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A dominant negative mutation of transforming growth factor-beta receptor type II gene in microsatellite stable
1Department of Surgery II, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Abstract:
Recent investigations revealed microsatellite instability in colon cancers are associated with mutations of the transforming growth factor-beta receptor type II gene (TGF-beta RII) that encodes a transmembrane protein containing an intracellular serine/threonine kinase domain. Activation of TGF-beta receptor type I (RI) and RII by TGF-beta induces nuclear translocation of Smad proteins including Smad2 and Smad4 that have been originally identified as tumour suppressor genes. We have previously reported six cases with microsatellite instability in 32 oesophageal carcinomas. In this study, we analysed genetic mutations of TGF-beta RII, Smad2 and Smad4 in these oesophageal carcinoma tissues and established 16 cell lines. No genetic mutation was detected in any tissues or cell lines except one tissue sample of microsatellite stable oesophageal carcinoma, that is, a mis-sense mutation of glutamic acid to glutamine at codon 526 (E526Q) in the TGF-beta RII serine/threonine kinase domain. Interestingly, the mutant TGF-beta RII E526Q can completely inhibit TGF-beta-induction of nuclear translocation of Smad4 protein in oesophageal carcinoma cells. This mutation of TGF-beta RII that is not associated with microsatellite instability might make a dominant negative effect on TGF-beta signal transduction in oesophageal carcinoma.
Insights
A novel mutation in the transforming growth factor-beta receptor type II (TGF-beta RII) gene was found in esophageal carcinoma. This TGF-beta RII mutation inhibits Smad4 protein translocation, impacting TGF-beta signaling.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Microsatellite instability in colon cancer is linked to mutations in the transforming growth factor-beta receptor type II (TGF-beta RII) gene.
- TGF-beta RII mutations affect TGF-beta signaling pathways involving Smad proteins, which are crucial tumor suppressors.
- Previous work identified microsatellite instability in 32 esophageal carcinomas.
Purpose of the Study:
- To investigate genetic mutations in TGF-beta RII, Smad2, and Smad4 in esophageal carcinoma tissues and cell lines.
- To determine the functional impact of any identified TGF-beta RII mutations on TGF-beta signaling.
Main Methods:
- Analysis of genetic mutations in TGF-beta RII, Smad2, and Smad4 genes.
- Utilized 16 esophageal carcinoma cell lines and corresponding tumor tissues.
- Assessed the effect of a specific TGF-beta RII mutation on Smad4 nuclear translocation.
Main Results:
- No mutations were found in microsatellite unstable esophageal carcinomas.
- A single missense mutation (E526Q) in the TGF-beta RII kinase domain was identified in a microsatellite-stable esophageal carcinoma sample.
- The identified TGF-beta RII E526Q mutation potently inhibited TGF-beta-induced nuclear translocation of Smad4.
Conclusions:
- The TGF-beta RII E526Q mutation, independent of microsatellite instability, can exert a dominant-negative effect on TGF-beta signal transduction in esophageal carcinoma.
- This finding suggests a novel mechanism of TGF-beta pathway dysregulation in esophageal cancer.