BIOSYNTHESIS OF PROSTAGLANDINS, HYDROXY-FATTY ACIDS AND LEUKOTRIENSES

前列腺素、羟基脂肪酸和白细胞三烯的生物合成

• 批准号: 3855976
• 负责人: T E ELING
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3855976
• 关键词: DNA replication; arachidonate; cell growth regulation; eicosanoid metabolism; enzyme biosynthesis; enzyme induction /repression; enzyme mechanism; enzyme substrate; epidermal growth factor; fatty acid biosynthesis; hydroxy fatty acid; leukotrienes; linolenate; lipoxygenase; nucleic acid inhibitor; omega 3 fatty acid; oncogenes; oxidation; oxidoreductase inhibitor; peroxidases; prostaglandin endoperoxide synthase; prostaglandins; suppressor mutations

Investigations are concerned with the oxidation of arachidonic and linoleic acid acids to prostaglandins (PG), leukotrienes and hydroxy-fatty acids and the relationship of this metabolism to the regulation or modulation of biological processes. We have studied the role of arachidonic and linoleic acids metabolism in the response of cells to growth factors. PGs are potent inhibitors of EGF-stimulated DNA synthesis ii Syrian hamster embryo (SHE) cells. The expression of c-myc is reduced in the presence of PG and appears not to be modulated in SHE cells by 13-HODE. In response to EGF both the BALBc cells and SHE cells metabolize linoleic acid to 9/13-hydroxyoctadecadienoic acid (9/13-HODE), which when added to these cells enhances DNA synthesis. Inhibition of the 15-lipoxygenase, that catalyzes this oxidation, inhibits DNA synthesis. The addition of 9/13-S-HODE significantly stimulated EGF dependent mitogenesis at concentration as low as 10E-10 M. EGF is required for the lipoxygenase to oxidize linoleic acid to 9/13-HODE. The data indicates that the 15-lipoxygenase is not induced but appears to be activated by either by translocation from the cytosol to the nuclear membranes or tyrosine phosphorylation of the 15-LO to an active form in cells. We have also studied the regulation of PHS expression in cells. TPA and other growth factors in synthesis of new PHS by enhancing the expression of PHS m-RNA. Other data indicates that steroids inhibit the expression of PHS. These findings suggest a possible important role for arachidonic and linoleic acid metabolism in regulating cell growth.

研究涉及花生四烯酸和亚油酸的氧化 酸性酸转化为洋地黄素（PG）、白三烯和羟基脂肪酸， 这种代谢与调节或调制的关系 生物过程。 我们研究了花生四烯酸和亚油酸的作用 细胞对生长因子反应中的酸代谢。 PG是 EGF刺激的DNA合成的有效抑制剂ii叙利亚仓鼠胚胎 (SHE)细胞 在PG存在下，c-myc的表达减少， 在SHE细胞中似乎不受13-HODE的调节。 关于EGF BALBc细胞和SHE细胞都代谢亚油酸， 9/13-羟基十八碳二烯酸（9/13-HODE），当加入这些 细胞增强DNA合成。 抑制15-脂氧合酶， 催化氧化抑制DNA合成 添加 9/13-S-HODE显著刺激EGF依赖的有丝分裂， 浓度低至10 E-10 M。 EGF是脂肪氧化酶所必需的。 将亚油酸氧化成9/13-HODE。 所述数据指示所述 15-脂氧合酶不被诱导，但似乎被以下两种物质激活： 从细胞质到核膜或酪氨酸的转运 在细胞中，15-LO磷酸化为活性形式。 我们还 研究了PHS在细胞中的表达调控。 TPA和其他增长 通过增强PHS m-RNA的表达来调节新PHS的合成。 其他数据表明，类固醇抑制PHS的表达。 这些 研究结果表明，花生四烯酸和亚油酸可能发挥重要作用， 酸代谢调节细胞生长。