Inactivation of SAG E3 ubiquitin ligase blocks embryonic stem cell differentiation and sensitizes leukemia cells to retinoid acid
| العنوان: | Inactivation of SAG E3 ubiquitin ligase blocks embryonic stem cell differentiation and sensitizes leukemia cells to retinoid acid |
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| المؤلفون: | Ning Xi, Yun Li, Yi Sun, Ruiguo Yang, Mingjia Tan |
| المصدر: | PLoS ONE PLoS ONE, Vol 6, Iss 11, p e27726 (2011) |
| سنة النشر: | 2011 |
| مصطلحات موضوعية: | Male, Cellular differentiation, Cancer Treatment, lcsh:Medicine, Apoptosis, Biochemistry, Mice, 0302 clinical medicine, Differentiation therapy, Molecular Cell Biology, Drug Interactions, Enzyme Inhibitors, lcsh:Science, 0303 health sciences, Multidisciplinary, biology, Stem Cells, Cell Differentiation, 3. Good health, Ubiquitin ligase, Enzymes, Leukemia, Leukemia, Myeloid, Acute, Proto-Oncogene Proteins c-bcl-2, Oncology, 030220 oncology & carcinogenesis, Medicine, Female, Oncology Agents, Cellular Types, medicine.drug, Research Article, Ubiquitin-Protein Ligases, Antineoplastic Agents, Tretinoin, Cyclopentanes, Enzyme Regulation, 03 medical and health sciences, Cell Line, Tumor, medicine, Animals, Humans, Biology, Embryonic Stem Cells, 030304 developmental biology, Cell growth, lcsh:R, JNK Mitogen-Activated Protein Kinases, Proteins, Chemotherapy and Drug Treatment, medicine.disease, Molecular biology, Regulatory Proteins, Enzyme Activation, Pyrimidines, Cell culture, biology.protein, lcsh:Q, Neddylation, Gene Deletion, Developmental Biology |
| الوصف: | Sensitive to Apoptosis Gene (SAG), also known as RBX2 (RING box protein-2), is the RING component of SCF (SKP1, Cullin, and F-box protein) E3 ubiquitin ligase. Our previous studies have demonstrated that SAG is an anti-apoptotic protein and an attractive anti-cancer target. We also found recently that Sag knockout sensitized mouse embryonic stem cells (mES) to radiation and blocked mES cells to undergo endothelial differentiation. Here, we reported that compared to wild-type mES cells, the Sag(-/-) mES cells were much more sensitive to all-trans retinoic acid (RA)-induced suppression of cell proliferation and survival. While wild-type mES cells underwent differentiation upon exposure to RA, Sag(-/-) mES cells were induced to death via apoptosis instead. The cell fate change, reflected by cellular stiffness, can be detected as early as 12 hrs post RA exposure by AFM (Atomic Force Microscopy). We then extended this novel finding to RA differentiation therapy of leukemia, in which the resistance often develops, by testing our hypothesis that SAG inhibition would sensitize leukemia to RA. Indeed, we found a direct correlation between SAG overexpression and RA resistance in multiple leukemia lines. By using MLN4924, a small molecule inhibitor of NEDD8-Activating Enzyme (NAE), that inactivates SAG-SCF E3 ligase by blocking cullin neddylation, we were able to sensitize two otherwise resistant leukemia cell lines, HL-60 and KG-1 to RA. Mechanistically, RA sensitization by MLN4924 was mediated via enhanced apoptosis, likely through accumulation of pro-apoptotic proteins NOXA and c-JUN, two well-known substrates of SAG-SCF E3 ligase. Taken together, our study provides the proof-of-concept evidence for effective treatment of leukemia patients by RA-MLN4924 combination. published_or_final_version |
| تدمد: | 1932-6203 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c32c38c6ac258a619c4cba771cbf2c4aTest https://pubmed.ncbi.nlm.nih.gov/22110742Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....c32c38c6ac258a619c4cba771cbf2c4a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19326203 |
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