VAULTS ARE UP-REGULATED IN MULTIDRUG-RESISTANT CANCER CELL-LINES

Vaults are 13-MDa ribonucleoprotein particles composed largely of a 10 4-kDa protein, termed major vault protein or MVP, and a small vault RN A, vRNA While MVP levels have been found to increase up to 15-fold in non-P-glycoprotein multidrug-resistant cell lines, the levels of vault particles have not been investigated, As both the function of vault p articles and the mechanism of drug resistance in non-P-glycoprotein ce lls are unknown, we decided to determine whether vault synthesis was c oupled to MDR. By cloning the human gene for vRNA and careful quantita tion of the MVP and vRNA levels in MDR cells, we find that vRNA is in considerable excess to MVP. Sedimentation measurements of vault partic les in multidrug resistance cells have indeed revealed up to a 15-fold increase in vault synthesis, coupled with a comparable shift of assoc iated vRNA, demonstrating that vault formation is limited by expressio n of MVP or the minor vault proteins, The observation that vault synth esis is linked directly to multidrug resistance supports a direct role for vaults in drug resistance.