Inhibition of protein translation as a novel mechanism for prostaglandin E2 regulation of cell functions.
Prostaglandin E2 (PGE2) regulates numerous biological processes by modulating transcriptional activation, epigenetic control, proteolysis, and secretion of various proteins. Scar formation depends on fibroblast elaboration of matrix proteins such as collagen, and this process is strongly suppressed by PGE2 through activation of cAMP-dependent protein kinase A (PKA). However, the actual mechanism by which PGE2-PKA signaling inhibits collagen expression in fibroblasts has never been delineated, and that was the objective of this study. PGE2 unexpectedly induced a rapid reduction in procollagen I protein expression in adult lung fibroblasts, with a half-maximum effect at 1.5 h. This effect reflected its inhibition of translation rather than transcription. Global protein synthesis was also inhibited by PGE2. This action was mediated by PKA and involved both activation of ribosomal protein (rpS6) and suppression of mammalian target of rapamycin (mTOR). Similar effects of PGE2 were demonstrated in mouse peritoneal macrophages (PMs). These findings identify inhibition of translation as a new mechanism by which PGE2 regulates cellular function and a novel example of translational inhibition mediated by opposing actions on two distinct translational control pathways. Translational inhibition would be expected to contribute to dynamic alterations in cell function that accompany the changing PGE2 levels observed in disease states and with various pharmacotherapies.
26301 MSRB III, 1150 W. Medical Center Drive, Ann Arbor, MI 48109-5642. petersm@umich.edu.
Katsuhide
K
Okunishi
Angela J
AJ
DeGraaf
Zbigniew
Z
Zasłona
Marc
M
Peters-Golden
D000818:Animals; D002460:Cell Line; D024042:Collagen Type I / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008168:Lung / Q000166:cytology / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D021381:Protein Transport / Q000502:physiology; D034622:RNA Interference; D038601:Ribosomal Protein S6 / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
D024042:Collagen Type I; D038601:Ribosomal Protein S6; D058570:TOR Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone
fibroblasts; macrophages; mammalian target of rapamycin; protein kinase A; ribosomal protein S6