Phosphorylation of topoisomerase II by casein kinase II and protein kinase C: effects on enzyme-mediated DNA cleavage/religation and sensitivity to the antineoplastic drugs etoposide and 4'-(9-acridinylamino)methane-sulfon-m-anisidide.
Phosphorylation of topoisomerase II by casein kinase II and protein kinase C: effects on enzyme-mediated DNA cleavage/religation and sensitivity to the antineoplastic drugs etoposide and 4'-(9-acridinylamino)methane-sulfon-m-anisidide.
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发表时间：
1992-04
期刊：
影响因子：
11.2
通讯作者：
Russell F. DeVore;Anita H. Corbett;N. Osheroff
中科院分区：
文献类型：
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作者：
Russell F. DeVore;Anita H. Corbett;N. Osheroff
丝氨酸磷酸化对拓扑异构酶II的DNA切割/再连接平衡的影响和酶对药物的敏感性进行了表征。酪蛋白激酶II和蛋白激酶C均用于这些研究。每个激酶掺入最多约1.4个磷酸分子/拓扑异构酶II的同源二聚体。当酶与两种激酶同时孵育时，磷酸盐掺入增加至约2.6个分子/同源二聚体。在没有抗肿瘤药物的情况下，磷酸化对拓扑异构酶II的DNA切割/再连接平衡只有轻微的影响。然而，在依托泊苷或4 '-（9-吖啶氨基）甲烷-磺酰-间-茴香胺存在下，磷酸化减弱了药物稳定酶-DNA切割复合物的能力。药物诱导的DNA裂解产物的水平下降约33%后，拓扑异构酶II的磷酸化酪蛋白激酶II，约17%后，蛋白激酶C修饰，约50%后，同时磷酸化的酶由两种激酶。后者50%的DNA裂解产物减少与约2倍的增加，同时修饰的拓扑异构酶II介导的DNA再连接的表观一级速率常数。这些结果有力地表明，拓扑异构酶II对顺铂的敏感性可以通过改变酶的磷酸化状态来调节。
The effects of serine phosphorylation on the DNA cleavage/religation equilibrium of topoisomerase II and the sensitivity of the enzyme to antineoplastic drugs were characterized. Both casein kinase II and protein kinase C were used for these studies. Each kinase incorporated a maximum of approximately 1.4 phosphate molecules per homodimer of topoisomerase II. When the enzyme was incubated with both kinases simultaneously, phosphate incorporation increased to approximately 2.6 molecules/homodimer. In the absence of antineoplastic drugs, phosphorylation had only a slight effect on the DNA cleavage/religation equilibrium of topoisomerase II. However, in the presence of etoposide or 4'-(9-acridinylamino)methane-sulfon-m-anisidide, phosphorylation attenuated the ability of drugs to stabilize enzyme-DNA cleavage complexes. Levels of drug-induced DNA cleavage products decreased approximately 33% following phosphorylation of topoisomerase II by casein kinase II, approximately 17% following modification by protein kinase C, and approximately 50% following simultaneous phosphorylation of the enzyme by both kinases. This latter 50% reduction in DNA cleavage products correlated with an approximately 2-fold increase in the apparent first order rate constant for DNA religation mediated by simultaneously modified topoisomerase II. These results strongly suggest that the sensitivity of topoisomerase II toward antineoplastic drugs can be modulated by altering the phosphorylation state of the enzyme.