Open AccessHuman Arm protein lost in epithelial cancers, on chromosome X 1 ( ALEX1 ) gene is transcriptionally regulated by CREB and Wnt/β‐catenin signaling
Author(s) -
Iseki Hiroyoshi,
Takeda Akihiko,
Andoh Toshiwo,
Takahashi Norio,
Kurochkin Igor V.,
Yarmishyn Aliaksandr,
Shimada Hideaki,
Okazaki Yasushi,
Koyama Isamu
Publication year - 2010
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2010.01541.x
Subject(s) - wnt signaling pathway , creb , biology , transcription factor , enhancer , promoter , signal transduction , beta catenin , gene knockdown , microbiology and biotechnology , carcinogenesis , cancer research , gene , gene expression , genetics
The aberrant activation of Wnt signaling is a key process in colorectal tumorigenesis. Canonical Wnt signaling controls transcription of target genes via β‐catenin and T‐cell factor/lymphoid enhancer factor family transcription factor complex. Arm protein lost in epithelial cancers, on chromosome X 1 ( ALEX1 ) is a novel member of the Armadillo family which has two Armadillo repeats as opposed to more than six repeats in the classical Armadillo family members. Here we examine cis ‐regulatory elements and trans ‐acting factors involved in the transcriptional regulation of the ALEX1 gene. Site‐directed mutations of a cyclic AMP response element (CRE) and an E‐box impaired the basal activity of human ALEX1 promoter in colorectal and pancreatic cancer cell lines. Moreover, overexpression of CRE‐binding protein (CREB) increased the ALEX1 promoter activity in these cell lines, whereas knockdown of CREB expression decreased the expression level of ALEX1 mRNA. Interestingly, luciferase reporter analysis and quantitative real‐time RT‐PCR demonstrated that the ALEX1 promoter was up‐regulated in a CRE‐dependent manner by continuous activation of Wnt/β‐catenin signaling induced by a glycogen synthase kinase‐3 inhibitor and overexpression of β‐catenin. These results indicate that the CRE and E‐box sites are essential cis ‐regulatory elements for ALEX1 promoter activity, and ALEX1 expression is regulated by CREB and Wntk/β‐catenin signaling. ( Cancer Sci 2010)