title: Parafibromin/Hyrax activates Wnt/Wg target gene transcription by direct association with beta-catenin/Armadillo.
abstract: The Wnt pathway controls cell fates, tissue homeostasis, and cancer. Its activation entails the association of beta-catenin with nuclear TCF/LEF proteins and results in transcriptional activation of target genes. The mechanism by which nuclear beta-catenin controls transcription is largely unknown. Here we genetically identify a novel Wnt/Wg pathway component that mediates the transcriptional outputs of beta-catenin/Armadillo. We show that Drosophila Hyrax and its human ortholog, Parafibromin, components of the Polymerase-Associated Factor 1 (PAF1) complex, are required for nuclear transduction of the Wnt/Wg signal and bind directly to the C-terminal region of beta-catenin/Armadillo. Moreover, we find that the transactivation potential of Parafibromin/Hyrax depends on the recruitment of Pygopus to beta-catenin/Armadillo. Our results assign to the tumor suppressor Parafibromin an unexpected role in Wnt signaling and provide a molecular mechanism for Wnt target gene control, in which the nuclear Wnt signaling complex directly engages the PAF1 complex, thereby controlling transcriptional initiation and elongation by RNA Polymerase II.
authors.affiliation: National Research Center Frontiers in Genetics, Institut für Molekularbiologie, Universität Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Mosimann
authors.forename: George
authors.initials: G
authors.lastname: Hausmann
authors.forename: Konrad
authors.initials: K
authors.lastname: Basler
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D060466:Axin Protein; D002460:Cell Line; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000033:anatomy & histology / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D010802:Phylogeny; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D014921:Wings, Animal / Q000033:anatomy & histology / Q000254:growth & development; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C467323:APC2 protein, Drosophila; D048868:Adaptor Proteins, Signal Transducing; D060466:Axin Protein; C118000:Axn protein, Drosophila; C454900:CDC73 protein, human; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D025521:Tumor Suppressor Proteins; D051153:Wnt Proteins; D051176:beta Catenin; C453400:pygo protein, Drosophila