Document Detail

Accelerated degradation of PML-retinoic acid receptor alpha (PML-RARA) oncoprotein by all-trans-retinoic acid in acute promyelocytic leukemia: possible role of the proteasome pathway.
MedLine Citation:
PMID:  8674046     Owner:  NLM     Status:  MEDLINE    
Acute promyelocytic leukemia (APL) is associated with a chromosomal translocation t(15;17) and successfully differentiated by all-trans-retinoic acid (ATRA) in vivo as well as in vitro. The PML-retinoic acid receptor alpha (RARA) oncoprotein, which is generated by the translocation, blocks the differentiation, and ATRA is thought to modulate the dominant negative function of PML-RARA. However, the molecular effect of ATRA on PML-RARA is unknown. In this study, we showed by means of immunoblotting that the expression of PML-RARA decreased within 12 h in APL cells treated with ATRA at concentrations greater than 0.1 microM. The decrease of PML-RARA was associated with restoration of the normal subcellular PML localization. PML-RARA transcripts were not down-regulated by ATRA. However, lactacystin, a specific inhibitor of the proteasome, almost completely inhibited the decrease of PML-RARA. These data indicate that the PML-RARA degradation is accelerated by pharmacological concentrations of ATRA, suggesting that ATRA allows APL cells to differentiate by relieving the differentiation block.
H Yoshida; K Kitamura; K Tanaka; S Omura; T Miyazaki; T Hachiya; R Ohno; T Naoe
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cancer research     Volume:  56     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  1996 Jul 
Date Detail:
Created Date:  1996-08-12     Completed Date:  1996-08-12     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  2945-8     Citation Subset:  IM    
Department of Medicine, Nagoya University Branch Hospital, Japan.
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MeSH Terms
Acetylcysteine / analogs & derivatives,  pharmacology
Cell Differentiation / drug effects
Cysteine Endopeptidases / metabolism*
Cysteine Proteinase Inhibitors / pharmacology
Drug Stability
Leukemia, Promyelocytic, Acute / drug therapy*,  metabolism*
Neoplasm Proteins / drug effects*,  metabolism*
Nuclear Proteins*
Oncogene Proteins, Fusion / drug effects*,  metabolism*
Receptors, Retinoic Acid / biosynthesis
Transcription Factors / biosynthesis
Tretinoin / pharmacology*
Tumor Cells, Cultured / drug effects
Tumor Suppressor Proteins
Reg. No./Substance:
0/Antibodies; 0/Cysteine Proteinase Inhibitors; 0/Neoplasm Proteins; 0/Nuclear Proteins; 0/Oncogene Proteins, Fusion; 0/Receptors, Retinoic Acid; 0/Transcription Factors; 0/Tumor Suppressor Proteins; 0/promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; 0/retinoic acid receptor alpha; 133343-34-7/lactacystin; 143220-95-5/PML protein, human; 302-79-4/Tretinoin; 616-91-1/Acetylcysteine; EC 3.4.22.-/Cysteine Endopeptidases

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