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

92 Citations (Scopus)

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

Fingerprint

Retinoic Acid Receptors
Oncogene Proteins
Autophagy
Myeloid Cells
Cell Differentiation
Leukemia
Tretinoin
Acute Promyelocytic Leukemia
Essential Genes
Sirolimus
Small Interfering RNA
Phosphotransferases

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Autophagy regulates myeloid cell differentiation by p62/SQSTM1-mediated degradation of PML-RARα oncoprotein. / Wang, Zhuo; Cao, Lizhi; Kang, Rui; Yang, Minghua; Liu, Liying; Zhao, Yiming; Yu, Yan; Xie, Min; Yin, Xiaocheng; Livesey, Kristen M.; Tang, Daolin.

In: Autophagy, Vol. 7, No. 4, 04.2011, p. 401-411.

Research output: Contribution to journalArticle

Wang, Z, Cao, L, Kang, R, Yang, M, Liu, L, Zhao, Y, Yu, Y, Xie, M, Yin, X, Livesey, KM & Tang, D 2011, 'Autophagy regulates myeloid cell differentiation by p62/SQSTM1-mediated degradation of PML-RARα oncoprotein', Autophagy, vol. 7, no. 4, pp. 401-411. https://doi.org/10.4161/auto.7.4.14397
Wang, Zhuo ; Cao, Lizhi ; Kang, Rui ; Yang, Minghua ; Liu, Liying ; Zhao, Yiming ; Yu, Yan ; Xie, Min ; Yin, Xiaocheng ; Livesey, Kristen M. ; Tang, Daolin. / Autophagy regulates myeloid cell differentiation by p62/SQSTM1-mediated degradation of PML-RARα oncoprotein. In: Autophagy. 2011 ; Vol. 7, No. 4. pp. 401-411.
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