Coupling of COX-1 to mPGES1 for prostaglandin E2 biosynthesis in the murine mammary gland.
The mammary gland, like most tissues, produces measurable amounts of prostaglandin E2 (PGE2), a metabolite of arachidonic acid produced by sequential actions of two cyclooxygenases (COX-1 and COX-2) and three terminal PGE synthases: microsomal prostaglandin E2 synthase-1 (mPGES1), mPGES2, and cytosolic prostaglandin E2 synthase (cPGES). High PGE2 levels and COX-2 overexpression are frequently detected in mammary tumors and cell lines. However, less is known about PGE2 metabolic enzymes in the context of normal mammary development. Additionally, the primary COX partnerships of terminal PGE synthases and their contribution to normal mammary PGE2 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 PGE2 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 PGE2 receptors, EP2 and EP4, is also temporally regulated, with highest levels detected at stages of maximal proliferation. PGE2 production is dependent on COX-1, as PGE2 levels are nearly undetectable in COX-1-deficient mammary glands. Interestingly, PGE2 levels are similarly reduced in lactating glands of mPGES1-deficient mice, indicating that PGE2 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.
Chandrasekharan
Subhashini
S
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Foley
Nicholas A
NA
Jania
Leigh
L
Clark
Patsy
P
Audoly
Laurent P
LP
Koller
Beverly H
BH
D000818:Animals; D051545:Cyclooxygenase 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D008321:Mammary Glands, Animal / Q000254:growth & development / Q000378:metabolism*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011247:Pregnancy; D011451:Prostaglandin-Endoperoxide Synthases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018078:Receptors, Prostaglandin E / Q000235:genetics; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype
D008565:Membrane Proteins; C545645:Ptger2 protein, mouse; C545651:Ptger4 protein, mouse; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D051545:Cyclooxygenase 1; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D015232:Dinoprostone