A dominant negative mutation of transforming growth factor-β receptor type II gene in microsatellite stable oesophageal carcinoma

Recent investigations revealed microsatellite instability in colon cancers are associated with mutations of the transforming growth factor-β receptor type II gene (TGF-β RII) that encodes a transmembrane protein containing an intracellular serine/threonine kinase domain. Activation of TGF-β receptor type I (RI) and RII by TGF-β 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-β 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-β RII serine/threonine kinase domain. Interestingly, the mutant TGF-β RII E526Q can completely inhibit TGF-β-induction of nuclear translocation of Smad4 protein in oesophageal carcinoma cells. This mutation of TGF-β RII that is not associated with microsatellite instability might make a dominant negative effect on TGF-β signal transduction in oesophageal carcinoma. (C) 2000 Cancer Research Campaign.