Targeted disruption of the mouse mdr1b gene reveals that steroid hormones enhance mdr gene expression.
Targeted disruption of the mouse mdr1b gene reveals that steroid hormones enhance mdr gene expression.
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对小鼠 mdr1b 基因的靶向破坏揭示了类固醇激素增强了 mdr 基因的表达。
DOI：
10.1016/s0021-9258(19)74226-4
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发表时间：
1993
期刊：
影响因子：
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通讯作者：
M. Gottesman
中科院分区：
文献类型：
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作者：
S. Altuvia;W. Stein;S. Goldenberg;S. Kane;I. Pastan;M. Gottesman
为了评估 P-糖蛋白在肾上腺细胞类固醇分泌中的作用，我们使用基因靶向在小鼠 Y1 肾上腺细胞的 mdr1b 基因的一个等位基因中引入无效突变。野生型和突变细胞系的表征揭示了以下内容。 1) mdr1b 的表达通过反馈调节机制被类固醇激素增强。 2-aminogluthimide 抑制类固醇生物合成可阻断促肾上腺皮质激素 (ACTH) 诱导的 mdr1b mRNA 水平增加。 2)突变细胞系中ACTH刺激的类固醇分泌显着减少。尽管 mdr1b mRNA 和 P-糖蛋白水平增加，但突变细胞中类固醇分泌却减少。在 ACTH 刺激的类固醇生成过程中，对野生型和突变细胞系中长春花碱和道诺霉素积累的动力学分析表明，在突变细胞中，两种药物的积累水平高于 Y1 细胞，表明突变细胞中剩余的 mdr1b 等位基因作为类固醇的输出者相对不活跃，或者 mdr1b 等位基因的靶向破坏与突变细胞中阻止 ACTH 刺激的类固醇分泌的其他变化相关。
To evaluate the role of P-glycoprotein in steroid secretion in adrenal cells, we have used gene targeting to introduce a null mutation into one allele of the mdr1b gene in mouse Y1 adrenal cells. Characterization of both the wild-type and the mutant cell lines revealed the following. 1) The expression of mdr1b is enhanced by steroid hormones, in a feedback regulatory mechanism. Inhibition of steroid biosynthesis by 2-aminoglutethimide blocks the adrenocorticotropin (ACTH)-induced increase in mdr1b mRNA levels. 2) ACTH-stimulated steroid secretion is markedly decreased in the mutant cell line. This decreased steroid secretion in the mutant cells occurs despite an increase in the levels of mdr1b mRNA and P-glycoprotein. Kinetic analyses of vinblastine and daunomycin accumulation in both the wild-type and the mutant cell lines during ACTH-stimulated steroidogenesis show that in the mutant cells both drugs accumulated to higher levels than in Y1 cells, suggesting that the remaining mdr1b allele in the mutant cells is relatively inactive as an exporter of steroids, or that the targeted disruption of the mdr1b allele is associated with other changes in the mutant cells which block ACTH-stimulated steroid secretion.