BIOSYNTHESIS OF PROSTAGLANDINS, HYDROXY-FATTY ACIDS, AND LEUKOTRIENES

前列腺素、羟基脂肪酸和白三烯的生物合成

• 批准号: 3755498
• 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/3755498
• 关键词: arachidonate; biological signal transduction; enzyme activity; epidermal growth factor; epithelium; fatty acid biosynthesis; gene expression; growth factor receptors; hydroxy fatty acid; laboratory rat; leukotrienes; linoleate; lipoxygenase; messenger RNA; molecular cloning; nucleic acid sequence; oxidation; phorbols; phosphorylation; prostaglandin endoperoxide synthase; prostaglandins; protein tyrosine kinase; receptor expression

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. Epidermal growth factor(EGF) treatment of SHE cells stimulates the metabolism of linoleic acid to 13-(S)-HODE. The "activation" of this apparently unique lipoxygenase is dependent on the tyrosine kinase activity of the EGF receptor but the mechanism is poorly understood. In response to EGF a very rapid formation of 13-HODE was observed followed by a more extensive but slower increase in formation. Inhibition of 13- HODE formation inhibits EGF mitogenesis and the addition to cells greatly enhances the response to EGF. The importance of this 15-lipoxygenase in EGF dependent mitogenesis is established in Syrian hamster embryo cells (SHE) cells. Balb MK keratinocytes which are dependent on EGF for growth metabolize arachidonic acid to PGE2 and linoleic acid to 9- and 13- HODE. However, formation of the HODE metabolites was catalyzed by PHS-2 rather than a 15-lipoxygenase as determined by inhibitor and chiral analysis of the metabolites. Studies are currently underway to further investigate the mechanism for the activation of the 15-lipoxygenase by EGF using both biochemical and molecular biology techniques. We have also cloned the PHS whose expression in rat tracheal epithelial cells is regulated by 12-O-tetra-decanoylphorbol-13-acetate(TPA). Analysis of the partial sequence of several clones suggest that a possible third form of PHS is present in these cells. Further studies are in progress to fully characterize this form of PHS.

研究涉及花生四烯酸和亚油酸的氧化 酸性酸对甘草素（PG）、白三烯和羟基脂肪酸的影响 以及这种代谢与调节或调节 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。 表皮生长因子（EGF）治疗SHE细胞刺激细胞增殖。 亚油酸代谢为13-（S）-HODE。 这种“激活” 显然独特的脂氧合酶依赖于酪氨酸激酶 EGF的作用机制还不清楚。 在 EGF反应后，观察到13-HODE的快速形成， 通过更广泛但更缓慢的形成增加。抑制13- HODE的形成大大抑制了EGF的有丝分裂和向细胞的添加 对EGF的反应 这种15-脂氧合酶在 表皮生长因子依赖的有丝分裂在叙利亚仓鼠胚胎细胞中建立 (SHE)细胞 Balb MK角质形成细胞依赖于EGF， 生长代谢花生四烯酸为PGE 2和亚油酸为9-和13- HODE。 然而，HODE代谢产物的形成是由PHS-2催化的， 而不是通过抑制剂和手性测定的15-脂氧合酶 代谢物的分析。 目前正在进行研究， 研究15-脂氧合酶的激活机制， EGF是一种生物化学和分子生物学技术。 我们有 还克隆了PHS，其在大鼠气管上皮细胞中的表达是 由12-O-四癸酰基佛波醇-13-乙酸酯（TPA）调节。 分析 几个克隆的部分序列表明，可能的第三种形式的 PHS存在于这些细胞中。 进一步的研究正在进行中， 这就是PHS的特点。