Aberrant signaling of TGF-beta1 by the mutant Smad4 in gastric cancer cells.
TGF-beta1 has been known to suppress the growth of gastric cancer cells. Interestingly, TGF-beta1 treatment increased the proliferation of human gastric cancer cell line, SNU-216 cells, while it reduced the proliferation of other tumor cells including SNU-620 cells. TGF-beta1-mediated down-regulation of c-Myc and induction of p21CIP1 were observed in SNU-620, but there was no change in SNU-216 in response to TGF-beta1. Similarly, TGF-beta1 receptors were upregulated by TGF-beta1 treatment in SNU-620, but they were not responded in SNU-216. By a single strand conformation polymorphism analysis, a repeated insertion of 37 nucleotides in the exon 8 of Smad4, resulting in premature termination at codon 362, was found in SNU-216. Furthermore, this truncated Smad4 functioned as a dominant negative form in TGF-beta1-mediated reporter activity and TGF-beta1 receptor expression. However, the proliferation of tumor cells was not affected by Smad4 mutation, but it was modulated by PD98059. Taken together, a mutation in Smad4 in addition to mitogen-activated protein kinase altered the TGF-beta1-mediated signaling, which is one of key events of gastric tumorigenesis.
Ju
Hyang Ran
HR
Laboratory of Immunology, Korea Research Institute of Bioscience and Biotechnology, Eoun-Dong 52, Yusong, Taejon 305-333, South Korea.
Jung
Uhee
U
Sonn
Chung Hee
CH
Yoon
Suk Ran
SR
Jeon
Jun Ho
JH
Yang
Young
Y
Lee
Kee Nyung
KN
Choi
Inpyo
I
D004268:DNA-Binding Proteins / Q000235:genetics*; D006801:Humans; D009154:Mutation; D018807:Polymorphism, Single-Stranded Conformational; D015398:Signal Transduction; D051901:Smad4 Protein; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; C497796:SMAD4 protein, human; D051901:Smad4 Protein; C508960:TGFB1 protein, human; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1