GENETIC ANALYSIS OF MALIGNANCY

本研究计划的总体目的是分析功能 癌基因和肿瘤抑制基因在人类中的意义 癌症。这两类基因在体内经常发生变化。 肿瘤进展，但这些变化的功能意义 对于人类癌症，人们知之甚少。特别是，关于 显性作用癌基因及其在肿瘤中的关键作用 换算是从啮齿动物实验获得的数据得出的 系统。这些说法还没有得到证实，当人类实验 已经利用了模型系统。提出了四个主要目标： 1)高度保守的qm基因的分子特征 多基因家族的成员，该家族是肿瘤的有力候选者 抑制子基因。研究包括对蛋白质产品的表征， 鉴定其作为转录因子的特性 与c-jun的相互作用及其潜在的肿瘤抑制因子分析 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，无论是结构性的还是 小鼠QM基因的组织特异性和靶向性敲除，从而 产生QM缺陷小鼠。这些研究应该会让我们深入了解 QM在发育、分化和癌症中的作用。 3)继续我们的Wilms肿瘤研究。我们扩大了我们的业务范围 包括其他真正的Wilms肿瘤细胞系的体外模型。这个 几个Wilms肿瘤候选TS基因WT1的功能作用 QM和H19，将进行检查。此外，我们还将继续合作 与Bernard Weissman博士一起克隆映射到染色体的WT2基因 11p15。 4)继续我们对结直肠癌的研究。我们将延长我们的 APC、DCC和P53基因在调控中的功能研究 结直肠癌细胞系及其致瘤表型的研究 确定恢复野生型可能的功能后果 多种TS基因的表达。我们继续探索有趣的 APC调控c-myc表达的可能性及其后果 关于控制细胞增殖的问题。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性-负性 恢复野生型对转化和致瘤作用的结果 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.