also developed a genetically engineered mouse model for MRT development that indicates that SNF5 loss does not inactivate the activities of the pRb family in MRT development. Our studies also suggest that MRTs may arise from a population of neural progenitor cells. Based on these studies, we hypothesize that SNF5 controls normal cell cycle arrest by recruitment of specific transcription factors to the promoters of specific cell cycle regulatory genes. Wefurther hypothesize that loss of SNF5 expression and the concomitant disruptjon of normal growth regulation during a narrow window of neural cell development promotes rhabdoid oncogenesis. To test this hypothesis, we propose 3 specific aims. In the first, we will investigate the mechanism of SNF5-induced growth arrest in MRT cell lines using RT-PCR arrays in our cell culture model. The second specific aim will identify downstream targets of SNF5 associated with MRT development using a combination of ChlP-chjp and gene expression array analyses. In the third specific aim, we will determine the role of Snf5 inactivation in neural cell development and malignant rhabdoid tumorigenesis using novel genetically engineered mouse models. The dissection of the role SNF5 plays in MRT development will broaden our understanding of its normal biological and biochemical activities, provide new insights into the function of the SWI/SNF complex in cell cycle regulation and normal development and identify new avenues of treatment for this highly aggressive tumor.