ROLE OF THE FHIT LOCUS IN ENVIRONMENTAL CARCINOGENESIS

在肿瘤和癌细胞系中，在基因组最脆弱的位点3p14.2的FHIT中发现了频繁的纯合和复合杂合缺失。Fhit蛋白是嘌呤核苷酸结合蛋白新家族的典型成员，在肿瘤和癌细胞系中由于缺失而减少或无法检测到。在缺乏内源性FHIT的肺癌、肾癌和胃癌细胞系中表达外源性FHIT可抑制裸鼠肿瘤的形成。因此，Fhit是一种潜在的肿瘤抑制因子，适用于已知涉及环境因素的大部分多部位癌症。本项目将通过三个项目调查FHIT在癌症中的作用，由核心A和B进行给药和核酸分析。Kay Huebner，项目1的项目主任和负责人，将研究Fhit蛋白的功能，重点是相互作用蛋白的表征，为了解其在癌症中的作用提供基础。由Carlo Croce领导的项目2将使用包含主要脆弱区域的FHIT基因序列来确定癌症衍生细胞系中精确的缺失终点，以阐明脆弱部位相对于环境因素的断裂机制，并使用该信息来诊断早期病变的断点。项目3的负责人Charles Brenner将研究最近发现的NitFhit蛋白，这是一种nitrrile - fhit开放阅读框的组合，以寻找NitFhit信号通路功能的线索。他将确定NitFhit晶体结构，使用Nit负酵母细胞捕获Nit底物并寻找Nit功能的抑制剂。核心A和核心B将提供行政支持和核酸分析，这是三个互动项目中必不可少的。因此，这个重点突出的多学科项目在FHIT中看到了解决一些最紧迫的癌症问题的机会：基因重排及其与易感性的关系；以及导致肿瘤的信号通路的分子和细胞功能。

DESCRIPTION (Applicant's Description) Frequent homozygous and compound heterozygous deletions in FHIT at 3p14.2, the genome's most fragile site, are found in tumors and cancer cell lines. Fhit protein, the prototypical member of a new family of purine nucleotide-binding proteins, is reduced or undetectable in tumors and cancer cell lines with deletions. Expression of exogenous FHIT in lung, kidney and gastric cancer cell lines lacking endogenous FHIT suppresses tumor formation in nude mice. Thus, Fhit is a potential tumor suppressor for a large fraction of cancers of multiple sites known to involve environmental factors. This Program will investigate the involvement of FHIT in cancer with three Projects, aided by Cores A and B for Administration and Nucleic Acid analysis. Kay Huebner, Program Director and leader of Project 1, will study the function of the Fhit protein, with an emphasis on characterization of interacting proteins, to provide a basis for understanding its role in cancer. Project 2, led by Carlo Croce, will use the sequence of the FHIT gene encompassing the major fragile region to determine precise deletion endpoints in cancer-derived cell lines to clarify mechanisms of breakage at the fragile sites vis a vis environmental factors, and use this information to diagnose breakpoints in early lesions. Charles Brenner, leader of Project 3, will study the recently discovered NitFhit protein, a combined nitrilase-Fhit open reading frame, for clues to function of the NitFhit signaling pathway. He will determine NitFhit crystal structure, use Nit minus yeast cells to trap the Nit substrate and seek inhibitors of Nit function. Cores A and B will provide administration support and nucleic acid analysis which is essential in the three interactive projects. Thus, this focused, yet multidisciplinary Project sees in FHIT opportunities to grapple with some of the most pressing problems of cancer: genetic rearrangement and its relationship to susceptibility; and the molecular and cellular functions of signaling pathways that lead to tumors.