A novel dominant negative Smad2 mutation in a TGFbeta-resistant human carcinoma cell line

This study was conducted to determine if resistance to TGFβ growth inhibition contributes to malignant transformation of oral squamous cell carcinomas. Human squamous cell carcinoma lines was screened for resistance to TGFβ mediated growth inhibition. SCC12 showed TGFβ resistance and a Smad2 mutation with a single base pair deletion in exon 11 of the gene was characterized. The mutant Smad2 protein exhibited decreased association with the TGFβ receptor complex, is not phosphorylated in response to TGFβ, fails to associate with Smad4 and does not localize to the nucleus. Expression of this mutant Smad2 protein in a TGFβ sensitive carcinoma line induced resistance to this growth inhibitory factor and deregulated TGFβ-responsive gene expression. Overexpression of wild type Smad2 did not rescue the TGFβ response suggesting dominant negative activity of the mutant Smad2. The study identified a novel Smad2 mutation that can induce TGFβ resistance in human squamous cell carcinomas.