Loss-of-function mutations in the transcription factor 7 (T cell factor-1) gene in hepatogastrointestinal cancersopen access
- Authors
- 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
- Issue Date
- Sep-2010
- Keywords
- Alimentary tract cancers; Loss of heterozygosity; Somatic mutations; TCF7; Wnt signaling pathway
- Citation
- Molecular and Cellular Toxicology, v.6, no.3, pp 271 - 278
- Pages
- 8
- Journal Title
- Molecular and Cellular Toxicology
- Volume
- 6
- Number
- 3
- Start Page
- 271
- End Page
- 278
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/65073
- DOI
- 10.1007/s13273-010-0037-y
- ISSN
- 1738-642X
2092-8467
- Abstract
- 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 twohybrid assay, most of the mutants showed varying degrees of decreased binding to an amino-terminal enhancer of split (AES), a truncated form of Grouchorelated 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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