Blockade of the ubiquitin protease UBP43 destabilizes transcription factor PML/RAR? and inhibits the growth of acute promyelocytic leukemia.

ABSTRACT: 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)/RAR?, 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/RAR? 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/RAR? 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/RAR? protein levels and inhibited RA-sensitive or RA-resistant cell growth by destabilizing the PML domain of PML/RAR?. 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/RAR? protein and inhibited apoptosis. Taken together, our findings define the ubiquitin protease UBP43 as a novel candidate drug target for APL treatment.

SUBMITTER: Guo Y 

PROVIDER: S-EPMC2999664 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature