title: Identification of a novel role of ZMIZ2 protein in regulating the activity of the Wnt/β-catenin signaling pathway.
abstract: ZMIZ2, also named ZIMP7, is a protein inhibitor of activated STAT (PIAS)-like protein and a transcriptional coactivator. In this study, we investigated the interaction between ZMIZ2 and β-catenin, a key regulator of the Wnt signaling pathway. We demonstrated that the expression of exogenous ZMIZ2 augments TCF (T cell factor) and β-catenin-mediated transcription. In contrast, shRNA knockdown of ZMIZ2 expression specifically represses the enhancement of TCF/β-catenin-mediated transcription by ZMIZ2. Using Wnt3a-conditioned medium, we demonstrated that ZMIZ2 can enhance Wnt ligand-induced TCF/β-catenin-mediated transcription. We also showed a promotional role of ZMIZ2 in enhancing β-catenin downstream target gene expression in human cells and in Zmiz2 null (Zmiz2(-/-)) mouse embryonic fibroblasts (MEFs). The regulatory role of Zmiz2 in Wnt-induced TCF/β-catenin-mediated transcription can be restored in Zmiz2(-/-) MEFs that were infected with adenoviral expression vectors for Zmiz2. Moreover, enhancement of Zmiz2 on TCF/β-catenin-mediated transcription was further demonstrated in Zmiz2 knockout and Axin2 reporter compound mice. Furthermore, the protein-protein interaction between ZMIZ2 and β-catenin was identified by co-immunoprecipitation and in vitro protein pulldown assays. We also observed recruitment of endogenous ZMIZ2 onto the promoter region of the Axin 2 gene, a β-catenin downstream target promoter, in a Wnt ligand-inducible manner. Finally, a promotional role of ZMIZ2 on cell growth was demonstrated in human cell lines and Zmiz2 knockout MEFs. Our findings demonstrate a novel interaction between ZMIZ2 and β-catenin and elucidate a novel mechanism for PIAS-like proteins in regulating Wnt signaling pathways.
authors.affiliation: From the Departments of Urology and Genetics, Stanford University School of Medicine, Stanford, California 94305-5328.
authors.forename: Suk Hyung
authors.initials: SH
authors.lastname: Lee
authors.forename: Chunfang
authors.initials: C
authors.lastname: Zhu
authors.forename: Yue
authors.initials: Y
authors.lastname: Peng
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Johnson
authors.forename: Lynn
authors.initials: L
authors.lastname: Lehmann
authors.forename: Zijie
authors.initials: Z
authors.lastname: Sun
mesh_terms: D000818:Animals; D060466:Axin Protein / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation; D005260:Female; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D050828:Protein Inhibitors of Activated STAT; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D060466:Axin Protein; C111729:Axin2 protein, mouse; D018960:Hyaluronan Receptors; D047908:Intracellular Signaling Peptides and Proteins; D050828:Protein Inhibitors of Activated STAT; D051820:TCF Transcription Factors; D051153:Wnt Proteins; C528562:Zimp7 protein, mouse; D051176:beta Catenin; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Cell Signaling; PIAS-like Proteins; Protein-Protein Interactions; Transcription Regulation; Wnt Ligand; Wnt Signaling; ZMIZ2; β-Catenin