Abstract
The c-Myb protein is controlled by intramolecular interactions, and point mutations can enhance its oncogenic activity. We tested whether conformational changes regulate c-Myb and found that Cyp-40, a widely distributed cyclophilin and peptidyl-prolyl isomerase, could inhibit c-Myb DNA binding activity. Inhibition by Cyp-40 required both its C-terminal protein-interaction domain, which bound specifically to c-Myb, and its N-terminal catalytic domain and was blocked by the competitive inhibitor cyclosporin A. Cyp-40 failed to bind or inhibit the oncogenic derivative v-Myb, which has a mutated Cyp-40 binding site. These results suggest that mutations in v-Myb allow it to evade a negative regulatory mechanism mediated by enzymes such as Cyp-40, and implicate peptidyl-prolyl isomerases in the regulation of transcription, transformation, and differentiation.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Base Sequence
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Chickens
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Cyclophilins*
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DNA-Binding Proteins / metabolism
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Gene Expression Regulation, Enzymologic / physiology
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Gene Expression Regulation, Neoplastic / physiology
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Humans
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Jurkat Cells / chemistry
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Jurkat Cells / enzymology
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Molecular Sequence Data
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Mutagenesis / physiology
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Oncogene Proteins v-myb
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Peptidyl-Prolyl Isomerase F
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Peptidylprolyl Isomerase / genetics
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Peptidylprolyl Isomerase / metabolism*
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Point Mutation / physiology*
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Protein-Tyrosine Kinases / genetics
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-myb
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Retroviridae Proteins, Oncogenic / antagonists & inhibitors
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Retroviridae Proteins, Oncogenic / genetics*
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Retroviridae Proteins, Oncogenic / metabolism
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Trans-Activators / antagonists & inhibitors
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Transcription, Genetic / physiology
Substances
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Carrier Proteins
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Peptidyl-Prolyl Isomerase F
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DNA-Binding Proteins
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Nuclear Proteins
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Oncogene Proteins v-myb
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-myb
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Recombinant Fusion Proteins
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Retroviridae Proteins, Oncogenic
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Trans-Activators
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Protein-Tyrosine Kinases
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Cyclophilins
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Peptidylprolyl Isomerase