ROLE OF PROTEIN-KINASES IN ANTITUMOR DRUG-RESISTANCE
ROLE OF PROTEIN-KINASES IN ANTITUMOR DRUG-RESISTANCE
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DOI：
10.1007/bf01757347
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发表时间：
1994-07-01
影响因子：
3.5
通讯作者：
UBERALL, F
中科院分区：
文献类型：
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作者：
GRUNICKE, H;HOFMANN, J;UBERALL, F
参与抗肿瘤药物抗性发展的几种蛋白质的活性受蛋白质磷酸化调节。这些蛋白质包括mdr-1编码的P-糖蛋白（Pgp）和拓扑异构酶II（topo II）。相应的证据进行审查，并试图通过蛋白激酶C抑制剂调节多药耐药（MDR）的描述。在耐药性中必不可少的几种蛋白质的表达在转录水平上受到调节，涉及通过蛋白激酶C（PKC）家族、酪蛋白激酶II（CKII）等的成员进行的蛋白质磷酸化。这些蛋白质包括mdr-1编码的P-糖蛋白，金属硫蛋白，谷胱甘肽S-转移酶（GST），dTMP合酶，和蛋白质Fos和Jun。相应的基因是在ras的正调控下，这反过来又需要激活蛋白激酶级联反应才能发挥其功能。因此，蛋白激酶是潜在的有用的目标，在减少蛋白质的表达参与的多因素耐药性的发展所引起的转化ras基因的表达。试图抑制Ras诱导的Fos表达的蛋白激酶C（伊莫福新）的抑制剂进行了描述。蛋白激酶抑制剂也能够协同增强顺铂的细胞毒性，这被认为是由于PKC依赖性fos表达的减少。
The activity of several proteins involved in the development of antitumor drug resistance is regulated by protein phosphorylation. These proteins include the mdr-1-encoded P-glycoprotein (Pgp) and topoisomerase II (topo II). The corresponding evidence is reviewed and attempts to modulate multidrug resistance (MDR) by protein kinase C inhibitors are described. The expression of several proteins which are essential in drug resistance is regulated at the transcriptional level, involving protein phosphorylation by members of the protein kinase C (PKC) family, casein kinase II (CKII), and others. These proteins include mdr-1-encoded P-glycoprotein, metallothionein, glutathione S-transferase (GST), dTMP synthase, and the proteins Fos and Jun. The corresponding genes are under positive regulation of ras, which in turn requires the activation of a protein kinase cascade for its function. Protein kinases are therefore potentially useful targets in reducing the expression of proteins involved in the development of multifactorial drug resistance caused by the expression of transforming ras-genes. Attempts to inhibit the ras-induced fos expression by an inhibitor of protein kinase C (ilmofosine) are described. Protein kinase inhibitors are also able to synergistically enhance the cytotoxicity of cis-platinum, which is discussed as resulting from a reduction of PKC-dependent fos expression.