Regulation of intracellular cyclooxygenase levels by gene transcription and protein degradation.
Cyclooxygenases-1 and -2 (COX-1 and -2) catalyze the committed step in prostaglandin formation. Each isozyme subserves different biological functions. This is, at least in part, a consequence of differences in patterns of COX-1 and COX-2 expression. COX-1 is induced during development, and COX-1 mRNA and COX-1 protein are very stable. These latter properties can explain why COX-1 protein levels usually remain constant in those cells that express this isozyme. COX-2 is usually expressed inducibly in association with cell replication or differentiation. Both COX-2 mRNA and COX-2 protein have short half-lives relative to those of COX-1. Therefore, COX-2 protein is typically present for only a few hours after its synthesis. Here we review and develop the concepts that (a) COX-2 gene transcription can involve at least six different cis-acting promoter elements interacting with trans-acting factors generated by multiple, different signaling pathways, (b) the relative contribution of each cis-acting COX-2 promoter element depends on the cell type, the stimulus and the time following the stimulus and (c) a unique 27 amino acid instability element located just upstream of the C-terminus of COX-2 targets this isoform to the ER-associated degradation system and proteolysis by the cytosolic 26S proteasome.
Kang
Yeon-Joo
YJ
Department of Biological Chemistry, University of Michigan Medical School, 5301 Medical Science Research Building III, Ann Arbor, MI 48109, USA.
Mbonye
Uri R
UR
DeLong
Cynthia J
CJ
Wada
Masayuki
M
Smith
William L
WL
D000818:Animals; D051545:Cyclooxygenase 1 / Q000235:genetics* / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D014158:Transcription, Genetic / Q000235:genetics*
D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2