Regulation of intracellular cyclooxygenase levels by gene transcription and protein degradation

• Published in: Progress in lipid research Vol. 46; no. 2; pp. 108 - 125
• Main Authors: Kang, Yeon-Joo, Mbonye, Uri R., DeLong, Cynthia J., Wada, Masayuki, Smith, William L.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.03.2007
• Subjects: Animals; Aspirin; COX-2; Cyclooxygenase 1 - genetics; Cyclooxygenase 1 - metabolism; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; ER-associated protein degradation; Gene Expression Regulation, Enzymologic; Gene regulation; Humans; Nonsteroidal anti-inflammatory drugs; Prostaglandin endoperoxide H synthase; Transcription, Genetic - genetics; TRAF; JNK; TRADD; PGH 2; IL-1R; ECSIT; AP-1; TNF; MyD88; TRAM; ER-associated protein degradation; NF-κB; TBK1; PI3K; PPRE; TAK-1; IL-1; PKA; PKC; CAK; IRAK; CRE; TKR; TRIF; TLR4; ERK; C/EBP; COX-2; PLC; Gene regulation; SRE; LPS; IκB; CREB; Prostaglandin endoperoxide H synthase; NSAIDs; HUVEC; MKKK; Nonsteroidal anti-inflammatory drugs; TNFR; Aspirin; PMA; ASK1; IKK; USF; MKK; COX; CR; NIK; ATF; RIP; PAK
• ISSN: 0163-7827; 1873-2194
• DOI: 10.1016/j.plipres.2007.01.001

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.