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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

在本研究中获得了以下关于Wnt信号和致癌作用的观察结果。(1)APC通过Axin与GSK-3形成复合物，增强GSK-3依赖的β-catenin磷酸化。PR 61的B亚基与Axin结合，增强β-catenin依赖的Tcf-4转录活性。PKA磷酸化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β-连环蛋白稳定性的调节是重要的。(2)Wnt信号通路中新型调节蛋白的鉴定Axam、Shakespex和Duplin分别被鉴定为新型Axin-、Dvl-和β-连环蛋白结合蛋白。所有这些新的蛋白质都负调控Wnt信号，并且它们的敲除小鼠是胚胎致死的，表明这些新的蛋白质在发育过程中是重要的。(3)通过类泛素化Axam调节Wnt信号通路 ...更多信息通过其去小泛素化活性诱导β-连环蛋白降解。用SUMO修饰Tcf-4，SUMO化增强Tcf-4的转录活性。因此，类小泛素化和去类小泛素化对于Wnt信号的调节是重要的。(4)GSK-3结合蛋白的鉴定及其功能AKAP 220和h-prune被鉴定为GSK-3结合蛋白。AKAP 220与PKA结合，参与GSK-3活性的调节。H-prune定位于粘着斑，并通过与GSK-3结合参与细胞迁移。因此，GSK-3决定其活性和功能，取决于结合伴侣。(5)转移相关蛋白的功能用针对上述蛋白的抗体进行的免疫组织化学分析显示，h-prune和Wnt-5a在结肠癌、胰腺癌和恶性黑色素瘤中高度表达。它们的表达水平与肿瘤的侵袭性和淋巴结转移有关。这些抗体可用于诊断肿瘤侵袭性。少