Abstract
The promyelocytic leukemia gene was first identified through its fusion to the gene encoding the retinoic acid receptor alpha (RARalpha) in acute promyelocytic leukemia (APL) patients. The promyelocytic leukemia gene product (PML) becomes conjugated in vivo to the small ubiquitin-like protein SUMO-1, altering its behavior and capacity to recruit other proteins to PML nuclear bodies (PML-NBs). In the NB4 cell line, which was derived from an APL patient and expresses PML:RARalpha, we observed a retinoic acid-dependent change in the modification of specific proteins by SUMO-1. To dissect the interaction of PML with the SUMO-1 modification pathway, we used the budding yeast Saccharomyces cerevisiae as a model system through expression of PML and human SUMO-1 (hSUMO-1). We found that PML stimulated hSUMO-1 modification in yeast, in a manner that was dependent upon PML's RING-finger domain. PML:RARalpha also stimulated hSUMO-1 conjugation in yeast. Interestingly, however, PML and PML:RARalpha differentially complemented yeast Smt3p conjugation pathway mutants. These findings point toward a potential function of PML and PML:RARalpha as SUMO E3 enzymes or E3 regulators, and suggest that fusion of RARalpha to PML may affect this activity.
Publication types
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Research Support, N.I.H., Intramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Substitution
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor / drug effects
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Cytoskeletal Proteins / metabolism
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Genetic Complementation Test
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Humans
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Leukemia, Promyelocytic, Acute / genetics
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Leukemia, Promyelocytic, Acute / metabolism
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Leukemia, Promyelocytic, Acute / pathology
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Multiprotein Complexes / biosynthesis
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Mutagenesis, Site-Directed
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Nocodazole / pharmacology
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Nuclear Proteins / genetics
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Nuclear Proteins / physiology*
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / physiology*
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Promyelocytic Leukemia Protein
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Protein Structure, Tertiary
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Recombinant Fusion Proteins / physiology
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Repressor Proteins / genetics
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Repressor Proteins / physiology
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SUMO-1 Protein
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Saccharomyces cerevisiae / metabolism
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Saccharomyces cerevisiae Proteins / genetics
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Saccharomyces cerevisiae Proteins / metabolism
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Saccharomyces cerevisiae Proteins / physiology
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Small Ubiquitin-Related Modifier Proteins / genetics
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Small Ubiquitin-Related Modifier Proteins / metabolism*
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Species Specificity
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Transcription Factors / genetics
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Transcription Factors / physiology*
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Transfection
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Tretinoin / pharmacology
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / physiology*
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Ubiquitin-Protein Ligases / metabolism
Substances
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CDC11 protein, S cerevisiae
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Cell Cycle Proteins
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Cytoskeletal Proteins
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Multiprotein Complexes
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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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Recombinant Fusion Proteins
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Repressor Proteins
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SMT3 protein, S cerevisiae
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SUMO-1 Protein
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SUMO1 protein, human
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Saccharomyces cerevisiae Proteins
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Siz2 protein, S cerevisiae
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Small Ubiquitin-Related Modifier Proteins
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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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PML protein, human
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Tretinoin
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Ubiquitin-Protein Ligases
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Siz1 protein, S cerevisiae
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Nocodazole