期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：1999
卷号：96
期号：4
页码：1603-1608
DOI：10.1073/pnas.96.4.1603
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Mutations in the adenomatous polyposis coli or {beta}-catenin gene lead to cytosolic accumulation of {beta}-catenin and, subsequently, to increased transcriptional activity of the {beta}-catenin-T cell-factor/lymphoid-enhancer-factor complex. This process seems to play an essential role in the development of most colorectal carcinomas. To identify genes activated by {beta}-catenin overexpression, we used colorectal cell lines for transfection with the {beta}-catenin gene and searched for genes differentially expressed in the transfectants. There are four genes affected by {beta}-catenin overexpression; three overexpressed genes code for two components of the AP-1 transcription complex, c-jun and fra-1, and for the urokinase-type plasminogen activator receptor (uPAR), whose transcription is activated by AP-1. The direct interaction of the {beta}-catenin-T cell-factor/lymphoid-enhancer-factor complex with the promoter region of c-jun and fra-1 was shown in a gel shift assay. The concomitant increase in {beta}-catenin expression and the amount of uPAR was confirmed in primary colon carcinomas and their liver metastases at both the mRNA and the protein levels. High expression of {beta}-catenin in transfectants, as well as in additionally analyzed colorectal cell lines, was associated with decreased expression of ZO-1, which is involved in epithelial polarization. Thus, accumulation of {beta}-catenin indirectly affects the expression of uPAR in vitro and in vivo. Together with the other alterations, {beta}-catenin accumulation may contribute to the development and progression of colon carcinoma both by dedifferentiation and through proteolytic activity.
