Dysregulation of the E-cadherin/catenin complex by irreversible mutations in human carcinomas.
The different proteins of the E-cadherin/catenin cell-cell adhesion complex are believed to play a predominant role in carcinogenesis. Aberrant expression of these proteins has been found in many different human carcinomas, indicating abnormal regulation. In general, inactivating mutations of the human E-cadherin gene are rare; they are, however, highly frequent in infiltrating lobular breast carcinomas and in diffuse gastric carcinomas. These mutations mostly occur in combination with loss of heterozygosity (LOH) of the wild-type allele. Mutations were found at very early non-invasive stages, thus associating E-cadherin mutations with loss of growth control and defining E-cadherin as a real tumour suppressor for these particular tumour types. Defects affecting both alleles of the alpha E-catenin gene have been found in different human carcinoma cell lines, resulting in the loss of E-cadherin-mediated cell-cell adhesion. Mutations of the beta-catenin gene in colon tumours and melanomas were found to result in an accumulation of the protein in the cytosol. Upon translocation to the nucleus, this beta-catenin enhances TCF/LEF-dependent transcriptional activity. This suggests that mutated beta-catenin can act as an oncogene in these particular tumour types. The multiple interaction partners of beta-catenin are known to be involved in signal transduction, actin organization, protein phosphorylation or transcriptional regulation. This makes this protein an intriguing alternative target for either activation or inactivation in human cancer types characterized by frequent E-cadherin or APC deficiencies.
Berx
G
G
Department of Molecular Biology, Molecular Cell Biology Unit, V.I.B.-University of Ghent, Belgium.
Nollet
F
F
van Roy
F
F
D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D009154:Mutation; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators; D051176:beta Catenin
C495270:CTNNB1 protein, human; D015820:Cadherins; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin