Blockade of the Ubiquitin Protease UBP43 Destabilizes Transcription Factor PML/RARα and Inhibits the Growth of Acute Promyelocytic Leukemia

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Zeitschriftentitel:	Cancer Research
Personen und Körperschaften:	Guo, Yongli, Dolinko, Andrey V., Chinyengetere, Fadzai, Stanton, Bruce, Bomberger, Jennifer M., Demidenko, Eugene, Zhou, Da-Cheng, Gallagher, Robert, Ma, Tian, Galimberti, Fabrizio, Liu, Xi, Sekula, David, Freemantle, Sarah, Dmitrovsky, Ethan
In:	Cancer Research, 70, 2010, 23, S. 9875-9885
Format:	E-Article
Sprache:	Englisch
veröffentlicht:	American Association for Cancer Research (AACR)
Schlagwörter:	Cancer Research Oncology

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Zusammenfassung:	<jats:title>Abstract</jats:title> <jats:p>More effective treatments for acute promyelocytic leukemia (APL) are needed. APL cell treatment with all-trans-retinoic acid (RA) degrades the chimeric, dominant-negative–acting transcription factor promyelocytic leukemia gene (PML)/RARα, which is generated in APL by chromosomal translocation. The E1-like ubiquitin-activating enzyme (UBE1L) associates with interferon-stimulated gene ISG15 that binds and represses PML/RARα protein. Ubiquitin protease UBP43/USP18 removes ISG15 from conjugated proteins. In this study, we explored how RA regulates UBP43 expression and the effects of UBP43 on PML/RARα stability and APL growth, apoptosis, or differentiation. RA treatment induced UBE1L, ISG15, and UBP43 expression in RA-sensitive but not RA-resistant APL cells. Similar in vivo findings were obtained in a transgenic mouse model of transplantable APL, and in the RA response of leukemic cells harvested directly from APL patients. UBP43 knockdown repressed PML/RARα protein levels and inhibited RA-sensitive or RA-resistant cell growth by destabilizing the PML domain of PML/RARα. This inhibitory effect promoted apoptosis but did not affect the RA differentiation response in these APL cells. In contrast, elevation of UBP43 expression stabilized PML/RARα protein and inhibited apoptosis. Taken together, our findings define the ubiquitin protease UBP43 as a novel candidate drug target for APL treatment. Cancer Res; 70(23); 9875–85. ©2010 AACR.</jats:p>
Umfang:	9875-9885
ISSN:	0008-5472 1538-7445
DOI:	10.1158/0008-5472.can-10-1100