REGULATION OF PGHS-2 SYNTHESIS--ROLE OF LIPID MEDIATORS

PGHS-2 合成的调节--脂质介质的作用

• 批准号: 2696343
• 负责人: LARRY W DANIEL
• 金额: $ 20.98万
• 依托单位: WAKE FOREST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2696343
• 关键词: MDCK cell; biological signal transduction; cell growth regulation; eicosanoid metabolism; eicosanoids; enzyme induction /repression; gene expression; oncoproteins; phorbols; phosphatidate; phospholipase D; prostaglandin endoperoxide synthase; protein kinase; protein kinase C

Our long-term goal is to determine the role of prostaglandin synthesis in cellular growth control. Several recent studies indicate the importance of prostaglandin endoperoxide synthase, type 2 (PGHS-2) in cellular homeostasis. Deletion of the PGHS-2 gene results in severe renal pathology in mice. In contrast, overexpression of PGHS-2 results in resistance to apoptosis which may contribute to carcinogenesis. These observations suggest potential mechanisms to explain the observation that inhibition of prostaglandin synthesis decreases cancer risk in humans. To approach this long-term goal we will determine the role of lipid mediators in the regulation of prostaglandin synthesis. In our previous studies, we have used the Madin-Darby canine kidney cell line to study prostaglandin synthesis in response to the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA). We find that TPA stimulates phosphatidic acid (PA) production by phospholipase D (PLD). In TPA-stimulated cells, the PA produced by PLD is required for membrane association of Raf-1 and for induction of PGHS-2 gene expression. In contrast, induction of PGHS-2 by epidermal growth factor is not dependent on PLD or protein kinase C (PKC). These data indicate that there are distinct pathways that result in PGHS-2 induction. One of the pathways apparently requires PKC, PLD and Raf-1. Another pathway requires neither PKC nor PLD but may require Raf-1 or a similar kinase activity. To further define these pathways for the control of PGHS-2 synthesis we will pursue the following specific aims: 1) to determine the role of phospholipase D in protein kinase C-dependent signalling and 2) to define the role of Raf-1 in the control of prostaglandin synthesis. Together these studies will give us a better understanding of the control of prostaglandin synthesis and lead to further studies of the role of PGHS-2 in growth control. In addition, new targets for therapeutic intervention should become apparent that can be used to develop treatment strategies that are more selective and have less adverse effects than those currently available.

我们的长期目标是确定前列腺素合成的作用 在细胞生长控制中。 最近的一些研究表明 前列腺素内过氧化物合酶的重要性，第2型（PGHS-2）中的重要性 细胞稳态。 PGHS-2基因的缺失导致严重 小鼠肾脏病理。 相反，PGHS-2结果的过表达 在抗凋亡的耐药性方面可能有助于癌变。 这些观察结果提出了解释的潜在机制 观察到抑制前列腺素合成可降低癌症 人类的风险。 为了实现这一长期目标，我们将确定 脂质介质在前列腺素合成调节中的作用。 在我们先前的研究中，我们使用了Madin-Darby犬肾细胞 响应肿瘤启动子研究前列腺素合成的线 12-O-四烷酰基-13-乙酸酯（TPA）。 我们发现TPA 通过磷脂酶D（PLD）刺激磷脂酸（PA）。 在TPA刺激的细胞中，膜需要PLD产生的PA RAF-1的关联和诱导PGHS-2基因表达。 在 对比，表皮生长因子诱导PGHS-2不是 取决于PLD或蛋白激酶C（PKC）。 这些数据表明 有不同的途径导致PGHS-2诱导。 中的一个 途径显然需要PKC，PLD和RAF-1。 另一个途径 既不需要PKC也不需要PLD，但可能需要RAF-1或类似的激酶 活动。 进一步定义了控制PGHS-2的途径 综合我们将追求以下特定目的：1）确定 磷脂酶D在蛋白激酶C依赖性信号传导和 2）定义RAF-1在控制前列腺素中的作用 合成。 这些研究共同使我们有了更好的理解 控制前列腺素合成并导致进一步研究 PGHS-2在生长控制中的作用。 此外，新的目标 治疗干预应该变得明显 制定更具选择性和更少的治疗策略 不良影响比当前可用的效果。