TCF/beta-catenin plays an important role in HCCR-1 oncogene expression.
BACKGROUND
Oncogene HCCR-1 functions as a negative regulator of the p53 and contributes to tumorigenesis of various human tissues. However, it is unknown how HCCR-1 contributes to the cellular and biochemical mechanisms of human tumorigenesis.


RESULTS
In this study, we showed how the expression of HCCR-1 is modulated. The luciferase activity assay indicated that the HCCR-1 5'-flanking region at positions -166 to +30 plays an important role in HCCR-1 promoter activity. Computational analysis of this region identified two consensus sequences for the T-cell factor (TCF) located at -26 to -4 (Tcf1) and -136 to -114 (Tcf2). Mutation at the Tcf1 site led to a dramatic decrease in promoter activity. Mobility shift assays (EMSA) revealed that nuclear proteins bind to the Tcf1 site, but not to the Tcf2 site. LiCl, Wnt signal activator by GSK-3beta inhibition, significantly increased reporter activities in wild-type Tcf1-containing constructs, but were without effect in mutant Tcf1-containing constructs in HEK/293 cells. In addition, endogenous HCCR-1 expression was also increased by treatment with GSK-3beta inhibitor, LiCl or AR-A014418 in HEK/293 and K562 cells. Finally, we also observed that the transcription factor, TCF, and its cofactor, beta-catenin, bound to the Tcf1 site.


CONCLUSIONS
These findings suggest that the Tcf1 site on the HCCR-1 promoter is a major element regulating HCCR-1 expression and abnormal stimulation of this site may induce various human cancers.
Cho
Goang-Won
GW
Department of Neurology, College of Medicine, Hanyang University, 17 Haengdang-dong, Seongdong-gu, Seoul, 133-791, Korea. gwcho7@hanyang.ac.kr
Kim
Mi-Hwa
MH
Kim
Seung Hyun
SH
Ha
Seon-Ah
SA
Kim
Hyun Kee
HK
Kim
Sanghee
S
Kim
Jin W
JW
D001665:Binding Sites; D002460:Cell Line; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
C476732:LETMD1 protein, human; D011518:Proto-Oncogene Proteins; D051820:TCF Transcription Factors; D051176:beta Catenin