肿瘤促进剂过氧化苯甲酰引发巯基氧化蛋白激酶C:其可逆性细胞抵抗peroxide-induced细胞毒性有关。

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科尔伯恩Gopalakrishna R, Gundimeda U,安德森WB, NH, Slaga TJ

肿瘤促进剂过氧化苯甲酰引发巯基氧化蛋白激酶C:其可逆性细胞抵抗peroxide-induced细胞毒性有关。

拱生物化学Biophys。1999年3月15日,363 (2):246 - 58。doi: 10.1006 / abbi.1999.1100。

PubMed ID

10068446 (在PubMed

]

文摘

因为肿瘤促进剂过氧化苯甲酰(BPO)模仿佛波醇酯在某些方面,其影响蛋白激酶C (PKC)以前的研究。然而,在这些研究由于存在PKC的硫醇代理准备,BPO的敏感反应与PKC redox-active半胱氨酸残基并没有观察到。在这项研究中,由不含硫醇特工出现在纯化PKC准备,低浓度的BPO修改PKC,导致损失的激酶活性和佛波醇酯绑定(IC50 = 0。2到0.5 microM)。这一修改,依赖于过渡金属,完全被各种各样的硫醇代理包括谷胱甘肽,它直接与业务流程外包。亚化学计量的大量的业务流程外包(0.4摩尔/摩尔的PKC)氧化两个巯基PKC和灭活酶由二硫苏糖醇容易逆转。监管领域拥有锌硫醇盐结构支持membrane-inserting地区PKC的特异性反应提供了业务流程外包,分区成膜。与过氧化氢,BPO没有诱导Ca2 +的生成/ lipid-independent PKC激活的形式。蛋白激酶等redox-sensitive酶,蛋白质磷酸化酶激酶和磷酸酶2要求近25 - 100倍浓度更高的BPO失活。业务流程外包也灭活PKC在不同的细胞类型。 In the JB6 (30 P-) nonpromotable cell line and other normal cell lines, where BPO was more cytotoxic, it readily inactivated PKC due to a slow reversibility of this inactivation by the cell. However, in the JB6 (41 P+) promotable cell line, C3H10T1/2 and B16 melanoma cells, where BPO was less cytotoxic, it did not readily inactivate PKC due to a rapid reversibility of this inactivation by an endogenous mechanism. Nevertheless, BPO inactivated PKC at an equal rate in the homogenates prepared from all these cell types. Inclusion of NADPH reversed this inactivation in the homogenates to a different extent, presumably due to a difference in distribution of a protein disulfide reductase, which reverses this oxidative modification. BPO-induced modification of PKC occurred independent of the cellular status of GSH. However, externally added GSH and cell-impermeable thiol agents prevented the BPO-induced modification of PKC. Since BPO readily partitions into membranes, its reaction with redox-cycling thiols of membrane proteins such as PKC may trigger epigenetic events to prevent cytotoxicity, but favor tumor promotion.

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药物靶点

药物	目标	类	生物	药理作用	行动
过氧化苯甲酰	蛋白激酶C(蛋白质组)	蛋白质组	人类	未知的	抑制剂	细节