Point mutations in v-Myb disrupt a cyclophilin-catalyzed negative regulatory mechanism.
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.
Leverson
J D
JD
Northwestern University, Department of Biochemistry, Molecular Biology, and Cell Biology, Evanston, Illinois 60208-3500, USA.
Ness
S A
SA
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002645:Chickens; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins; D004268:DNA-Binding Proteins / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D019169:Jurkat Cells / Q000737:chemistry / Q000201:enzymology; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D020626:Oncogene Proteins v-myb; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism*; D017354:Point Mutation / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020598:Proto-Oncogene Proteins c-myb; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015682:Retroviridae Proteins, Oncogenic / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology
D002352:Carrier Proteins; D000081406:Peptidyl-Prolyl Isomerase F; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D020626:Oncogene Proteins v-myb; D011518:Proto-Oncogene Proteins; D020598:Proto-Oncogene Proteins c-myb; D011993:Recombinant Fusion Proteins; D015682:Retroviridae Proteins, Oncogenic; D015534:Trans-Activators; D011505:Protein-Tyrosine Kinases; D021983:Cyclophilins; D019696:Peptidylprolyl Isomerase