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.
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.
Yoshida
H
H
Department of Medicine, Nagoya University Branch Hospital, Japan.
Kitamura
K
K
Tanaka
K
K
Omura
S
S
Miyazaki
T
T
Hachiya
T
T
Ohno
R
R
Naoe
T
T
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000906:Antibodies; D002454:Cell Differentiation / Q000187:drug effects; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004355:Drug Stability; D006801:Humans; D015151:Immunoblotting; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000187:drug effects* / Q000378:metabolism*; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion / Q000187:drug effects* / Q000378:metabolism*; D000071156:Promyelocytic Leukemia Protein; D011817:Rabbits; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors / Q000096:biosynthesis; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D025521:Tumor Suppressor Proteins
D000906:Antibodies; D015853:Cysteine Proteinase Inhibitors; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D000071156:Promyelocytic Leukemia Protein; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; C067713:lactacystin; C070576:PML protein, human; D014212:Tretinoin; D003546:Cysteine Endopeptidases; D000111:Acetylcysteine