Bradshaw D, Hill C H, Nixon J S, Wilkinson S E
Research Centre, Roche Products Ltd., Welwyn Garden City, Herts., UK.
Agents Actions. 1993 Jan;38(1-2):135-47. doi: 10.1007/BF02027225.
The serine/threonine protein kinase, protein kinase C (PKC) is a family of closely related isoforms which are physiologically activated by diacylglycerol generated by the binding of a variety of agonists to their cellular receptors. Free fatty acids may also play a role in activating PKC. The enzyme apparently mediates a wide range of signal transduction processes in cells and, therefore, inhibitors directed selectively against PKC may have wide-ranging therapeutic potential. This review highlights the evidence that inappropriate activation of PKC occurs in a number of disease states. Such evidence, however, is often seriously flawed because it relies on the use of phorbol esters, which are potent and direct PKC activators but may not mimic the physiological triggering of the enzyme in cells, or on the use of non-selective protein kinase inhibitors such as H7 and staurosporine. A new generation of bis-indolylmaleimides, derived from the lead provided by staurosporine, shows a high degree of selectivity for PKC over closely related protein kinases and such agents may provide more appropriate tools to investigate the role of PKC in cellular processes.
丝氨酸/苏氨酸蛋白激酶，即蛋白激酶C（PKC），是一族密切相关的同工型，在生理状态下，它们可被多种激动剂与其细胞受体结合所产生的二酰甘油激活。游离脂肪酸在激活PKC过程中也可能发挥作用。该酶显然介导细胞内广泛的信号转导过程，因此，选择性针对PKC的抑制剂可能具有广泛的治疗潜力。本综述着重介绍了PKC在多种疾病状态下出现不适当激活的证据。然而，此类证据往往存在严重缺陷，因为它依赖于佛波酯的使用，佛波酯是强效且直接的PKC激活剂，但可能无法模拟该酶在细胞内的生理触发机制，或者依赖于使用非选择性蛋白激酶抑制剂，如H7和星形孢菌素。新一代源自星形孢菌素的双吲哚马来酰胺对PKC的选择性高于密切相关的蛋白激酶，此类药物可能为研究PKC在细胞过程中的作用提供更合适的工具。
