MECHANISMS OF TUMOR PROMOTION AND CARCINOGENESIS

肿瘤促癌机制

• 批准号: 2843978
• 负责人: RICHARD E HONKANEN
• 金额: $ 24.48万
• 依托单位: UNIVERSITY OF SOUTH ALABAMA
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-01-01 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2843978
• 关键词: MCF7 cell; apoptosis; biological signal transduction; carcinogenesis; cell growth regulation; cell proliferation; corticosteroid receptors; enzyme activity; enzyme mechanism; expression cloning; fluorescence microscopy; gene induction /repression; glucocorticoids; hormone regulation /control mechanism; immunocytochemistry; immunofluorescence technique; neoplastic cell; northern blottings; okadaic acid; phosphatase inhibitor; phosphoprotein phosphatase; protein sequence; transfection; transforming growth factors; tumor promoters

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.

确定允许肿瘤细胞经历的机制 不受控制的增殖对于理解癌变至关重要。 最近的一些研究表明，蛋白质磷酸酶，例如蛋白质 激酶，在细胞周期调节中起重要而特定的作用； 因此，这些蛋白质表达或调节的改变可能 影响细胞周期的进展，甚至可以允许细胞发生 不受管制的增殖。 蛋白质磷酸酶在肿瘤中的作用 促进过程也来自冈田酸的研究， 微囊蛋白藻蛋白LR和钙蛋白A，三个高度特异性和有效 某些丝氨酸/苏氨酸蛋白磷酸酶（PPases）的抑制剂 具有肿瘤促进活性的。 我们已经克隆并描述了 三个人类PPases和一个指定的PP5特别有吸引力 进行进一步研究。 PP5被冈田酸和 钙蛋白A，小鼠皮肤中的两个有效的肿瘤启动子。 但是，与众不同 以恒定水平表达的其他已知PPases PP5 在对数阶段生长期间的表达很高，在 静止或分化的细胞培养物。 PP5的表达是 通过在某些细胞中添加血清和/或17beta-雌二醇诱导 类型，PP5表达的抑制可以增强两者的能力 p53肿瘤抑制蛋白和地塞米松，一种合成 糖皮质激动剂诱导p21 cyclin-的表达 A549细胞中的依赖性激酶抑制剂蛋白。 在一起 研究表明，PP5在调节G1/s-中起重要作用 相变。 该建议旨在检验以下假设 蛋白质磷酸酶在细胞周期进程中起重要作用。 因此，其活动的干扰可能导致异常 肿瘤细胞的增殖行为。 这些研究将集中 以下面的特定目的：目标1。进一步描述角色 在细胞周期进程的正常和异常控制下，PP5的of。 AIM 2.将PP5在糖皮质激素介导的 抑制细胞生长和信号网络之间的“交叉谈话” 由激素和生长因子诱导。 瞄准3.特征 调节PP5表达的机制。 通过这些研究我们 希望进一步表征蛋白质磷酸酶在 调节细胞周期并深入了解蛋白质 磷酸酶可能参与肿瘤的异常增殖 细胞。