Journal Article

Regulation of <i>AKT1</i> expression by beta-catenin/Tcf/Lef signaling in colorectal cancer cells

Susanne Dihlmann, Matthias Kloor, Christine Fallsehr and Magnus von Knebel Doeberitz

in Carcinogenesis

Volume 26, issue 9, pages 1503-1512
Published in print September 2005 | ISSN: 0143-3334
Published online May 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi120
Regulation of AKT1 expression by beta-catenin/Tcf/Lef signaling in colorectal cancer cells

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The serine/threonine kinase AKT plays a critical role in controlling the balance between cell survival and apoptosis. Several reports implicated AKT in the molecular pathogenesis of different human malignancies and overexpression of AKT was recently demonstrated to be an early event in colorectal carcinogenesis. We report here the identification of nine putative Tcf/Lef-binding elements (TBEs) upstream to the ATG initiation site of the AKT1 gene. Four of these TBEs are located upstream of the transcriptional start, whereas five TBEs are situated in Exon 1 of the AKT1 gene. Accordingly, we hypothesized that AKT1 expression might be regulated by Wnt/β-catenin signaling. To elucidate the regulation of AKT expression in colon cancer cells, we generated reporter constructs containing the luciferase gene under the control of different regions derived from the AKT1 promoter/enhancer. Transient expression of the constructs in colorectal cancer (CRC) cell lines resulted in significant activation of the reporter gene. Luciferase was stimulated 20- to 50-fold in SW480, SW948 and HCT116 CRC cells. In contrast, the AKT1 promoter/enhancer constructs showed only a weak response in 293 embryonic kidney cells. Coexpression of a constitutively active β-catenin mutant in colon cancer cells further enhanced reporter gene activation from the AKT1 promoter/enhancer, whereas it was downregulated by introduction of either wild-type APC or dnTcf-4. In addition, immunohistochemical staining of tumor sections derived from CRC patients showed elevated expression levels of AKT1, correlating with enhanced cytoplasmic/nuclear expression of β-catenin. In summary our data suggest that β-catenin/Tcf contributes to the transcriptional regulation of the AKT1 gene.

Keywords: AP-1, activation protein 1; ARF, alternative reading frame; CBP, cAMP-responsive element binding protein; CRC, colorectal cancer; Lef, lymphocyte enhancer factor; MMP-7, matrix metalloproteinase-7; NFκB, nuclear factor kappa B; PML, promyelocytic leukemia; RT–PCR, reverse transcription–PCR; TBE, TCF-binding element; Tcf, T-cell factor

Journal Article.  6006 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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