GENES FROM THE FAP LOCUS

结直肠肿瘤通过一系列明确的临床和 组织病理学分期。这一进程伴随着一系列 包括几种肿瘤抑制基因失活在内的基因变化 基因。多项研究表明，一种或多种肿瘤抑制因子 染色体5q21上的基因在结直肠癌的早期阶段是重要的 肿瘤发生学。最近，我们发现了两种候选肿瘤 染色体5q21区的抑癌基因(APC和MCC)。这两个 在结直肠癌中发现APC和MCC基因发生体细胞突变 癌症。此外，还发现APC基因在 几个患有家族性腺瘤性息肉病的家系 (FAP)或Gardner综合征(GS)，两种易患遗传性疾病 结肠癌。 这项提案中概述的研究旨在扩大这些 在以下方面与APC和MCC取得了成果。首先，临床 APC和MCC在结直肠癌中的意义将被确定。 这将包括确定APC和MCC的流行率。 人类大肠肿瘤和个体生殖系中的突变 FAP和GS。其次，MCC和APC的生化性质将 被研究。这将包括生产针对APC和MCC的抗体， APC和MCC蛋白产物的表征及测定 APC和MCC在成体和发育组织中的表达。第三， 将研究APC和MCC的功能特性。这将包括 正常APC和MCC诱导表达效果的测定 大肠肿瘤细胞系中的蛋白质及其作用机制的研究 使用反义技术降低内源性APC和MCC的表达。 以上研究的结合应该会提供重要的见解。 探讨APC和MCC在结直肠肿瘤发生中的作用。

Colorectal tumors progress through a series of well defined clinical and histopathological stages. This progression is accompanied by a series of genetic changes which include inactivation of several tumor suppressor genes. Several studies have suggested that one or more tumor suppressor genes on chromosome 5q2l are important in the early stages of colorectal tumorigenesis. Recently, we have identified two candidate tumor suppressor genes (APC and MCC) from the chromosome 5q2l region. Both the APC and MCC genes were found to be somatically mutated in colorectal cancers. Furthermore, the APC gene was found to be mutated in the germline of several kindreds with either Familial Adenomatous Polyposis (FAP) or Gardner's Syndrome (GS), two inherited diseases which predispose to colon cancer. The studies outlined in this proposal are aimed at extending these results with APC and MCC in the following areas. First, the clinical significance of APC and MCC in colorectal cancer will be determined. This will include the determination of the prevalence of APC and MCC mutations in human colorectal tumors and in the germline of individuals with FAP and GS. Second, the biochemical properties of MCC and APC will be studied. This will include production of antibodies to APC and MCC, characterization of the APC and MCC protein products, and determination of APC and MCC expression in adult and developing tissues. Third, the functional properties of APC and MCC will be studied. This will include determining the effects of inducing expression of normal APC and MCC protein in colorectal tumor cell lines and determining the effects of reducing endogenous APC and MCC expression using anti-sense technology. The combination of the above studies should provide important insights into the role of APC and MCC in colorectal tumorigenesis.