Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcysteine / analogs & derivatives
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Acetylcysteine / pharmacology
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Animals
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Antibodies
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Cell Differentiation / drug effects
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Cysteine Endopeptidases / metabolism*
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Cysteine Proteinase Inhibitors / pharmacology
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Drug Stability
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Humans
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Immunoblotting
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Leukemia, Promyelocytic, Acute / drug therapy*
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Leukemia, Promyelocytic, Acute / metabolism*
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Neoplasm Proteins / drug effects*
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Neoplasm Proteins / metabolism*
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Nuclear Proteins*
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Oncogene Proteins, Fusion / drug effects*
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Oncogene Proteins, Fusion / metabolism*
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Promyelocytic Leukemia Protein
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Rabbits
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Receptors, Retinoic Acid / biosynthesis
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Retinoic Acid Receptor alpha
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Transcription Factors / biosynthesis
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Tretinoin / pharmacology*
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Tumor Cells, Cultured / drug effects
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Tumor Suppressor Proteins
Substances
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Antibodies
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Cysteine Proteinase Inhibitors
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Neoplasm Proteins
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Nuclear Proteins
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Oncogene Proteins, Fusion
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Promyelocytic Leukemia Protein
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RARA protein, human
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Receptors, Retinoic Acid
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Retinoic Acid Receptor alpha
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Transcription Factors
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Tumor Suppressor Proteins
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promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein
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lactacystin
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PML protein, human
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Tretinoin
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Cysteine Endopeptidases
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Acetylcysteine