Autophagy regulates myeloid cell differentiation by p62/SQSTM1-mediated degradation of PML-RARα oncoprotein
| Autor: | Min Xie, Daolin Tang, Lizhi Cao, Zhuo Wang, Rui Kang, Yan Yu, Minghua Yang, Kristen M. Livesey, Liying Liu, Yiming Zhao, Xiaocheng Yin |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Sequestosome-1 Protein
Time Factors Atg1 Oncogene Proteins Fusion viruses Cellular differentiation ATG5 Retinoic acid Apoptosis HL-60 Cells Biology Models Biological chemistry.chemical_compound Microscopy Electron Transmission Myeloid Cell Differentiation Autophagy Humans Myeloid Cells RNA Small Interfering neoplasms Molecular Biology Adaptor Proteins Signal Transducing Sirolimus Gene Expression Regulation Leukemic virus diseases Cell Differentiation Cell Biology Basic Research Paper Cell biology Retinoic acid receptor Microscopy Fluorescence chemistry Leukocytes Mononuclear |
| Zdroj: | Autophagy. 7:401-411 |
| ISSN: | 1554-8635 1554-8627 |
| DOI: | 10.4161/auto.7.4.14397 |
| Popis: | PML-RARα oncoprotein is a fusion protein of promyelocytic leukemia (PML) and the retinoic acid receptor-α (RARα) and causes acute promyelocytic leukemias (APL). A hallmark of all-trans retinoic acid (ATRA) responses in APL is PML-RARα degradation, which promotes cell differentiation. Here, we demonstrated that autophagy is a crucial regulator of PML-RARα degradation. Inhibition of autophagy by short hairpin (sh) RNA that target essential autophagy genes such as ATG1, ATG5 and PI3KC3, and by autophagy inhibitors (e.g., 3-methyladenine), blocked PML-RARα degradation and subsequently granulocytic differentiation of human myeloid leukemic cells. In contrast, rapamycin, the mTOR kinase inhibitor, enhanced autophagy and promoted ATRA-induced PML-RARα degradation and myeloid cell differentiation. Moreover, PML-RARα co-immunoprecipitated with the ubiquitin-binding adaptor protein p62/SQSTM1, which is degraded through autophagy. Furthermore, knockdown of p62/SQSTM1 inhibited ATRA-induced PML-RARα degradation and myeloid cell differentiation. The identification of PML-RARα as a target of autophagy provides new insight into the mechanism of action of ATRA and its specificity for APL. |
| Databáze: | OpenAIRE |
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