Mossink Marieke H, van Zon Arend, Fränzel-Luiten Erna, Schoester Martijn, Kickhoefer Valerie A, Scheffer George L, Scheper Rik J, Sonneveld Pieter, Wiemer Erik A C
Department of Hematology, Erasmus University Rotterdam, 3015 GE Rotterdam, The Netherlands.
Cancer Res. 2002 Dec 15;62(24):7298-304.
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.
穹窿体是一种核糖核蛋白颗粒，具有独特的结构且在物种间高度保守。尽管目前尚未明确该复合体的功能，但有证据表明穹窿体在多药耐药中发挥作用。为了证实穹窿体与多药耐药之间的直接关系，并探究穹窿体的其他可能功能，我们构建了主要穹窿蛋白（MVP/肺耐药相关蛋白）基因敲除小鼠模型。MVP(-/-)小鼠能够存活且健康，未表现出明显异常。我们研究了源自MVP基因缺陷小鼠的MVP(-/-)胚胎干细胞和骨髓细胞对具有不同作用机制的各种细胞抑制剂的敏感性。与野生型细胞相比，MVP(-/-)胚胎干细胞和MVP(-/-)骨髓细胞对所检测的任何一种药物均未表现出敏感性增加。此外，这些细胞中ABC转运蛋白P-糖蛋白、多药耐药相关蛋白和乳腺癌耐药蛋白的活性在缺失MVP后未发生改变。另外，用蒽环类药物阿霉素对MVP野生型和缺陷型小鼠进行治疗。两组小鼠对阿霉素治疗的反应相似。我们的结果表明，MVP/穹窿体不直接参与对细胞抑制剂的耐药。
