Inactivating mutations of the Siah-1 gene in gastric cancer.
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.
Kim
Chang Jae
CJ
Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Cho
Yong Gu
YG
Park
Cho Hyun
CH
Jeong
Seong Whan
SW
Nam
Suk Woo
SW
Kim
Su Young
SY
Lee
Sug Hyung
SH
Yoo
Nam Jin
NJ
Lee
Jung Young
JY
Park
Won Sang
WS
D017209:Apoptosis; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D021381:Protein Transport; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015534:Trans-Activators / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D051176:beta Catenin; D000098563:Seven in Absentia Proteins
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D009687:Nuclear Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D019938:Cyclin D1; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins