1. Nuclear receptor TLX inhibits TGF-β signaling in glioblastoma
- Author
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Erik Johansson, Qiwei Zhai, Keiko Funa, Zhao-jun Zeng, and Takeshi Yoshida
- Subjects
0301 basic medicine ,Ubiquitin-Protein Ligases ,Receptors, Cytoplasmic and Nuclear ,Smad Proteins ,03 medical and health sciences ,0302 clinical medicine ,Transforming Growth Factor beta ,Cell Line, Tumor ,Glioma ,medicine ,Humans ,Gene silencing ,Gene Silencing ,Progenitor cell ,Cell Proliferation ,Cell Nucleus ,Oncogene ,biology ,Brain Neoplasms ,Protein Stability ,Ubiquitination ,Cell Biology ,Transforming growth factor beta ,Orphan Nuclear Receptors ,medicine.disease ,HEK293 Cells ,030104 developmental biology ,Nuclear receptor ,Gene Knockdown Techniques ,030220 oncology & carcinogenesis ,Proteolysis ,biology.protein ,Cancer research ,Stem cell ,Signal transduction ,Glioblastoma ,Receptors, Transforming Growth Factor beta ,Signal Transduction - Abstract
TLX (also called NR2E1) is an orphan nuclear receptor that maintains stemness of neuronal stem cells. TLX is highly expressed in the most malignant form of glioma, glioblastoma multiforme (GBM), and is important for the proliferation and maintenance of the stem/progenitor cells of the tumor. Transforming Growth Factor-β (TGF-β) is a cytokine regulating many different cellular processes such as differentiation, migration, adhesion, cell death and proliferation. TGF-β has an important function in cancer where it can work as either a tumor suppressor or oncogene, depending on the cancer type and stage of tumor development. Since glioblastoma often have dysfunctional TGF-β signaling we wanted to find out if there is any interaction between TLX and TGF-β in glioblastoma cells. We demonstrate that knockdown of TLX enhances the canonical TGF-β signaling response in glioblastoma cell lines. TLX physically interacts with and stabilizes Smurf1, which can ubiquitinate and target TGF-β receptor II for degradation, whereas knockdown of TLX leads to stabilization of TGF-β receptor II, increased nuclear translocation of Smad2/3 and enhanced expression of TGF-β target genes. The interaction between TLX and TGF-β may play an important role in the regulation of proliferation and tumor-initiating properties of glioblastoma cells.
- Published
- 2016
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