Analyses of prostaglandin E synthases that represent a potential target for novel anti-inflammatory drugs

对代表新型抗炎药物潜在靶标的前列腺素 E 合酶的分析

• 批准号: 15390031
• 负责人: MURAKAMI Makoto
• 金额: $ 9.79万
• 依托单位: Tokyo Metropolitan Organization for Medical Research (2005)Showa University (2003-2004)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15390031/
• 关键词: prostaglandin E2; PGE synthase; cyclooxygenase; arachidonate metabolism; iknockout mice; inflammation; cancer; anti-inflammatory drug; プロスタグランジンE2; PGE合成酵素; 潰瘍性大腸炎; 生殖; 抗炎症薬; RGE_2合成酵素; 免疫組織化学; PGE2; PGE2合成酵素

This study aims to clarify the functional aspects of three PGE_2 synthases (mPGES-1, mPGES-2 and cPGES) both in vitro and in vivo. In cell culture studies, mPGES-1, a stimulus-inducible, perinuclear enzyme, shows preferential functional coupling with the inducible cyclooxygenase (COX) isozyme, COX-2, to produce PGE_2. mPGES-2, a constitutive enzyme that is initially expressed as a Golgi membrane-associated protein and then released into the cytoplasm after proteolytic removal of the N-terminal hydrophobic domain, is coupled with both constitutive COX-1 and inducible COX-2. cPGES is a cytosolic, constitutive enzyme, and its association with Hsp90 and concomitant phsophorylation by casein kinase-2, an Hsp90 client protein, following Ca^<2+>-evoked stimuli eventually leads to a temporal COX-1-dependent PGE_2 generation. Whereas mPGES-1-deficient mice are normally born, grow and are fertile under normal housing condition, they exhibit reduced nociceptive response, inflammatory granulation … More and arthritis, and tumor growth and metastasis relative to replicate wild-type mice, implying the role of mPGES-1-derived PGE_2 in pain, inflammation and cancer. In contrast, there is an exacerbation of inflammatory bowel disease in mPGES-1-null mice compared with that in wild-type littermates, suggesting an additional contribution of mPGES-1 to the production of the gastrointestinal tissue-protective PGE_2. Thus, even though putative chemicals that specifically inhibit mPGES-1 might be useful as anti-nociceptive, inflammatory, and cancer drugs, some adverse side-effects such as gastrointestinal ulcer should be taken into consideration. Mice deficient in cPGES are perinatal lethal. Some developmental defects are found in several tissues of cPGES-null mice such as skin and lung, in which PGE_2 levels are markedly decreased. In contrast, PGE_2 levels in tissues seemingly unaffected by cPGES knockout, such as heart and liver, are similar between cPGES-null and wild-type mice. However, no such abnormalities have been reported for mice deficient in upstream PGE_2-biosynthetic enzymes or PGE_2 receptors, suggesting that the severe phenotypes occurred in cPGES-deficient mice might result from the lack of some unique function(s), rather than the PGE_2-synthetic function, of cPGES. Less

本研究旨在阐明三种PGE_2脱氢酶（mPGES-1、mPGES-2和cPGES）在体外和体内的功能。在细胞培养研究中，mPGES-1，一种刺激诱导的核周酶，显示出与诱导型环氧合酶（考克斯）同工酶考克斯-2优先的功能偶联，以产生PGE_2。mPGES-2是一种组成型酶，最初表达为高尔基体膜相关蛋白，然后在蛋白水解去除N-末端疏水结构域后释放到细胞质中，与组成型考克斯-1和诱导型考克斯-2偶联。cPGES是一种胞质组成型酶，它与热休克蛋白90的结合以及伴随的酪蛋白激酶-2磷酸化，酪蛋白激酶-2是一种热休克蛋白90的客户蛋白，在Ca^<2+>诱导的刺激后，最终导致暂时的考克斯-1依赖性PGE_2的产生。尽管mPGES-1缺陷型小鼠在正常的饲养条件下正常出生、生长和生育，但它们表现出降低的伤害性反应、炎性肉芽形成和炎性肉芽肿。 ...更多信息 和关节炎，以及肿瘤生长和转移相对于复制野生型小鼠，暗示mPGES-1衍生的PGE_2在疼痛，炎症和癌症中的作用。与此相反，mPGES-1基因敲除小鼠的炎症性肠病较野生型小鼠加重，表明mPGES-1对胃肠道组织保护性PGE_2的产生有额外的贡献。因此，尽管特异性抑制mPGES-1的推定化学物质可能用作抗伤害、炎症和癌症药物，但应考虑到一些不良副作用，如胃肠道溃疡。缺乏cPGES的小鼠是围产期致死的。cPGES基因敲除小鼠的皮肤、肺等组织存在一定的发育缺陷，其中PGE_2水平明显降低。与此相反，在cPGES敲除小鼠和野生型小鼠之间，似乎不受cPGES敲除影响的组织（如心脏和肝脏）中的PGE_2水平相似。然而，在缺乏前列腺素E_2生物合成酶或前列腺素E_2受体的小鼠中，未见此类异常的报道，提示cPGES缺陷小鼠出现的严重表型可能是由于cPGES缺乏某些独特的功能，而不是由于其PGE_2合成功能。少

项目成果

Contribution of membrane-associated prostaglandin E2 synthase (mPGES) to bone resorption.

膜相关前列腺素 E2 合酶 (mPGES) 对骨吸收的贡献。

• 发表时间: 2003
• 期刊: J.Cell Physiol. 197
• 作者: Saegusa;M.;Murakami;M.;Nakatani;Y.;Yamakawa;K.;Katagiri;M.;Matsuda;K.;Nakamura;K.;Kudo;I.;Kawaguchi;H.
• 通讯作者: H.

Coupling between cyclooxygenases and prostaglandin F_<2α> synthase: detection of an inducible, glutathione-activated, membrane-bound prostaglandin F_<2α> -synthetic activity.

环氧合酶和前列腺素F_ 2α 合酶之间的偶联：检测可诱导的、谷胱甘肽激活的、膜结合的前列腺素F_ 2α 合成活性。

• 发表时间: 2003
• 期刊: Biochim.Biophys.Acta 1633
• 作者: Nakashima;K.;Ueno;N.;Kamei;D.;Tanioka;T.;Nakatani;Y.;Murakami;M.;Kudo;I.
• 通讯作者: I.

Regulatory functions of prostaglandin E_2 synthases.

前列腺素 E_2 合酶的调节功能。

• 发表时间: 2003
• 期刊: Adv.Exp.Med.Biol. 525
• 作者: Kudo;I.;Murakami;M.
• 通讯作者: M.

Regulatory functions of prostaglandin E_2 synthases

前列腺素E_2合酶的调节功能

• 发表时间: 2003
• 期刊: Adv. Exp. Med. Biol. 525
• 作者: Kudo;I.;Murakami;M.
• 通讯作者: M.

Nakashima, K. et al.: "Coupling between cyclooxygenases and prostaglandin F2α synthase : detection of an inducibe, glutathione-activated, membrane-bound prostaglandin F2α-synthetic activity."Biochim.Biophys.Acta. 1633. 96-105 (2003)

Nakashima，K.等人：“环加氧酶和前列腺素F2α合酶之间的偶联：检测诱导的、谷胱甘肽激活的、膜结合的前列腺素F2α合成活性。”Biochim.Biophys.Acta.1633.96-105(2003)。