title: Autophagy regulates myeloid cell differentiation by p62/SQSTM1-mediated degradation of PML-RARα oncoprotein.
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 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.
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Wang
authors.forename: Lizhi
authors.initials: L
authors.lastname: Cao
authors.forename: Rui
authors.initials: R
authors.lastname: Kang
authors.forename: Minghua
authors.initials: M
authors.lastname: Yang
authors.forename: Liying
authors.initials: L
authors.lastname: Liu
authors.forename: Yiming
authors.initials: Y
authors.lastname: Zhao
authors.forename: Yan
authors.initials: Y
authors.lastname: Yu
authors.forename: Min
authors.initials: M
authors.lastname: Xie
authors.forename: Xiaocheng
authors.initials: X
authors.lastname: Yin
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Livesey
authors.forename: Daolin
authors.initials: D
authors.lastname: Tang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism / Q000502:physiology*; D017209:Apoptosis; D001343:Autophagy; D002454:Cell Differentiation; D015973:Gene Expression Regulation, Leukemic; D018922:HL-60 Cells; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008856:Microscopy, Fluorescence / Q000379:methods; D008954:Models, Biological; D022423:Myeloid Cells / Q000166:cytology*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D020123:Sirolimus / Q000494:pharmacology; D013997:Time Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015514:Oncogene Proteins, Fusion; D034741:RNA, Small Interfering; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D020123:Sirolimus