ROLE OF TUMOR SUPPRESSOR GENE IN CHEMICALS CARCINOGENESI

我们实验室的目标是了解癌基因的作用， 肿瘤抑制基因在肿瘤发生、发展和进展中的作用 肿瘤形成 为了达到这个目标，我们使用化学诱导的啮齿动物肿瘤 模型系统 新生期暴露诱发大鼠乳腺和肾脏肿瘤 到N-亚硝基N '甲基脲（NMU），发现含有点突变的H-和 K-ras癌基因。 定义了两个步骤：1）ras启动肿瘤 激活乳腺和肾脏; 2）促进乳腺 激素引起的肿瘤 为了研究参与的其他遗传变化， NMU的肿瘤发生，我们建议研究肾母细胞瘤的作用， 抑癌基因（WT 1）在肾肿瘤发生中的作用。 大鼠 肾肿瘤类似于人肾母细胞瘤，由侵袭性 间叶细胞瘤和肾母细胞瘤起源于 胚胎后肾间充质 WT 1基因通常缺失或突变 在人类肾脏肿瘤中。 为了研究相似的分子机制 在大鼠和人类肿瘤中起作用，我们克隆了全长大鼠WT 1 cDNA。 我们最近发现，WT 1 mRNA表达的峰值在大肠杆菌中， 大鼠在一周龄时发生，与以下时间一致： 大鼠对NMU介导的肾肿瘤发展最敏感。 我们发现，肿瘤中WT 1的mRNA水平异常高， 与成人肾脏相比，肾脏肿瘤，表明基因丢失 调节肿瘤。 因此，肾脏肿瘤显示出巨大的希望， 肾母细胞瘤分子生物学基础研究模型 人类的发展。 根据我们初步调查的线索 结果，我们将1）寻找通过缺失和/或突变的改变， WT 1基因及其5'调控区，2）决定是否 肿瘤中WT 1蛋白的表达改变，3）研究肿瘤中WT 1蛋白的表达是否改变。 正常WT 1基因具有抑癌功能; 4）确定WT 1基因是否具有抑癌功能 有助于体外细胞的肿瘤转化。

The objective of our laboratory is to understand the role of oncogenes and tumor suppressor genes in the inception, development and progression of neoplasia. Towards this goal, we are using chemically-induced rodent tumor model systems. Rat mammary and kidney tumors induced by neonatal exposure to N-nitroso N'methylurea (NMU) were found to contain point mutated H-and K-ras oncogenes. Two steps were defined 1) tumor initiation by ras activation in both mammary gland and kidney and 2) promotion of mammary tumorigenesis by hormones. In an effort to investigate additional genetic changes involved in tumorigenesis by NMU, we propose to study the role of the Wilms' tumor suppressor gene (WT1) in the development of kidney neoplasms. The rat kidney tumors resemble human Wilms' tumors, consisting of aggressive mesenchymal tumors and nephroblastomas that originate from the cells of the embryonal metanephric mesenchyme. The WT1 gene is often deleted or mutated in the human kidney tumors. To study whether similar molecular mechanisms are at play in the rat and human tumors, we cloned the full length rat WT1 cDNA. We have recently discovered that the peak of WT1 mRNA expression in the rat occurs at one week of age, coinciding with the time during which the rats are most susceptible to NMU-mediated development of kidney tumors. We found that mRNA levels of WT1 in the tumors are abnormally high in the kidney tumors compared to the adult kidney, suggesting a loss of gene regulation in the tumors. Thus, the kidney tumors show great promise as a model for studying the molecular and biological basis of Wilms' tumor development in human. Pursuing the leads offered by our preliminary results, we will 1) look for alterations by deletion and/or mutation in the WT1 gene as well as its 5' regulatory region, 2) determine whether the expression of WT1 protein is altered in the tumors, 3) study whether the normal WT1 gene has tumor suppressor functions and 4) determine whether WT1 contributes to neoplastic transformation of cells in vitro.