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KMID : 1034820100060030271
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Molecular & Cellular Toxicology
2010 Volume.6 No. 3 p.271 ~ p.278
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Loss-of-function mutations in the Transcription Factor 7 (T cell factor-1) gene in hepatogastrointestinal cancers
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Jung Kwang-Hwa
Yoon Kang-Jun
Song Jae-Hwi
Lee Sung-Hak
Eun Jung-Woo
Noh Ji-Heon
Kim Jeong-Kyu
Bae Hyun-Jin
Lee Jang-Eun
Kim Sang-Woo
Choi Myung-Gyu
Kim Su-Young
Park Won-Sang
Nam Suk-Woo
Lee Jung-Young
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Abstract
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Inappropriate activation of the Wnt signaling pathway has been repeatedly implicated in the tumorigenesis of colon, liver, and gastric cancers. There is accumulating evidences that transcriptional factor 7 (TCF7; also called T cell factor 1) might also be one of the tumor suppressor genes in the Wnt pathway. We performed PCR-based sequencing analysis of the TCF7 gene in 234 alimentary tract cancers. The TCF7 mutants detected in this study were functionally analyzed after they were generated by a QuickChange site-directed mutagenesis kit. We detected 7 somatic mutations in the TCF7 gene, including 4 missense, 2 frameshift, and one 28-bp deletion. In a yeast two-hybrid assay, most of the mutants showed varying degrees of decreased binding to an amino-terminal enhancer of split (AES), a truncated form of Groucho-related protein lacking WD40 repeats. To determine whether mutant TCF7 proteins had decreased DNA binding, we performed electrophoretic mobility shift assays, and the 2 frameshift mutants were shown to have no DNA binding activity. Furthermore, luciferase reporter assays revealed that TCF7 mutants in the presence of AES failed in the AES-dependent transcriptional repression of the reporter gene. In addition, human embryonic kidney 293 cells transfected with TCF7 mutants expressed high levels of cyclin D1, up to 6 times more than cells transfected with wild-type TCF7. Therefore, the TCF7 mutations detected in this study seem to be “loss-of-function mutations“ caused by loss of TCF7 repressor activity through decreased binding to Groucho-related protein and/or DNA, thereby contributing to neoplastic transformation by causing accumulation of cylin D1.
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KEYWORD
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TCF7, Wnt signaling pathway, Somatic mutations, Loss of heterozygosity, Alimentary tract cancers
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