Fhit Function in Human Cancer

描述：（申请人的描述）FHIT基因的一个或两个等位基因 在许多不同类型的人类肿瘤中大部分被破坏。在 具有确定的FHIT DNA改变的肿瘤衍生细胞系和原发性肿瘤， DNA变异、RT-PCR检测变异之间存在相关性， 产品和Fhit蛋白水平的降低。此外，本发明还 肿瘤细胞系中Fhit表达的替代抑制了致瘤性。 这一结果已被另一个实验室最近的研究所证实， 腺病毒/Fhit载体。最近，免疫组织化学研究 宫颈癌、肺癌、胃癌、膀胱癌、胰腺癌和肾癌已经显示 这些原发性肿瘤的大部分表达降低的水平或没有Fhit 蛋白本项目将继续研究Fhit函数， 从D. 以果蝇NitFhit为诱饵的酵母双杂交诱集黑素受体文库 实验候选的相互作用蛋白是：1）C-末端的 蝇类蛋白质，哺乳动物4.1蛋白质同系物; 2）脂肪酸 结合蛋白同源物; 3）蝇多肽，Dcl 5，没有已知的同源物。 这些相互作用将在苍蝇或人类的生化试验中得到证实 系统.每一种相互作用途径将被剖析，以了解其 在Fhit信号中的作用。 与此同时，项目1研究者将参与表征 FHIT/FRA 3B在特定癌细胞中的缺失和排列（ 项目2），并将在 项目3的结构预测。

DESCRIPTION: (Applicant's Description) One or both alleles of the FHIT gene are disrupted in a large fraction of many different types of human tumors. In tumor-derived cell lines and primary tumors with defined FHIT DNA alterations, there is a correlation between DNA alteration, detection of altered RT-PCR products and reduction in the level of Fhit protein. Additionally, replacement of Fhit expression in tumor cell lines suppresses tumorigenicity. This result has been confirmed by recent studies from another laboratory using an adenovirus/Fhit vector. Most recently, immunohistochemical studies of cervical, lung, gastric, bladder, pancreatic and kidney carcinomas have shown that large fractions of these primary tumors express reduced levels or no Fhit protein. This project will continue to study Fhit function by characterizing three possible Fhit, Nit or NitFhit interacting proteins identified from a D. melanogastor library using fly NitFhit as bait in yeast two-hybrid trapping experiments. The candidate interacting proteins are: 1) the c-terminus of the fly coracle protein, a homolog of mammalian 4.1 proteins; 2) a fatty acid binding protein homolog; 3) a fly polypeptide, Dcl5, without known homologs. The interactions will be confirmed in biochemical assays in fly or human systems. Each interaction pathway will then be dissected to understand its role in Fhit signaling. In parallel, Project 1 investigators will participate in characterization of deletions and arrangements of FHIT/FRA3B in specific cancer cells (with Project 2) and will prepare mutant Nit and Fhit proteins in the framework of structural predictions with Project 3.