Abstract
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 β-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 β-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 β-catenin. Interestingly, two mutants of Siah-1 stabilized cytoplasmic levels of β-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 β-catenin stabilization and apoptosis block.
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Acknowledgements
We thank Dr Su-Jae Lee (Korea Institute of Radiological & Medical Sciences, Korea) for providing the p53 mutant expression vector system. This work was supported by the Korea Science & Engineering Foundation (KOSEF) through the Cell Death Disease Research Center at The Catholic University of Korea (R13-2002-005-01004-0).
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Kim, C., Cho, Y., Park, C. et al. Inactivating mutations of the Siah-1 gene in gastric cancer. Oncogene 23, 8591–8596 (2004). https://doi.org/10.1038/sj.onc.1208113
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DOI: https://doi.org/10.1038/sj.onc.1208113
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