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

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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