title: A novel role for the tumour suppressor Nitrilase1 modulating the Wnt/β-catenin signalling pathway.
abstract: Nitrilase1 was classified as a tumour suppressor in association with the fragile histidine-triad protein Fhit. However, knowledge about nitrilase1 and its tumour suppressor function is still limited. Whereas nitrilase1 and Fhit are discrete proteins in mammals, they are merged in Drosophila melanogaster and Caenorhabditis elegans. According to the Rosetta-Stone hypothesis, proteins encoded as fusion proteins in one organism and as separate proteins in another organism may act in the same signalling pathway. Although a direct interaction of human nitrilase1 and Fhit has not been shown, our previous finding that Fhit interacts with β-catenin and represses its transcriptional activity in the canonical Wnt pathway suggested that human nitrilase1 also modulates Wnt signalling. In fact, human nitrilase1 forms a complex with β-catenin and LEF-1/TCF-4, represses β-catenin-mediated transcription and shows an additive effect together with Fhit. Knockdown of human nitrilase1 enhances Wnt target gene expression. Moreover, our experiments show that β-catenin competes away human nitrilase1 from LEF-1/TCF and thereby contributes to the activation of Wnt-target gene transcription. Inhibitory activity of human nitrilase1 on vertebrate Wnt signalling was confirmed by repression of Wnt-induced double axis formation in Xenopus embryogenesis. In line with this finding, the Drosophila fusion protein Drosophila NitFhit directly binds to Armadillo and represses the Wingless pathway in reporter gene assays. Genetic experiments confirmed the repressive activity of Drosophila NitFhit on Wingless signalling in the Drosophila wing imaginal disc. In addition, colorectal tumour microarray analysis revealed a significantly reduced expression of human nitrilase1 in poorly differentiated tumours. Taken together, repression of the canonical Wnt pathway represents a new mechanism for the human nitrilase1 tumour suppressor function.
authors.affiliation: Institute of Biochemistry, Department of Biochemistry II, Jena University Hospital, Friedrich-Schiller-University Jena , Jena, Germany.
authors.forename: Sonnhild
authors.initials: S
authors.lastname: Mittag
authors.affiliation: Institute of Molecular Life Sciences, University of Zurich , Zurich, Switzerland.
authors.forename: Tomas
authors.initials: T
authors.lastname: Valenta
authors.affiliation: Institute of Laboratory Medicine and Pathobiochemistry, Charité-Universitätsmedizin Berlin , Berlin, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Weiske
authors.affiliation: Institute of Biochemistry, Department of Biochemistry II, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany; Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Bloch
authors.affiliation: Department of Cell and Developmental Biology, Zoological Institute, Karlsruhe Institute of Technology , Karlsruhe, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Klingel
authors.affiliation: Department of Cell and Developmental Biology, Zoological Institute, Karlsruhe Institute of Technology , Karlsruhe, Germany.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Gradl
authors.affiliation: Institute of Biochemistry, Department of Biochemistry II, Jena University Hospital, Friedrich-Schiller-University Jena , Jena, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Wetzel
authors.affiliation: Institute of Pathology, Jena University Hospital, Friedrich-Schiller-University Jena , Jena, Germany.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Institute of Pathology, Jena University Hospital, Friedrich-Schiller-University Jena , Jena, Germany.
authors.forename: Iver
authors.initials: I
authors.lastname: Petersen
authors.affiliation: Institute of Molecular Life Sciences, University of Zurich , Zurich, Switzerland.
authors.forename: Konrad
authors.initials: K
authors.lastname: Basler
authors.affiliation: Institute of Biochemistry, Department of Biochemistry II, Jena University Hospital, Friedrich-Schiller-University Jena, Jena, Germany; Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.
authors.forename: Otmar
authors.initials: O
authors.lastname: Huber
keywords: DNitFhit; Rosetta-Stone hypothesis; Wnt signalling; catenin; colorectal cancer; nitrilase1; tumour suppressor gene