MECHANISMS OF TUMOR PROMOTION AND CARCINOGENESIS

确定允许肿瘤细胞经历 不受控制的增殖对于理解癌症的发生至关重要。 最近的几项研究表明，蛋白质磷酸酶，就像蛋白质一样 激酶在细胞周期调控中发挥着重要而独特的作用； 因此，这些蛋白质的表达或调节的变化可能 影响细胞周期进程，甚至可能允许细胞经历 不受管制的扩散。蛋白磷酸酶在肿瘤中的作用 促进过程也出现在冈田酸的研究中， 微囊藻毒素-LR和纤毛菌素A，三种高度特异和有效的 某些丝氨酸/苏氨酸蛋白磷酸酶(PPase)的抑制剂 具有促进肿瘤活性的物质。我们已经克隆并鉴定了 三个人类PPase，其中一个被命名为PP5，特别有吸引力 以供进一步研究。PP5被冈田酸和 小鼠皮肤中的两种有效的肿瘤促进剂--花盏蛋白A。然而，不同于 其他已知的PPase在恒定水平上表达，PP5 在对数生长期高表达，低表达或不可检测 静止期或分化的细胞培养。PP5的表达为 在某些细胞中加入血清和/或17β-雌二醇所致 类型，抑制PP5的表达增强了这两种类型的能力 P53抑癌蛋白和地塞米松，合成的 糖皮质激素激动剂，诱导p21细胞周期蛋白的表达- A549细胞中的依赖性激酶抑制蛋白。把这些放在一起 研究表明，PP5在G1/S的调节中起重要作用。 相变。这项提议旨在检验这样一个假设： 蛋白磷酸酶在细胞周期进程中发挥重要作用； 因此，它们活动的干扰可能会导致这种异常。 肿瘤细胞的增殖行为。这些研究将集中于 关于以下具体目标：目标1.进一步确定角色特征 PP5在细胞周期进程的正常和异常控制中的作用。 目的2.研究PP5在糖皮质激素调节中的作用 抑制细胞生长和信号网络之间的“串扰” 由激素和生长因子诱导。目标3.描述 PP5表达的调控机制。通过这些研究，我们 希望进一步研究蛋白磷酸酶在细胞周期中的作用。 调节细胞周期并深入了解蛋白质是如何 磷酸酶可能参与肿瘤的异常增殖 细胞。

Determining the mechanisms that allow neoplastic cells to undergo uncontrolled proliferation is crucial to understanding carcinogenesis. Several recent studies indicate that protein phosphatases, like protein kinases, play important and specific roles in cell-cycle regulation; thus alterations in the expression or regulation of these proteins may affect cell-cycle progression and could even allow cells to undergo unregulated proliferation. A role for protein phosphatases in the tumor promotion process has also emerged from studies with okadaic acid, microcystin-LR, and calyculin A, three highly specific and potent inhibitors of certain serine/threonine protein phosphatases (PPases) that have tumor promoting activity. We have cloned and characterized three human PPases, and one, designated PP5, is particularly attractive for further studies. PP5 is potently inhibited by okadaic acid and calyculin A, two potent tumor promoters in mouse skin. However, unlike the other known PPases, which are expressed at constant levels, PP5 expression is high during log phase growth and low or undetectable in quiescent or differentiated cell cultures. The expression of PP5 is induced by the addition of serum and/or 17beta-estradiol in some cell types, and the inhibition of PP5 expression enhances the ability of both the p53 tumor suppressor protein and dexamethasone, a synthetic glucocorticoid agonist, to induce the expression of the p21 cyclin- dependent kinase inhibitor protein in A549 cells. Together these studies suggest that PP5 plays an important role in the regulation G1/S- phase transition. This proposal is designed to test the hypothesis that protein phosphatases play an important role in cell cycle progression; thus, the interference of their activity may contribute to the aberrant proliferative behavior of neoplastic cells. These studies will focus on the following specific aims: Aim 1. Further characterize the roles of PP5 in the normal and aberrant control of cell cycle progression. Aim 2.Characterize the relationship of PP5 in glucocorticoid mediated inhibition of cell growth and "cross talk" between signaling networks induced by hormones and growth factors. Aim 3.Characterize the mechanisms regulating the expression of PP5. Through these studies we hope to further characterize the role of protein phosphatases in the regulation of cell cycle and gain insight into the how protein phosphatases may be involved in the aberrant proliferation of neoplastic cells.