Target genes of beta-catenin-T cell-factor/lymphoid-enhancer-factor signaling in human colorectal carcinomas.
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.
Mann
B
B
Department of Surgery, Universitätsklinikum Benjamin Franklin, Freie Universität Berlin, 12200 Berlin, Germany. mann@ukbf.fu-berlin.de
Gelos
M
M
Siedow
A
A
Hanski
M L
ML
Gratchev
A
A
Ilyas
M
M
Bodmer
W F
WF
Moyer
M P
MP
Riecken
E O
EO
Buhr
H J
HJ
Hanski
C
C
D000230:Adenocarcinoma; D015820:Cadherins / Q000502:physiology; D002460:Cell Line; D016764:Cell Polarity; D003106:Colon / Q000473:pathology; D003110:Colonic Neoplasms; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D016758:Genes, jun; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics; D008954:Models, Biological; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D009367:Neoplasm Staging; D010750:Phosphoproteins / Q000235:genetics; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics*; D055293:Receptors, Urokinase Plasminogen Activator; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D062826:Zonula Occludens-1 Protein; D051176:beta Catenin; D000099169:Fos-Related Antigen 1