Review
Regulation of intracellular cyclooxygenase levels by gene transcription and protein degradation

https://doi.org/10.1016/j.plipres.2007.01.001Get rights and content

Abstract

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.

Introduction

Cyclooxygenases-1 and -2 (COX-1 and -2)1 convert arachidonic acid, hydrolyzed from cell membrane phospholipids by a phospholipase A2, to prostaglandin endoperoxide H2 (PGH2), the precursor of the prostanoids–thromboxane A2 and the prostaglandins (PGD2, PGE2, PGF and PGI2) [1], [2], [3], [4]. Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat inflammation, pain and fever, and these actions are generally attributed to inhibition of COX-2 [5], [6], [7]. Prostanoids are lipid mediators that normally act in a paracrine and autocrine manner to coordinate intercellular events stimulated by a circulating hormone [1]. Their over-production is associated with pathologies such as tumorigenesis and arthritis whereas atherogenesis is associated with decreased formation of certain prostanoids [8], [9], [10], [11], [12].

COX-1 and COX-2 are the products of different genes [1], [13], [14]. COX-1 is present in many but not all cell types [15] and when present is usually expressed constitutively. COX-1 gene expression is developmentally controlled and can be upregulated by tumor-promoting phorbol esters or growth factors as seen with primary megakaryocytes and megakaryoblast cell lines (Table 1) [16], [17], [18], [19], [20]. In contrast to COX-1, COX-2 expression is typically transient. Depending on the cell type COX-2 expression can be rapidly induced by bacterial endotoxin (LPS), cytokines such as IL-1, IL-2, and TNF-α, growth factors, and the tumor promoter phorbol myristate acetate (PMA) [1], [13], [14] (Table 2). It should be noted that some cells in lung [21], brain [22] and kidney [23], pancreatic β-cells [24], and gastrointestinal carcinomas [11], [25], [26] exhibit constitutive COX-2 expression.

Although the COX-1 and COX-2 proteins are highly homologous, they have some obvious sequence and structural differences including different signal peptides and significant sequence differences in their membrane binding domains [1], [3], [4]. Most notably, COX-2 but not COX-1 contains a unique 27 amino acid sequence near its C-terminus (Fig. 1). This is an instability element involved in COX-2 protein degradation that is discussed later in this review.

While relatively little information has been published about the transcriptional regulation of the COX-1 gene or the mechanism of COX-1 or COX-2 protein degradation, the regulation of COX-2 gene expression has been investigated rather extensively. In this review, we focus on recent advances in our understanding of COX-1 and COX-2 gene expression and the degradation of COX-1 and COX-2 proteins.

Section snippets

Regulation of COX-1 gene expression

The human COX-1 gene (Ptgs1), located on chromosome 9, is approximately 22 kb in length and contains 11 exons [27], [28]. The COX-1 promoter lacks a TATA or CAAT box, has a high GC content, and contains several transcriptional start sites. All of these properties are characteristic of “housekeeping” genes [14], [29]. Although COX-1 protein is constitutively expressed in most tissues, COX-1 is upregulated by PMA in some cell types including monocytes [30], human umbilical vein endothelial cells

Regulation of COX-2 gene expression

The human COX-2 gene (Ptgs2), located on chromosome 1, is about 8.3 kb long and has 10 exons. Except for the first exon the intron/exon boundaries of the COX-1 and COX-2 genes are the same [14], [35]. There are two major transcripts of COX-2–a 4.5 kb full length mRNA and a 2.6 kb polyadenylated variant that lacks the terminal 1.9 kb of the 3′-untranslated region (UTR). The 3′-UTR of the human COX-2 gene contains 23 copies of the ‘ATTTA’ RNA instability element that participates in

COX-1 and COX-2 protein degradation

There are large differences between the t1/2 values for the degradation of COX-1 and COX-2 proteins [26], [93], [94], [95], [96], [97]. In several different cell types, co-expressing the enzymes, COX-1 degradation is slow or undetectable while the t1/2 for COX-2 protein degradation varies from 2–7 h. These studies suggest that COX-2 degradation is specifically programmed to limit the amount of COX-2. There is anecdotal evidence that prolonged, overexpression of COX-2 is not well tolerated by

Concluding comments

Regulation of COX gene expression is a complex process that varies in different cell types and even between the same cell types in different species. COX-1 and COX-2 genes are activated by a wide variety of stimuli acting through numerous signaling pathways and the relative contribution of each depends upon the stimulus, the cell type, and the time of stimulation. These factors and conditions determine which transcription factors are associated with the COX gene response elements. Although we

Acknowledgements

The portion of the work reviewed in this paper that was performed in the laboratory of the corresponding author was supported by NIH Grant GM68848.

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