SIAH-1: is the mammalian homolog of Drosophila seven in absentia (sina) and has been identified as a p53-inducible gene. Siah-1 can induce cell cycle arrests, tumor suppression, and apoptosis through a novel beta-catenin degradation pathway. To determine whether genetic alterations of Siah-1 gene are involved in the development and/or progression of gastric cancer, we searched for mutation of the Siah-1 gene in 95 gastric cancers by single-strand conformational polymorphism and sequencing. The effect of Siah-1 on beta-catenin degradation was further examined in wild- and mutant-type Siah-1-transfected HEK 293T cells. We found two missense mutations of the Siah-1 gene. The cases with Siah-1 mutation showed nuclear translocation and cytoplasmic staining of beta-catenin. Interestingly, two mutants of Siah-1 stabilized cytoplasmic levels of beta-catenin, even after treatment of adriamycin. Furthermore, both mutants failed to suppress cyclin D1 expression and to induce apoptosis. These data suggest that inactivating mutations of the Siah-1 may contribute to the development of gastric cancer through beta-catenin stabilization and apoptosis block.