GENETIC ANALYSIS OF MALIGNANCY

本研究计划的总体目的是分析功能 癌基因和抑癌基因在人类中意义 癌这两类基因在发育过程中经常发生改变。 肿瘤进展，但这些变化的功能意义 对人类癌症的了解很少。具体而言， 显性作用癌基因及其在肿瘤发生中的关键作用 转换来自啮齿动物实验获得的数据 系统.这些说法尚未得到证实，当人类实验 模型系统已被使用。提出了四个主要目标： 1)QM基因的分子特征-高度保守的 多基因家族的成员，是肿瘤的强候选者 抑制基因研究包括蛋白质产物的表征， 其作为转录因子的特性的表征， 与c-jun相互作用及其潜在抑癌基因分析 功能 2)QM基因的转基因小鼠研究。其中包括 人QM过度表达的后果，包括组成型和 组织特异性和靶向敲除小鼠QM基因，从而 产生QM缺陷小鼠。这些研究应该有助于深入了解 QM在发育、分化和癌症中的作用。 3)继续我们的肾母细胞瘤研究我们已经扩大了我们在 体外模型，包括其他真正的肾母细胞瘤细胞系。的 几个候选的肾母细胞瘤TS基因，即WT 1， 将对QM和H19进行检查。此外，我们继续与 与伯纳德·韦斯曼博士一起克隆了定位在染色体上的WT 2基因， 11p15. 4)继续我们的结直肠癌研究。我们将扩大我们的 APC、DCC和p53基因在控制肿瘤细胞凋亡中的功能研究 结直肠癌细胞系的致瘤表型以及 确定恢复野生型的可能功能后果 多个TS基因的表达。我们继续探索有趣的 APC可能调节c-myc表达的可能性及其后果 对细胞增殖的控制。最后，我们发起了 错配修复基因的功能分析，特别是 这些突变的隐性或显负性质以及 在转化和致瘤细胞上恢复野生型活性的结果 表型

The overall purpose of this research program is to analyze the functional significance of oncogenes and tumor suppressor (TS) genes in human cancer. These two classes of gene are frequently altered during neoplastic progression, but the functional significance of these changes for human cancer is poorly understood. In particular, the claims for dominantly-acting oncogenes and their critical role in neoplastic conversion was derived from data obtained from rodent experimental systems. These claims have not been substantiated when human experimental model systems have been utilized. Four major aims are presented: 1) The molecular characterization of the QM gene - a highly conserved member of a multiple gene family which is a strong candidate for a tumor suppressor gene. Studies include characterization of the protein product, characterization of its properties as a transcription factor that interacts with c-jun, and analysis of its potential tumor suppressor function. 2) Transgenic mouse studies of the QM gene. These include the consequences of overexpression of human QM, both constitutively and tissue-specific, and targeted knockout of the mouse QM gene, thereby generating QM-deficient mice. These studies should shed insight into the role of QM in development, differentiation and cancer. 3) Continuation of our Wilms' tumor studies. We have expanded our in vitro models to include other bona fide Wilms' tumor cell lines. The functional roles of several candidate Wilms' tumor TS genes, namely WT1, QM and H19, will be examined. in addition, we continue to collaborate with Dr. Bernard Weissman in cloning the WT2 gene that maps to chromosome 11p15. 4) Continuation of our colorectal cancer studies. We will extend our studies on the functional role of APC, DCC and p53 cDNAs in controlling the tumorigenic phenotype of colorectal carcinoma cell lines as well as determining the possible functional consequences of restoring wild type expression of multiple TS genes. We continue to explore the interesting possibility that APC may regulate c-myc expression and the consequences of that on control of cell proliferation. Finally, we have initiated functional analyses of mismatch repair genes, with specific reference to the recessive or dominant-negative nature of these mutations and the result of restoring wild type activity on the transformed and tumorigenic phenotypes.