Mutational activation of the beta-catenin proto-oncogene is a common event in the development of Wilms' tumors.
Activation of beta-catenin-mediated transcription is the nuclear end point of organ-specific Wnt signaling. In the developing kidney, Wnt-4, a secreted glycoprotein, acts as an autoinducer of the mesenchymal to epithelial transition that underlies normal nephron development. Dysregulation of this epithelial transformation process may lead to Wilms' tumors (WTs). In this study, we investigated the potential role of the beta-catenin proto-oncogene, a candidate downstream target molecule of Wnt-4 signaling, in the development of WTs. In 6 of 40 tumors (15%), mutation analysis revealed heterozygous missense mutations or small deletions that result in the loss of important regulatory phosphorylation sites within the beta-catenin protein. These findings indicate that activating beta-catenin mutations may play a significant role in the development of WTs and establish a direct link between Wilms' tumorigenesis and the Wnt signal transduction pathway governing normal kidney development.
Koesters
R
R
Department of Surgery, University of Heidelberg, Germany. R.Koesters@DKFZ-Heidelberg.de
Ridder
R
R
Kopp-Schneider
A
A
Betts
D
D
Adams
V
V
Niggli
F
F
Briner
J
J
von Knebel Doeberitz
M
M
D003598:Cytoskeletal Proteins / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D016162:Genes, Wilms Tumor; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D015534:Trans-Activators; D009396:Wilms Tumor / Q000235:genetics* / Q000473:pathology; D051153:Wnt Proteins; D060528:Wnt4 Protein; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; C555581:WNT4 protein, human; D051153:Wnt Proteins; D060528:Wnt4 Protein; D051176:beta Catenin