title: A novel dominant negative Smad2 mutation in a TGFbeta resistant human carcinoma cell line.
abstract: An important biological mechanism contributing to the transformed phenotype of cancer cells is the ability to escape normal growth regulatory signals. In epithelial cells, transforming growth factor beta (TGFbeta) inhibits cell cycle progression in the G1-phase. The abnormal ability of cancer cells to escape TGFbeta-induced cell cycle inhibition may lead to deregulated mitosis, providing a growth advantage to these clones. The effects of TGFbeta are mediated through type I and type II receptors, which are transmembrane proteins possessing cytoplasmic serine/threonine kinase domains for signal propagation. TGFbeta binds to the type II receptor which then phosphorylates the cytoplasmic domain of the type I receptor. The receptor complex recruits and phosphorylates the downstream signaling proteins, Smad2 and Smad3, which then associate with Smad4. The Smad complex translocates to the nucleus to regulate target gene expression resulting in cell cycle inhibition. We have identified a new Smad2 mutation in a TGFbeta-resistant human carcinoma line. The mutant Smad2 protein exhibits decreased association with the receptor complex, is not phosphorylated in response to TGFbeta, fails to associate with Smad4 and does not localize to the nucleus. Expression of the mutant Smad2 protein in a TGFbeta sensitive carcinoma line induces resistance to this growth inhibitory factor and deregulates TGFbeta-responsive gene expression. These results indicate that this novel Smad2 mutant protein has dominant negative activity in cultured cells.
authors.affiliation: Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles 90033, USA.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Tsang
authors.forename: David
authors.initials: D
authors.lastname: Tsang
authors.forename: Tamara N
authors.initials: TN
authors.lastname: Brown
authors.forename: David L
authors.initials: DL
authors.lastname: Crowe
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005091:Exons; D005799:Genes, Dominant; D006801:Humans; D009154:Mutation; D010766:Phosphorylation; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D051899:Smad2 Protein; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology* / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta