Coupling of COX-1 to mPGES1 for prostaglandin E2 biosynthesis in the murine mammary gland
Coupling of COX-1 to mPGES1 for prostaglandin E2 biosynthesis in the murine mammary gland
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DOI：
10.1194/jlr.m500213-jlr200
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发表时间：
2005-12-01
影响因子：
6.5
通讯作者：
Koller, BH
中科院分区：
文献类型：
--
作者：
Chandrasekharan, S;Foley, NA;Koller, BH
像大多数组织一样，乳腺产生可测量的前列腺素E-2(PGE(2))，这是一种花生四烯酸的代谢物，由两个环氧合酶(COX-1和COX-2)和三个末端PGE合成酶(MPGES1)、mPGES2和胞浆前列腺素E-2合成酶(CPGES)的顺序作用产生。在乳腺肿瘤和细胞系中经常检测到高PGE(2)水平和COX-2过表达。然而，在正常乳腺发育的背景下，对PGE(2)代谢酶知之甚少。此外，PGE末端合成酶的初级COX伙伴关系及其对正常乳腺PGE(2)生物合成的贡献还知之甚少。我们证明，通常被认为是结构性的COX-1的表达随着小鼠乳腺的乳源性分化而急剧增加。与之一致的是，总前列腺素E(2)水平在整个乳房发育过程中都在增加，其中在哺乳组织和母乳中的水平最高。相比之下，COX-2的表达极低，在乳腺退化期仅有轻微的增加。G(S)偶联的前列腺素E(2)受体EP2和EP4的表达也受到时间的调节，在最大增殖阶段检测到最高水平。PGE(2)的产生依赖于COX-1，因为在COX-1缺乏的乳腺中几乎检测不到PGE(2)水平。有趣的是，在mPGES1缺陷的小鼠的乳腺体中，PGE(2)的水平也同样降低，这表明PGE(2)的生物合成是COX-1和mPGES1协同活动的结果。因此，我们首次为COX-1和mPGES1在活体小鼠乳腺中的功能偶联提供了证据。
The mammary gland, like most tissues, produces measurable amounts of prostaglandin E-2 (PGE(2)), a metabolite of arachidonic acid produced by sequential actions of two cyclooxygenases (COX-1 and COX-2) and three terminal PGE synthases: microsomal prostaglandin E-2 synthase-1 (mPGES1), mPGES2, and cytosolic prostaglandin E-2 synthase (cPGES). High PGE(2) levels and COX-2 overexpression are frequently detected in mammary tumors and cell lines. However, less is known about PGE(2) metabolic enzymes in the context of normal mammary development. Additionally, the primary COX partnerships of terminal PGE synthases and their contribution to normal mammary PGE(2) biosynthesis are poorly understood. We demonstrate that expression of COX-1, generally considered constitutive, increases dramatically with lactogenic differentiation of the murine mammary gland. Concordantly, total PGE(2) levels increase throughout mammary development, with highest levels measured in lactating tissue and breast milk. In contrast, COX-2 expression is extremely low, with only a modest increase detected during mammary involution. Expression of the G(s)-coupled PGE(2) receptors, EP2 and EP4, is also temporally regulated, with highest levels detected at stages of maximal proliferation. PGE(2) production is dependent on COX-1, as PGE(2) levels are nearly undetectable in COX-1-deficient mammary glands. Interestingly, PGE(2) levels are similarly reduced in lactating glands of mPGES1-deficient mice, indicating that PGE(2) biosynthesis results from the coordinated activity of COX-1 and mPGES1. We thus provide evidence for the first time of functional coupling between COX-1 and mPGES1 in the murine mammary gland in vivo.