Identification of intercellular signal transduction molecules and analysis of their functional abnormality in human cancer

人类癌症细胞间信号转导分子的鉴定及其功能异常分析

基本信息

批准号：
12219214
负责人：
KIKUCHI Akira
金额：
$ 127.62万
依托单位：
HIROSHIMA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2004
项目状态：
已结题

项目摘要

The following observations concerning Wnt signal and carcinogenesis were obtained in this research.(1) Regulation of β-catenin stabilityAPC formed a complex with GSK-3 through Axin and enhanced GSK-3-dependent phosphorylation of β-catenin. The B subunit of PR61 bound to Axin and enhanced β-catenin-dependent Tcf-4 transcriptional activity. PKA phosphorylated β-catenin and inhibited its ubiquitination, thereby stabilizing β-catenin. Therefore, it is clear that phosphorylation events of the molecules in the Axin complex are important for the regulation of β-catenin stability.(2) Identification of novel regulatory proteins in the Wnt signal pathwayAxam, Idax, and Duplin were identified as novel Axin-, Dvl-, and β-catenin-binding proteins, respectively. All of them negatively regulated the Wnt signal, and their knockout mice were embryonic lethal, indicating that these novel proteins were important for developmental process.(3) Regulation of the Wnt signal pathway through sumoylationAxam in … More duced degradation of β-catenin through its desumoylation activity. Tcf-4 was modified with SUMO and sumoylation enhanced the transcriptional activity of Tcf-4. Therefore, sumoylation and desumoylation are important for the regulation of the Wnt signal.(4) Identification of GSK-3-binding proteins and their functionsAKAP220 and h-prune were identified as GSK-3 binding proteins. AKAP220 bound to PKA and was involved in the regulation of GSK-3 activity. H-prune was localized to focal adhesions and involved in cell migration through the binding to GSK-3. Therefore, GSK-3 determines its activity and functions, dependent on the binding partners.(5) Functions of metastatic related proteinsImunohistochemical analyses with the antibodies against the proteins described above revealed that h-prune and Wnt-5a are highly expressed in colon cancer, pancreatic cancer, and malignant melanoma. Their expression levels were correlated with the degree of the invasiveness of tumors and lymph node metastasis. These antibody may be useful for diagnosis for tumor aggressiveness. Less

在这项研究中获得了以下有关Wnt信号和致癌作用的观察结果。（1）调节β-catenin stematieAPC与GSK-3通过AXIN形成了复合物，并增强了GSK-3依赖性β-catenin的磷酸化。 PR61的B亚基与Axin结合并增强β-catenin依赖性TCF-4转录活性。 PKA磷酸化的β-catenin并抑制其泛素化，从而稳定β-catenin。因此，很明显，Axin复合物中分子的磷酸化事件对于调节β-catenin稳定性很重要。（2）鉴定Wnt信号途径，IDAX和DUPLIN中新型调节蛋白的鉴定被鉴定为新型Axin-，DVL-，DVL-，DVL-和β-catenin结合蛋白。所有这些都对Wnt信号进行了负调节，其敲除小鼠都是胚胎致死的，表明这些新型蛋白质对于发育过程很重要。（3）通过Sumoylationaxam在…中通过其降解性降解β-catenin的降解中Wnt信号途径的调节。用SUMO和Sumoylation修改TCF-4增强了TCF-4的转录活性。因此，sumoylation和desumoylation对于调节Wnt信号很重要。（4）鉴定GSK-3结合蛋白及其功能AKAP220和H-Prune被鉴定为GSK-3结合蛋白。 AKAP220与PKA结合，并参与了GSK-3活性的调节。 H-Prune局部定位于局灶性粘合剂，并通过与GSK-3结合而参与细胞迁移。因此，GSK-3决定了其活性和功能，取决于结合伴侣。（5）与上述蛋白质的抗体进行转移性相关蛋白含量组织化学分析的功能，表明H-Prune和Wnt-5a在结肠癌，pancreatic癌，pancreatic癌和恶性糖浆中高度表达在结肠癌中高度表达。它们的表达水平与肿瘤和淋巴结转移的侵入性程度相关。这些抗体对于肿瘤侵袭性的诊断可能很有用。较少的