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

Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China.

Autophagy 2011 Apr

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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.

Citation

Zhuo Wang, Lizhi Cao, Rui Kang, Minghua Yang, Liying Liu, Yiming Zhao, Yan Yu, Min Xie, Xiaocheng Yin, Kristen M Livesey, Daolin Tang. Autophagy regulates myeloid cell differentiation by p62/SQSTM1-mediated degradation of PML-RARα oncoprotein. Autophagy. 2011 Apr;7(4):401-11