【摘 要】
：
The stability of Ikaros family zinc finger protein 1 (Ikaros),a critical hematopoietic transcription factor,can be regulated by cereblon (CRBN) ubiquitin ligase stimulated by immunomodulatory drugs in multiple myeloma.However,other stabilization mechanism
【机 构】
：
Hongqiao International Institute of Medicine,Shanghai Tongren Hospital/Faculty of Basic Medicine,Che
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The stability of Ikaros family zinc finger protein 1 (Ikaros),a critical hematopoietic transcription factor,can be regulated by cereblon (CRBN) ubiquitin ligase stimulated by immunomodulatory drugs in multiple myeloma.However,other stabilization mechanisms of Ikaros have yet to be elucidated.In this study,we show that the pharmacologic inhibition or knockdown of Hsp90 downregulates Ikaros in acute myeloid leukemia (AML) cells.Proteasome inhibitor MG132 but not autophagy inhibitor chloroquine could suppress the Hsp90 inhibitor STA-9090-induced reduction of Ikaros,which is accompanied with the increased ubiquitination of Ikaros.Moreover,Ikaros interacts with E3 ubiquitin-ligase C terminal Hsc70 binding protein (CHIP),which mediates the STA-9090-induced ubiquitination of Ikaros.In addition,the knockdown of Ikaros effectively inhibits the pro-liferation of leukemia cells,but this phenomenon could be rescued by Ikaros overexpression.Collectively,our findings indicate that the interplay between HSP90 and CHIP regulates the stability of Ikaros in AML cells,which provides a novel strategy for AML treatment through targeting the HSP90/Ikaros/CHIP axis.
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