Activation of the Transcription Factor GLI1 by WNT Signaling Underlies the Role of SULFATASE 2 as a Regulator of Tissue Regeneration
| Autor: | Lisa D. Mills, Schuyler O. Sanderson, Luciana L. Almada, Catherine D. Moser, Martin E. Fernandez-Zapico, Eric A. Hanse, Sherine F. Elsawa, Ikuo Nakamura, Lewis R. Roberts, Maria C. Ortiz-Ruiz, Paola Romecín, Chunling Hu, Nicholas A. Akogyeram, Kadra H Gulaid, Jing Jing Han, Anne M. Vrabel, Maite G. Fernandez-Barrena, Jeffrey H. Albrecht, Satdarshan P.S. Monga, Jesús Prieto |
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| Rok vydání: | 2013 |
| Předmět: |
Beta-catenin
Kruppel-Like Transcription Factors Down-Regulation Models Biological Zinc Finger Protein GLI1 Biochemistry Mice Cyclin D1 Wnt3A Protein Animals Hepatectomy Hedgehog Proteins Wnt Signaling Pathway Molecular Biology Transcription factor beta Catenin Cell Proliferation integumentary system biology Regeneration (biology) Wnt signaling pathway Molecular Bases of Disease Cell Biology Liver regeneration Liver Regeneration Mice Inbred C57BL Hepatocytes biology.protein Cancer research Sulfatases Signal transduction |
| Zdroj: | Journal of Biological Chemistry. 288:21389-21398 |
| ISSN: | 0021-9258 |
| Popis: | Tissue regeneration requires the activation of a set of specific growth signaling pathways. The identity of these cascades and their biological roles are known; however, the molecular mechanisms regulating the interplay between these pathways remain poorly understood. Here, we define a new role for SULFATASE 2 (SULF2) in regulating tissue regeneration and define the WNT-GLI1 axis as a novel downstream effector for this sulfatase in a liver model of tissue regeneration. SULF2 is a heparan sulfate 6-O-endosulfatase, which releases growth factors from extracellular storage sites turning active multiple signaling pathways. We demonstrate that SULF2-KO mice display delayed regeneration after partial hepatectomy (PH). Mechanistic analysis of the SULF2-KO phenotype showed a decrease in WNT signaling pathway activity in vivo. In isolated hepatocytes, SULF2 deficiency blocked WNT-induced β-CATENIN nuclear translocation, TCF activation, and proliferation. Furthermore, we identified the transcription factor GLI1 as a novel target of the SULF2-WNT cascade. WNT induces GLI1 expression in a SULF2- and β-CATENIN-dependent manner. GLI1-KO mice phenocopied the SULF2-KO, showing delayed regeneration and decreased hepatocyte proliferation. Moreover, we identified CYCLIN D1, a key mediator of cell growth during tissue regeneration, as a GLI1 transcriptional target. GLI1 binds to the cyclin d1 promoter and regulates its activity and expression. Finally, restoring GLI1 expression in the liver of SULF2-KO mice after PH rescues CYCLIN D1 expression and hepatocyte proliferation to wild-type levels. Thus, together these findings define a novel pathway in which SULF2 regulates tissue regeneration in part via the activation of a novel WNT-GLI1-CYCLIN D1 pathway. |
| Databáze: | OpenAIRE |
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