title: Transcriptional regulation of cyclo-oxygenase expression: three pillars of control.
abstract: Blocking cyclo-oxygenase (COX) isoform activities with non-steroidal anti-inflammatory drugs (NSAIDS) is widely employed in the treatment of arthritis. These agents also hold great promise in the context of pre and post-neoplastic diseases such as colorectal cancer (CRC). Nevertheless, issues of isoform specificity and delivery necessitate the exploration of other strategies to specifically block expression of the COX genes. Approaches that target gene transcription may complement enzyme inhibition. Thus, understanding the regulation of COX isoform transcription may improve the specific inhibition of expression. Three tiers of transcriptional regulation are evident: initiation, alternative splicing and messenger RNA stability. Transcription factors that activate COX-2 expression are elevated in certain disease states and emergency responses such as infection and are therefore potential targets. These factors include C/EBP-beta, phospho- CREB, NF-IL6, AP1, NFkB, and TCF-4/LEF-1. In this review we highlight another factor, c-MYB as a key COX-2 regulator in CRC. Alternative exon usage is another tier of regulation that has not received much attention. For instance, COX-1 splice variants (also known as COX-3 and PCOX-1a) may broaden the spectrum of COX activities in disease. Similarly, whilst mRNA stability is clearly modulated by steroids in the case of COX-2, the wider implications of targeting mRNA stability have not been afforded the same attention. Finally, it seems that some NSAIDS exert part of their action directly on COX-2 transcriptional regulation explaining why such agents display greater effects on this isoform than enzyme inhibition data would suggest.
authors.affiliation: Differentiation and Transcription Group, Trescowthick Laboratories, Peter MacCallum Cancer Centre, Locked Bag #1 A' Beckett Street, Victoria, 8006, Australia. Rob.Ramsay@Petermac.org
authors.forename: R G
authors.initials: RG
authors.lastname: Ramsay
authors.forename: D
authors.initials: D
authors.lastname: Ciznadija
authors.forename: M
authors.initials: M
authors.lastname: Vanevski
authors.forename: T
authors.initials: T
authors.lastname: Mantamadiotis
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001483:Base Sequence; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases