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Disruption of the Murine Major Vault Protein (MVP/LRP) Gene Does Not Induce Hypersensitivity to Cytostatics¹

Department of Hematology, Erasmus University Rotterdam, 3015 GE Rotterdam, the Netherlands [M. H. M., A. v. Z., E. F-L., M. S., P. S., E. A. C. W.]; Department of Biological Chemistry and Jonsson Comprehensive Cancer Center, University of California Los Angeles, School of Medicine, Los Angeles, California 90095-1737 [V. A. K.]; and Department of Pathology, Academic Hospital "Vrije Universiteit" Amsterdam, 1081 HV Amsterdam, the Netherlands [G. L. S., R. J. S.]

Vaults are ribonucleoprotein particles with a distinct structure and a high degree of conservation between species. Although no function has been assigned to the complex yet, there is some evidence for a role of vaults in multidrug resistance. To confirm a direct relation between vaults and multidrug resistance, and to investigate other possible functions of vaults, we have generated a major vault protein (MVP/lung resistance-related protein) knockout mouse model. The MVP^-/- mice are viable, healthy, and show no obvious abnormalities. We investigated the sensitivity of MVP^-/- embryonic stem cells and bone marrow cells derived from the MVP-deficient mice to various cytostatic agents with different mechanisms of action. Neither the MVP^-/- embryonic stem cells nor the MVP^-/- bone marrow cells showed an increased sensitivity to any of the drugs examined, as compared with wild-type cells. Furthermore, the activities of the ABC-transporters P-glycoprotein, multidrug resistance-associated protein and breast cancer resistance protein were unaltered on MVP deletion in these cells. In addition, MVP wild-type and deficient mice were treated with the anthracycline doxorubicin. Both groups of mice responded similarly to the doxorubicin treatment. Our results suggest that MVP/vaults are not directly involved in the resistance to cytostatic agents.

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