A dominant negative mutation of transforming growth factor-beta 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-beta recept or type II gene (TGF-beta RII) that encodes a transmembrane protein contain ing 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 identifie d as tumour suppressor genes. We have previously reported six cases with mi crosatellite instability in 32 oesophageal carcinomas. In this study, we an alysed genetic mutations of TGF-beta RII, Smad2 and Smad4 in these oesophag eal carcinoma tissues and established 16 cell lines. No genetic mutation wa s detected in any tissues or cell lines except one tissue sample of microsa tellite stable oesophageal carcinoma, that is, a mis-sense mutation of glut amic acid to glutamine at codon 526 (E526Q) in the TGF-beta RII serine/thre onine kinase domain. Interestingly, the mutant TGF-beta RII E526Q can compl etely inhibit TGF-beta-induction of nuclear translocation of Smad4 protein in oesophageal carcinoma cells. This mutation of TGF-beta RII that is not a ssociated with microsatellite instability might make a dominant negative ef fect on TGF-beta signal transduction in oesophageal carcinoma. (C) 2000 Can cer Research Campaign.