RaRF confers RA resistance by sequestering RAR to the nucleolus and regulating MCL1 in leukemia cells
Autor: | Soo-Jong Um, Hye Kyung Lee, Eun-Joo Kim, Ui-Hyun Park, HyeSook Youn, Sohn Hr, BuHyun Youn |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Acute promyelocytic leukemia Cancer Research Receptors Retinoic Acid Retinoic acid Repressor Datasets as Topic Tretinoin Kaplan-Meier Estimate Biology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Downregulation and upregulation Leukemia Promyelocytic Acute Myeloblast Cell Line Tumor Genetics medicine Humans MCL1 Granulocyte Precursor Cells Molecular Biology Regulation of gene expression Gene Expression Regulation Leukemic Cell Differentiation medicine.disease Up-Regulation Repressor Proteins Leukemia 030104 developmental biology medicine.anatomical_structure chemistry Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research Myeloid Cell Leukemia Sequence 1 Protein Cell Nucleolus |
Zdroj: | Oncogene. 37(3) |
ISSN: | 1476-5594 |
Popis: | Retinoic acid (RA) has broad clinical applications for the treatment of various cancers, particularly acute promyelocytic leukemia. However, RA-based therapy is limited by relapse in patients associated with RA resistance, the mechanism of which is poorly understood. Here, we suggest a new molecular mechanism of RA resistance by a repressor, named RA resistance factor (RaRF). RaRF suppressed transcriptional activity of the RA receptor (RAR) by directly interacting with and sequestering RAR to the nucleolus in response to RA. RaRF was highly expressed in RA-resistant leukemia cells and its expression was strongly correlated with RA sensitivity. MCL1 was upregulated by RA treatment upon RaRF depletion, accompanying leukemic myeloblast differentiation, which is negatively regulated by ectopic RaRF expression. Collectively, we propose that RaRF may be a factor in the resistance mechanism and thus a potential target for leukemia therapy using RA. |
Databáze: | OpenAIRE |
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