Mini-review
Cyclooxygenase-1 and -2 isoenzymes

https://doi.org/10.1016/S1357-2725(98)00152-6Get rights and content

Abstract

The cyclooxygenase isoenzymes (COX-1 and -2) catalyze the rate-limiting steps in prostanoid biosynthesis. COX-1 and -2 genes encode two isoenzymes with overlapping yet distinct expression patterns and functions. Physiologically, various extracellular stimuli such as growth factors, cytokines and tumor promoters regulate the expression of COX-1 and -2 genes at both transcriptional and post-transcriptional levels. COX-2 is overexpressed in rheumatoid arthritis, colorectal and breast cancer. Prostanoids produced by the COX pathway signal via plasma membrane-localized, G-protein-coupled receptors as well as via nuclear receptors. Currently, several COX-2-selective inhibitors are developed to control the anti-inflammatory and anti-neoplastic activities of the COX-2 isoenzyme. Inhibition of the COX isoenzyme activity and/or expression may be the basis of future generation of anti-inflammatory and anti-neoplastic drugs.

Introduction

The cyclooxygenase (COX) enzyme (E.C.1.14.99.1; also known as prostaglandin H synthase) catalyzes the formation of the prostaglandin endoperoxide from arachidonic acid to PGH2. The purpose of this minireview is not to be comprehensive but rather to summarize recent findings on the regulation and functions of the COX-1 and -2 isoenzymes from the point of view of physiological and pathophysiological roles.

Although recognized as an important catalytic step, the concept of the COX enzyme as a major regulatory step in prostaglandin synthesis was proposed in the 1980 s by laboratories of Bailey and Needleman1, 2. This challenged the existing paradigm of the day that phospholipase step is the rate limiting step in prostanoid biosynthesis. Currently, it is accepted that the two isoforms of the COX enzymes are regulated at the level of expression and constitute an important regulatory event in the long-term control of prostanoid synthesis[3]. Regulation of phospholipase isoenzymes will not be covered in this minireview.

Section snippets

Structure

Pioneering work on enzymology and protein chemistry of the COX enzyme was conducted using the enzyme preparation from Ram seminal vesicle, which is highly enriched in this enzyme[4]. Purified enzyme was used to prepare antisera as well as to obtain the protein sequence and such probes were used to clone the cDNA for the enzyme, which was later shown to be the COX-1 isoform5, 6, 7. The COX-2 isoenzyme was cloned several years later8, 9, 10, 11. The two proteins are approximately 60% identical

Synthesis and degradation

Early studies indicated the high turnover rates of the COX enzymatic activity, which suggested regulation at the level of gene expression. The regulation of COX-2 gene expression is schematically depicted in Fig. 1. The genes for both COX-1 and -2 are highly regulated; COX-1 is generally induced by cell quiescence and differentiation whereas COX-2 is an immediate-early gene induced by a wide variety of stimuli including hormones, growth factors, cytokines and shear stress (reviewed in[14]). The

Medical/industrial application

Although COX-2 induction is a general response to cell activation, stress and injury, dysregulated COX-2 expression is associated with a variety of pathological conditions including colorectal cancer, rheumatoid arthritis, gastric cancer, breast cancer and non small cell lung cancer37, 38, 39, 40, 41. In many cases, COX-1 is also induced in pathological conditions37, 39, 40. Epidemeological studies have already provided evidence for the protective effects of non-steroidal anti-inflammatory

Acknowledgements

This work is supported by NIH grants HL49094 and HL54710. TH dedicates this work to the memory of the late U Thein Han.

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