Small molecule-mediated modulation of ubiquitination and neddylation improves HSC function ex vivo
| Autor: | Emre Can Tuysuz, Merve Uslu, Fatih Kocabas, Esra Albayrak, Sezer Akgol |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
NEDD8 Protein Physiology Clinical Biochemistry NEDD8 03 medical and health sciences Mice 0302 clinical medicine Downregulation and upregulation medicine Animals Humans Progenitor cell S-Phase Kinase-Associated Proteins Cell Proliferation Chemistry Cell Cycle Ubiquitination Endothelial Cells Cell Biology Cell cycle Hematopoietic Stem Cells Cell biology Haematopoiesis 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Bone marrow Neddylation Stem cell |
| Zdroj: | Journal of cellular physiologyREFERENCES. 236(12) |
| ISSN: | 1097-4652 |
| Popis: | Hematopoietic stem cells (HSCs) are particularly characterized by their quiescence and self-renewal. Cell cycle regulators tightly control quiescence and self-renewal capacity. Studies suggest that modulation of ubiquitination and neddylation could contribute to HSC function via cyclin-dependent kinase inhibitors (CDKIs). S-phase kinase-associated protein 2 (SKP2) is responsible for ubiquitin-mediated proteolysis of CDKIs. Here, we modulated overall neddylation and SKP2-associated ubiquitination in HSCs by using SKP2-C25, an SKP2 inhibitor, and MLN4924 (Pevonedistat) as an inhibitor of the NEDD8 system. Treatments of SKP2-C25 and MLN4924 increased both murine and human stem and progenitor cell (HSPC) compartments. This is associated with the improved quiescence of murine HSC by upregulation of p27 and p57 CDKIs. A colony-forming unit assay showed an enhanced in vitro self-renewal potential post inhibition of ubiquitination and neddylation. In addition, MLN4924 triggered the mobilization of bone marrow HSPCs to peripheral blood. Intriguingly, MLN4924 treatment could decrease the proliferation of murine bone marrow mesenchymal stem cells or endothelial cells. These findings shed light on the contribution of SKP2, and associated ubiquitination and neddylation in HSC maintenance, self-renewal, and expansion. |
| Databáze: | OpenAIRE |
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