Genetic and cellular characterizations of human TCF4 with microsatellite instability in colon cancer and leukemia cell lines.
It has been reported that the mutational inactivation of the adenomatous polyposis coli (APC) and beta-catenin genes play important roles in colorectal carcinogenesis. However, alteration of the components in the Wnt signaling pathway in colorectal cancer (CRC) with microsatellite instability (MSI) has been elucidated. To define the precise role of the Wnt signaling components in CRC and leukemia cell lines with MSI, mutational analyses of the T cell factor 4 (TCF4) genes were performed. Here we describe for the first time a TCF4 MSI+ phenotype in leukemia cell lines except in colon cancer cell lines. Moreover, we found that these cell lines exhibited deletion and insertion of 1-2A in an (A)9 repeat so as to result in (A)7, (A)8, (A)10 and (A)11 repeat, respectively. To characterize the cellular function of these special TCF4 mutant clones, transient transfection and fluorescent microscopy were analyzed and the results revealed that the TCF4 frameshift gene products all localized in nuclei. Surprisingly, these TCF4 frameshift mutants lost transcriptional activity with beta-catenin and down-regulate the target gene expression. These results delineate a novel role for MSI+TCF4 in leukemia and colon cancer progression.
Chang
Huoy-Rou
HR
Department of Biomedical Engineering, I-Shou University, Kaohsiung Hsien 840, Taiwan, ROC.
Cheng
Tian-Lu
TL
Liu
Tsan-Zon
TZ
Hu
Han-Shu
HS
Hsu
Li-Sung
LS
Tseng
Wei-Chang
WC
Chen
Ching-Hsein
CH
Tsao
Der-An
DA
D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D042822:Genomic Instability; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000473:pathology; D018895:Microsatellite Repeats; D009154:Mutation; D051820:TCF Transcription Factors / Q000235:genetics*; D058118:Transcription Factor 7-Like 2 Protein; D014158:Transcription, Genetic; D051176:beta Catenin / Q000235:genetics / Q000502:physiology
D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D051176:beta Catenin