Knockout mice lacking cPGES/p23, a constitutively expressed PGE2 synthetic enzyme, are peri-natally lethal.
Cytosolic prostaglandin (PG) E synthase (cPGES) is constitutively expressed in various cells and regulates cyclooxygenase (COX)-1-dependent immediate PGE(2) generation. Its primary structure is identical to co-chaperone p23, a heat shock protein 90 (Hsp90)-binding protein. We have revealed that Hsp90 regulated both cPGES/p23 and its client protein kinase CK2. In this study, in order to examine the role of cPGES/p23 in vivo, we generated mice deficient in cPGES/p23 by a targeted disruption of exons 2 and 3, containing Tyr9, which is essential for catalytic activity. Heterozygotes are viable, fertile, and appear normal, despite a decrease in cPGES/p23 protein level. A generation of offsprings derived from intercrosses of cPGES/p23 homozygous mice revealed that 109, 247, and 10 pups were wild type, heterozygous, and homozygous, respectively; however, all homozygotes died at birth. The absence of viable null mutants, with heterozygotes and wild-type offspring obtained at a ratio of approximately 2:1, indicated that homozygosity for the cPGES/p23 null mutant leads to peri-natal lethality. Embryos homozygous for cPGES/p23-null had lower body weights than wild-type embryos, and abnormal morphology of skin and lungs. Moreover, the PGE(2) content in the lungs of cPGES/p23-null embryos was lower than that of the wild type. These results indicate that cPGES-derived PGES is involved in the normal development of mouse embryonic lung.
Nakatani
Yoshihito
Y
Department of Health Chemistry, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagaw-ku, Tokyo 142-8555, Japan. nakatani@pharm.showa-u.ac.jp
Hokonohara
Yutaka
Y
Kakuta
Shigeru
S
Sudo
Katsuko
K
Iwakura
Yoichiro
Y
Kudo
Ichiro
I
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D001921:Brain / Q000196:embryology / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D004628:Embryonic Structures / Q000002:abnormalities / Q000378:metabolism; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics / Q000378:metabolism; D005318:Fetal Heart / Q000378:metabolism; D005804:Genes, Lethal; D005838:Genotype; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000196:embryology / Q000378:metabolism; D008168:Lung / Q000196:embryology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D000071876:Prostaglandin-E Synthases; D012867:Skin / Q000196:embryology / Q000378:metabolism
D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone