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pubmed:abstractText |
PML-RAR? oncoprotein is a fusion protein of promyelocytic leukemia (PML) and the retinoic acid receptor-? (RAR?) and causes acute promyelocytic leukemias (APL). A hallmark of all-trans retinoic acid (ATRA) responses in APL is PML-RAR? degradation which promotes cell differentiation. Here, we demonstrated that autophagy is a crucial regulator of PML-RAR? 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-RAR? degradation and subsequently granulocytic differentiation of human myeloid leukemic cells. In contrast, rapamycin, the mTOR kinase inhibitor, enhanced autophagy and promoted ATRA-induced PML-RAR? degradation and myeloid cell differentiation. Moreover, PML-RAR? co-immunoprecipitated with ubiquitin-binding adaptor protein p62/SQSTM1, which is degraded through autophagy. Furthermore, knockdown of p62/SQSTM1 inhibited ATRA-induced PML-RAR? degradation and myeloid cell differentiation. The identification of PML-RAR? as a target of autophagy provides new insight into the mechanism of action of ATRA and its specificity for APL.
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