POINT MUTATIONS IN V-MYB DISRUPT A CYCLOPHILIN-CATALYZED NEGATIVE REGULATORY MECHANISM

The c-Myb protein is controlled by intramolecular interactions, and po int mutations can enhance its oncogenic activity. We tested whether co nformational changes regulate c-Myb and found that Cyp-40, a widely di stributed cyclophilin and peptidyl-prolyl isomerase, could inhibit c-M yb DNA binding activity. Inhibition by Cyp-40 required both its C-term inal protein-interaction domain, which bound specifically to c-Myb, an d its N-terminal catalytic domain and was blocked by the competitive i nhibitor cyclosporin A. Cyp-40 failed to bind or inhibit the oncogenic derivative v-Myb, which has a mutated Cyp-40 binding site. These resu lts suggest that mutations in v-Myb allow it to evade a negative regul atory mechanism mediated by enzymes such as Cyp-40, and implicate pept idyl-prolyl isomerases in the regulation of transcription, transformat ion, and differentiation.