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

Zhuo Wang, Lizhi Cao, Rui Kang, Minghua Yang, Liying Liu, Yiming Zhao, Yan Yu, Min Xie, Xiaocheng Yin, Kristen M. Livesey, Daolin Tang

Research output: Contribution to journalArticle

98 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)401-411
Number of pages11
JournalAutophagy
Volume7
Issue number4
DOIs
StatePublished - Apr 2011
Externally publishedYes

Keywords

  • Autophagy
  • Degradation
  • Differentiation
  • Leukemia
  • Oncoprotein
  • PML-RARa
  • p62/SQSTM1

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Autophagy regulates myeloid cell differentiation by p62/SQSTM1-mediated degradation of PML-RARα oncoprotein'. Together they form a unique fingerprint.

  • Cite this