title: Human Arm protein lost in epithelial cancers, on chromosome X 1 (ALEX1) gene is transcriptionally regulated by CREB and Wnt/beta-catenin signaling.
abstract: The aberrant activation of Wnt signaling is a key process in colorectal tumorigenesis. Canonical Wnt signaling controls transcription of target genes via beta-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/beta-catenin signaling induced by a glycogen synthase kinase-3 inhibitor and overexpression of beta-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/beta-catenin signaling.
authors.affiliation: Department of Digestive Surgery, Saitama Medical University, Saitama, Japan.
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Iseki
authors.forename: Akihiko
authors.initials: A
authors.lastname: Takeda
authors.forename: Toshiwo
authors.initials: T
authors.lastname: Andoh
authors.forename: Norio
authors.initials: N
authors.lastname: Takahashi
authors.forename: Igor V
authors.initials: IV
authors.lastname: Kurochkin
authors.forename: Aliaksandr
authors.initials: A
authors.lastname: Yarmishyn
authors.forename: Hideaki
authors.initials: H
authors.lastname: Shimada
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Okazaki
authors.forename: Isamu
authors.initials: I
authors.lastname: Koyama
mesh_terms: D051186:Armadillo Domain Proteins / Q000235:genetics*; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology*; D005786:Gene Expression Regulation; D045325:HCT116 Cells; D006801:Humans; D015513:Oncogene Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D014158:Transcription, Genetic; D051153:Wnt Proteins / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology*
chemical_list: C422103:ARMCX1 protein, human; D051186:Armadillo Domain Proteins; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D015513:Oncogene Proteins; D051153:Wnt Proteins; D051176:beta Catenin
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