Mosimann Christian, Hausmann George, Basler Konrad
National Research Center Frontiers in Genetics, Institut für Molekularbiologie, Universität Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
Cell. 2006 Apr 21;125(2):327-41. doi: 10.1016/j.cell.2006.01.053.
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.
Wnt信号通路控制细胞命运、组织稳态及癌症。其激活需要β-连环蛋白与核内TCF/LEF蛋白结合，并导致靶基因的转录激活。核内β-连环蛋白控制转录的机制尚不清楚。在此，我们通过遗传学方法鉴定出一种新型Wnt/Wg信号通路组分，它介导β-连环蛋白/犰狳蛋白的转录输出。我们发现果蝇Hyrax及其人类同源物副纤维瘤蛋白（Polymerase-Associated Factor 1，PAF1复合物的组分）是Wnt/Wg信号核转导所必需的，且能直接结合β-连环蛋白/犰狳蛋白的C末端区域。此外，我们发现副纤维瘤蛋白/ Hyrax的反式激活潜能取决于Pygopus与β-连环蛋白/犰狳蛋白的结合。我们的研究结果赋予肿瘤抑制因子副纤维瘤蛋白在Wnt信号传导中一个意想不到的作用，并为Wnt靶基因调控提供了一种分子机制，即核内Wnt信号复合物直接与PAF1复合物相互作用，从而控制RNA聚合酶II的转录起始和延伸。
