ARACHIDONIC ACID AND LINOLEIC ACID METABOLISM IN CELL PROLIFERATION

我们研究了对生长因子（EGF、FGF和PGDF）的反应， 观察到叙利亚仓鼠胚胎细胞FGF的脂质代谢， 刺激PGHS-2的表达和有丝分裂。 FGF没有增强 亚油酸代谢为13-HODE。 一些数据表明， 拟南芥素参与FGF依赖的有丝分裂，但完全参与FGF依赖的有丝分裂。 缺乏证据。 EGF依赖的有丝分裂被抑制， 脂氧合酶抑制剂，但不减弱PGHS抑制剂。 EGF的作用 不刺激前列腺素的形成，但刺激新陈代谢 将亚油酸转化为13-HODE。 13-HODE的形成受到以下因素的调节： EGF受体的酪氨酸激酶活性，但其机制是 不太了解。 由于这些代谢研究使用外源性 底物，我们需要确定13-HODE是否内源性形成。 我们 使用GG-MS技术测量内源性13-HODE的形成。 13-HODE检测到足够的浓度，以提高EGF- 依赖性有丝分裂。 13-HODE的双相形成， EGF依赖于EGF受体酪氨酸激酶 活动 亚油酸代谢产物增强EGF依赖性 在supB+ SHE细胞中有丝分裂发生，而在supB-SHE细胞中没有。 我们还 研究了增强EGF所需的结构特征 有丝分裂 我们发现13-S-HpODE和13-S-HODE是最有效的 增强的有丝分裂对代谢物具有选择性，这表明 一种非常特异的生物学靶点，如未表征的受体。 EGF刺激c-myc、c-jun和junB的表达。 添加 PGE_2刺激cAMP的形成。 改变cAMP的其他药物 水平相应地改变有丝分裂。 最近的报道在 文献表明cAMP可以阻断或刺激生长因子 RAF-1激酶的信号通路。 数据显示， 代谢似乎在EGF信号通路中起重要作用 在SHE细胞中

We have studied the response to growth factors (EGF, FGF and PGDF) and lipid metabolism in Syrian hamster embryo cell FGF was observed to stimulate the expression of PGHS-2 and mitogenesis. FGF did not enhance the metabolism of linoleic acid to 13-HODE. Some data suggest that prostaglandins were involved in FGF dependent mitogenesis but complete evidence is lacking. EGF-dependent mitogenesis was inhibited by lipoxygenase inhibitors but not attenuated by PGHS inhibitors. EGF did not stimulate prostaglandin formation but did stimulate the metabolism of linoleic acid to 13-HODE. The formation of 13-HODE is regulated by the tyrosine kinase activity of the EGF receptor but the mechanism is poorly understood. Since these metabolism studies used exogenous substrates we need to determine if 13-HODE was endogenously formed. We used GG-MS techniques to measure the formation of endogenous 13-HODE. 13-HODE was detected in sufficient concentrations to enhance EGF- dependent mitogenesis. A biphasic formation of 13-HODE in response to EGF was observed which was dependent on the EGF receptor tyrosine kinase activity. The linoleic acid metabolites potentiated EGF-dependent mitogenesis in the supB+ SHE cells but not in the supB-. We have also examined the structural characteristics necessary for enhancing EGF mitogenesis. We found that 13-S-HpODE and 13-S-HODE are the most potent and enhanced mitogenesis was selective for the metabolites which suggest a very specific biological target such as an uncharacterized receptor. EGF stimulated the expression of c-myc, c-jun and junB. The addition of PGE2 stimulated the formation of cAMP. Other agents that changed cAMP levels correspondingly altered mitogenesis. Recent reports in the literature indicate that cAMP can block or stimulate growth factor signaling pathways at the RAF-1 kinase. The data indicate that lipid metabolism appears to play an important role in the EGF-signaling pathway in SHE cells.