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Autophagy regulates myeloid cell differentiation by p62/SQSTM1-mediated degradation of PML-RARα oncoprotein.

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 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.

Pubmed ID: 21187718

Authors

  • Wang Z
  • Cao L
  • Kang R
  • Yang M
  • Liu L
  • Zhao Y
  • Yu Y
  • Xie M
  • Yin X
  • Livesey KM
  • Tang D

Journal

Autophagy

Publication Data

April 30, 2011

Associated Grants

None

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Apoptosis
  • Autophagy
  • Cell Differentiation
  • Gene Expression Regulation, Leukemic
  • HL-60 Cells
  • Humans
  • Leukocytes, Mononuclear
  • Microscopy, Electron, Transmission
  • Microscopy, Fluorescence
  • Models, Biological
  • Myeloid Cells
  • Oncogene Proteins, Fusion
  • RNA, Small Interfering
  • Sirolimus
  • Time Factors