CANCER PREVENTION & IMBALANCE IN PROTEIN PHOSPHORYLATION

这项研究的长期目标是检验氧化剂的假设 可能导致蛋白质磷酸化系统失衡，并且 化学预防性抗氧化剂可能会抵消这一过程。 氧化剂有 在一个时代成为肿瘤促进的重要介质 蛋白激酶 C (PKC) 和蛋白质的致癌作用研究 磷酸酶 (PP) 1 和 2 A 已成为肿瘤促进剂的受体 在另一个。 尽管如此，这些调解者之间的相互联系是 不太了解。 我们的初步研究表明，氧化肿瘤 PP2A 易受氧化失活、氧化肿瘤促进剂的影响 可能会导致 PKC、PP1/PP2A 的分隔和失衡 系统。 相反，化学预防性抗氧化剂可能会破坏交叉 氧化剂和肿瘤促进剂受体之间的对话。 这些 研究将使用 C3H/10T1/2 细胞系和体外 转型模型。 主要重点是了解直接 影响 PKC/PP 系统及其的氧化剂的间接作用 抗氧化剂的直接抵消作用（间接作用）。 转型- 相关研究将仅限于鸟氨酸的诱导 脱羧酶、c-fos、c-myc 和转化灶的体外评分。 第一个目的是确定氧化性肿瘤促进剂 H202、 过氧化苯甲酰和佛波酯诱导的氧化剂可以诱导 PKC/PP 中的不平衡或分隔。 然后，研究延伸 了解 PKC/PP 的不平衡如何影响上述内容 提到了与转型相关的事件。 第二个目标是确定 非硫化学预防剂、类胡萝卜素（番茄红素、 β-胡萝卜素）、维生素 E 和鞣花酸可抵抗氧化剂 对 PKC、PP1 和 PP2A 的影响。 第三个目标是扩展这些研究 有机硫化合物二烯硫化物和吡噻硫酮（二硫硫酮） 评估硫剂的抗氧化作用是否不同于 即非硫剂。 最终目的是了解 有效的化学预防剂之间的相互作用 对抗肿瘤促进剂。 硒、维生素E的组合， 将研究维生素 C 和二烯丙基硫醚。 这些结果 研究可能进一步有助于理解相关的分子机制 癌症化学预防。

The long term goal of this study is to test a hypothesis that oxidants may induce an imbalance in protein phosphorylation systems, and chemopreventive antioxidants may counteract this process. Oxidants have emerged as important mediators of tumor promotion in one era of carcinogenesis research while protein kinase C (PKC) and protein phosphatase (PP) 1 and 2 A have emerged as receptors for tumor promoters in another. Nonetheless, the interlink between these mediators is poorly understood. Our preliminary studies revealed that oxidant tumor PP2A are susceptible to oxidative inactivation, oxidant tumor promoters may induce compartmentalization and imbalance in the PKC, PP1/PP2A system. Conversely, chemopreventive antioxidants may disrupt the cross- talk between the oxidants and the receptors for tumor promoters. These studies will be carried out with the C3H/10T1/2 cell line and an in vitro model of transformation. The primary focus is to understand the direct and indirect actions of oxidants that influence the PKC/PP system and its direct counteraction by antioxidants (indirect actions). Transformation- related studies will be restricted to induction of ornithine decarboxylase, c-fos, c-myc and in vitro scoring of the transformed foci. The first aim is to determine whether the oxidant tumor promoters H202, benzoyl peroxide and phorbol ester-induced oxidants can induce an imbalance or compartmentalization in PKC/PP. Then, studies are extended to understand how the imbalance in PKC/PP could affect the above mentioned transformation-related events. The second aim is to determine the abilities of nonsulfur chemopreventive agents, carotenoids (lycopene, Beta-carotene), vitamin E, and ellagic acid to counteract the oxidant effects on PKC, PP1, and PP2A. The third aim is to extend these studies to the organosulfur compounds diallysulfide and oltipraz (dithiolthiones) to assess whether the antioxidant actions of sulfur agents differ from that of nonsulfur agents. The final aim is to understand the interactions of chemopreventive agents that are effective in counteracting tumor promoters. The combination of selenium, vitamin E, Vitamin C, and diallylsulfide will be studied. The results of these studies may further help understand the molecular mechanisms involved in cancer chemoprevention.