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The arsenic-based cure of acute promyelocytic leukemia promotes cytoplasmic sequestration of PML and PML/RARA through inhibition of PML body recycling.
MedLine Citation:
PMID:  22692509     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Arsenic in the form of arsenic trioxide (ATO) is used as a therapeutic drug for treatment of acute promyelocytic leukemia (APL). The mechanism by which this agent cures this disease has previously been shown to involve direct interactions between ATO and the promyelocytic leukemia protein (PML) as well as accelerated degradation of the APL-associated fusion oncoprotein PML/retinoic acid receptor alpha (RARA). Here we have investigated the fate of PML-generated nuclear structures called PML bodies in ATO-treated cells. We found that ATO inhibits formation of progeny PML bodies while it stabilizes cytoplasmic precursor compartments, referred to as cytoplasmic assemblies of PML and nucleoporins (CyPNs), following cell division. This block in PML body recycling is readily detected at pharmacological relevant ATO concentrations (0.02 -0.5 µM) that do not cause detectable cell cycle defects, and it does not require modification of PML by SUMOylation. In addition, PML and PML/RARA carrying mutations previously identified in ATO-resistant APL patients are impeded in their ability to become sequestered within CyPNs. Thus, ATO may inhibit nuclear activities of PML and PML/RARA in post mitotic cells through CyPN-dependent cytoplasmic sequestration.
Authors:
Emma Lång; Amra Grudic; Serhiy Pankiv; Oystein Bruserud; Anne Simonsen; Rolf Bjerkvig; Magnar Bjørås; Stig Ove Bøe
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-6-12
Journal Detail:
Title:  Blood     Volume:  -     ISSN:  1528-0020     ISO Abbreviation:  -     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-6-13     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Dept of Microbiology, Institute of Clinical Biochemistry and Ctr of Molecular Biology & Neuroscience, Oslo University Hospital and University of Oslo, Rikshospitalet, Oslo, Norway;
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