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Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:679-685
Published online before print January 27, 2005, doi: 10.1161/01.ATV.0000157899.35660.61
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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:679.)
© 2005 American Heart Association, Inc.

Brief Reviews

Transcriptional Control of COX-2 via C/EBPß

Kenneth K. Wu; Jun-Yang Liou; Katarzyna Cieslik

From the Vascular Biology Research Center, Institute of Molecular Medicine and Division of Hematology, University of Texas Health Science Center at Houston, Tex.

Correspondence to Kenneth K. Wu, Vascular Biology Research Center, Institute of Molecular Medicine and Division of Hematology, University of Texas Health Science Center at Houston, 6431 Fannin, MSB 5.016, Houston, TX 77030. E-mail Kenneth.K.Wu{at}uth.tmc.edu


*    Abstract
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Cyclooxygenase-2 (COX-2) is a highly inducible enzyme exerting diverse actions on cell functions, including proliferation, migration, and DNA damage. Enhanced COX-2 expression may be protective, but excessive expression may be harmful, causing inflammation, atheromatous plaque instability, and intimal hyperplasia. COX-2 transcriptional activation by proinflammatory mediators has been extensively characterized. In this review, the role of C/EBP in regulating COX-2 transcription is highlighted. Recent advances in control of COX-2 transcription by aspirin and salicylate and by a cell cycle-dependent endogenous mechanism are described. The recent progress sheds light on the pathophysiological mechanisms of COX-2 and new transcription-based strategy for controlling COX-2 overexpression and COX-2–mediated cardiovascular diseases.

Cyclooxygenase-2 (COX-2) is a highly inducible enzyme exerting diverse actions on cell functions, including proliferation, migration, and DNA damage. Enhanced COX-2 expression may be protective, but excessive expression may be harmful, causing inflammation, atheromatous plaque instability, and intimal hyperplasia. In this review, the role of C/EBP in regulating COX-2 transcription is highlighted.


Key Words: aspirin • C/EBP • COX-2 • inflammation • NF-{kappa}B


*    Introduction
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Cyclooxygenase (COX, also known as prostaglandin [PG]H synthase or PGHS) occupies a pivotal position in PG and thromboxane A2 (TXA2) synthesis. It is a bifunctional enzyme containing a cyclooxygenase catalytic center, which adds 2 oxygen (bisoxygenation) to arachidonic acid (AA) to form a peroxide, PGG2, and a peroxidase active site, which reduces PGG2 to PGH2.1 PGH2 is a common precursor for synthesis of biologically active prostanoids, including PGE2, PGI2 (prostacyclin), TXA2, PGD2, and PGF2{alpha}. There are 2 isoforms of COX; COX-1 is constitutively expressed, whereas COX-2 is inducible by diverse cytokines, mitogenic factors, and endotoxins.2 These 2 isoforms of COX share a high degree of sequence identity and structural resemblance.1 Both are homodimers with a long substrate channel and a stretch of hydrophobic residues that anchor the enzymes to the inner surface of endoplasmic reticulum and nuclear envelope.3 Both enzymes contain heme with almost identical spectral characteristics and comparable catalytic parameters.1 Thus, these 2 enzymes catalyze the generation of a similar profile of AA metabolites and might seem to have overlapped cellular activities. However, results from recent studies have provided unequivocal evidence for distinct cellular activities and different pathophysiological roles between these 2 enzymes. COX-2 has been implicated in diverse physiological and pathophysiological processes from renal and cardiovascular physiology to inflammation and tumorigenesis.4–9 In this review, we concentrate on its roles in cardiovascular diseases, with a focus on novel aspects of its transcriptional activation by proinflammatory mediators and the control of its transcriptional activation by aspirin and an endogenous mechanism.

COX-2 Overexpression and Cardiovascular Diseases
Under physiological conditions, COX-2 expression in vascular and cardiac endothelial cells is stimulated primarily by physical forces such as shear stress.10,11 On endothelial activation, cytosolic phospholipase A2 is translocated and colocalized with COX-2 and prostacyclin (PGI2) synthase to endoplasmic reticulum and nuclear envelope,12 where it cleaves AA from membrane phospholipids and AA enters COX-2, where it is converted to PGH2. PGH2 is metabolized by PGI2 synthase to generate PGI2. PGI2 possesses several protective actions, including inhibition of platelet aggregation and smooth muscle cell contraction.13 Recent studies suggest that PGI2 protects endothelial cells from apoptosis and necrosis (unpublished data). PGI2 generated via the COX-2 metabolic pathway exceeds that produced by COX-1, which is constitutively expressed in endothelial cells and also colocalized with PGIS. It is generally believed that COX-1 is involved in producing a constant, albeit small, quantity of PGI2 to maintain a basal physiological function, whereas COX-2 is responsible for a stress-coupled production of robust PGI2 to protect vascular wall from injury by environmental insults.14 It has been suggested that in healthy human subjects without overt vascular diseases, PGI2 is contributed largely by COX-2, consistent with the viewpoint that COX-2 is a key player in protecting vascular wall and maintaining vascular integrity.15,16

PGI2 and TXA2 productions are highly elevated in patients with severe atherosclerosis.17 A recent study suggests that elevated PGI2 generation depends largely on COX-2 and to some extent on COX-1 as well.18 The cellular source of COX-2 that generates PGI2 in atherosclerosis is not entirely clear but is most likely from endothelial and smooth muscle cells. Through production of PGI2, COX-2 may play a protective role in controlling atherosclerotic progression. This notion is supported by a recent report on the formation of atherosclerotic lesions in prostacyclin receptor (IP) versus thromboxane receptor (TP) knockout mice. The atherosclerotic lesions were increased in IP-deleted mice, but when TP was deleted, prostacyclin became less important.19 These results suggest that PGI2 plays an important role in defending against TXA2-mediated vascular changes. However, COX-2 has been shown to be crucial for atherosclerotic lesion formation and atheromatous plaque instability. In low-density lipoprotein receptor-deficient mice fed with fat diet for 6 weeks, COX-2 deletion significantly reduced the atherosclerotic lesions.20 However, in an apolipoprotein E (apo E)-deficient and low-density lipoprotein receptor-deficient mice on a high-fat diet, selective COX-2 inhibition did not decrease the extent of atherosclerosis.21 Analysis of advanced human atheromatous arteries revealed expression of COX-2 in the atherosclerotic lesion.22 Interestingly, COX-2 and inducible microsomal PGE synthase are coexpressed in monocytes infiltrating the atheromatous plaque.23 These results suggest a shift of metabolism to PGE2 production in the plaque. PGE2 elicits inflammatory changes, tissue injury, and matrix degradation resulting in plaque instability.23

Contrary to the simplified concept that COX-2 expression is deleterious to myocardial injury, experimental data indicate that COX-2 also plays a complex role in myocardial infarction and heart failure. It has been shown that COX-2 mediates the cardioprotective effect of ischemic preconditioning through the production of PGI2 and PGE2.24 COX-2 has also been shown to protect heart from doxorubicin-induced injury by generating PGI2.25 By contrast, COX-2 has been implicated to mediate postischemic myocardial infarction and heart failure.26,27 Taken together, the experimental data and clinical findings indicate that COX-2 may be a friend or a foe of vascular integrity, depending on the cell types wherein its expression is induced, the downstream enzymes with which it is coupled, and the relative quantities of protective and damaging prostanoids that it generates.28 The complex roles that COX-2 plays in cardiovascular physiology and diseases may explain the disparity between clinical studies and animal experiments. In relatively healthy human subjects who were placed on selective COX-2 inhibitors for pain or for prevention of colon polyps, there were reports of an increased risk of coronary heart disease.29,30 Although the exact mechanism by which this occurs is not completely understood, it may be attributed to the inhibition of protective prostanoids generated from COX-2, which may be crucial for preventing unstable plaque formation and thrombosis. However, selective COX-2 inhibitors or COX-2 deletion by genetic targeting have been reported to retard atherosclerosis and attenuate cardiac and brain ischemia-reperfusion injuries in animal models. This may be attributed to the control of COX-2 activity in inflammatory cells that infiltrate the atherosclerotic lesions, thereby blocking the production of prostanoids that mediate vascular and tissue inflammation and injury (Figure 1). Because enhanced COX-2 transcriptional activation is pivotal to the understanding of the complex functions of COX-2 and for the design of targeted therapy, there have been considerable interests in characterizing the transcriptional regulation and identifying the key transactivators that are crucial for COX-2 transcriptional activation induced by diverse proinflammatory mediators, mitogenic factors, and shear stress. These subjects have been covered by excellent reviews31 and are not discussed in detail. Instead, we provide new information on the dynamic regulation of COX-2 transcriptional activation by CCAAT/enhancer binding proteins (C/EBP) and the transcription-based control of COX-2 expression that is relevant to cardiovascular diseases.



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  		Figure 1. Paradoxical roles of COX-2 in cardiovascular protection exemplified by endothelial cell (EC) PGI2 production via PGI2 synthase (PGIS) vs cardiovascular damage exemplified by monocyte (M{Phi}) PGE2 via microsomal PGE synthase (mPGES).

Dynamic Regulation of COX-2 Transcriptional Activation by C/EBPß
The core COX-2 promoter region harbors a canonical TATA element and several functionally important enhancer elements, which are well-conserved between humans and mice.32,33 The enhancer elements are localized within a 500-basepair 5'-untranslated region of human COX-2 promoter. Functional analysis of promoter activation in several laboratories including ours has shed light on several salient features regarding COX-2 transcriptional regulation. First, the cAMP response element (CRE) located at –59 to –53 from the transcription start site of human COX-2 is indispensable for basal and induced COX-2 transcriptional activation in human fibroblasts and endothelial cells, and mutation of the CRE element results in a complete collapse of promoter activity.34 A large number of transactivators including CRE binding protein (CREB), ATF, C/EBP, C-Jun, C-Fos, and USF bind to an overlapped CRE and AP-1 region located at –60 to –40 from the transcription start site.34 Binding of this cluster of transactivators to a small stretch of DNA sequence close to the TATA box is essential for basal and induced COX-2 transcriptional activation. Second, transactivation of COX-2 by proinflammatory mediators requires a concerted upregulation of binding of distinct transactivators to their respective enhancer elements. This point is illustrated by the regulation of transactivator binding in response to stimulation by phorbol 12-myristate 13-acetate (PMA), and tumor necrosis factor (TNF){alpha} (TNF{alpha}). PMA increases binding of CREB-2, C-Jun, and C-Fos to the CRE/AP-1 region and C/EBPß to the C/EBP element at –124 to –132 of human COX-2.34,35 Mutation of CRE site or C/EBP element completely abolishes the increase in COX-2 expression stimulated by PMA. These results indicate that COX-2 transcriptional activity by PMA depends on upregulation of CREB-2, C-Fos/C-Jun (AP-1), and C/EBPß binding to CRE region and C/EBP site, respectively. In contrast, TNF{alpha} induces activation and binding of NF-{kappa}B to 2 separate {kappa}B enhancer elements on the core promoter region and mutation of either enhancer element greatly reduces the TNF{alpha} transcriptional activity.36 Thus, COX-2 transcriptional activation by TNF{alpha} depends largely on NF-{kappa}B activation and binding. Third, DNA-bound transactivators induced by proinflammatory mediators recruit predominantly p300 coactivators to the complex, which interact with the transcription machinery. Furthermore, p300 histone acetyltransferase acetylates histones, thereby opening up chromatin to allow more access to transactivators and acetylates transactivators such as p50 NF-{kappa}B subunit to augment NF-{kappa}B binding.37 CREB binding protein, which is highly homologous to p300, plays a relatively unimportant role because it is expressed in very low abundance in primary cultured human cells such as human umbilical vein endothelial cells and fibroblasts. Lastly, COX-2 transcriptional activation by proinflammatory mediators is regulated by a time-dependent alteration in transactivator levels and switch in transactivator binding. One example is the switch of C/EBP isoforms during PMA-induced COX-2 transactivation.38

C/EBPß has emerged as a key transactivator for COX-2 expression induced by proinflammatory mediators. It has been shown to regulate COX-2 transcriptional activation in murine and human cells induced by diverse proinflammatory mediators.34,35,39 The C/EBP family proteins comprise 6 members of basic leucine zipper transcription factors.40,41 They are divided into 2 subgroups based on sequence homology: one group comprises C/EBP{alpha}, ß, and {delta}, and the other comprises C/EBP{gamma}, {epsilon}, and {zeta}. Several studies have shown that the ß and {delta} isoforms are involved in COX-2 transcriptional activation by proinflammatory mediators in murine and human cells.35,38,39 C/EBPß and C/EBP{delta} bind to C/EBP enhancer elements at –132/–124 and CRE at –59/–53 of human COX-2 promoter in resting fibroblasts or endothelial cells. After treatment with PMA, C/EBPß protein levels are unaltered, whereas C/EBP{delta} declines in a time-dependent manner. Binding of the ß isoform to C/EBP site is time-dependently increased. Overexpression of C/EBP{delta} in human fibroblasts by transient transfection results in a marked increase in basal but not PMA-induced COX-2 promoter activity, whereas overexpression of C/EBPß stimulates neither basal nor PMA-induced COX-2 promoter activity. These results suggest that C/EBP{delta} binds constitutively to CRE and C/EBP enhancer elements and is involved in regulating the basal COX-2 promoter activity. By contrast, C/EBPß is dormant and does not bind to C/EBP site at resting state. Its binding activity is increased by signaling from PMA, and its increased binding to the C/EBP site plays an important role in COX-2 transcriptional activation. It is interesting that C/EBP{delta} proteins undergo degradation after PMA treatment. It is unclear how C/EBP{delta} is degraded. Nevertheless, the results suggest that C/EBP{delta} degradation may be important for making the C/EBP enhancer element unoccupied and accessible to activated C/EBPß.

COX-2 transcriptional activation is further regulated by C/EBPß variants. Three variants of C/EBPß are detected in human fibroblasts and endothelial cells: 46-kDa full-length (FL), 41-kDa liver-enriched transcription activating protein (LAP), and 16-kDa liver-enriched transcription inhibitory protein (LIP). LAP and LIP are truncated forms of FL C/EBPß with deletion of the amino-terminal regions of C/EBPß. They are translated from C/EBPß mRNA by using alternative translation start sites because of a leaky ribosomal scanning mechanism.42,43 LAP, like FL C/EBPß, activates transcription, whereas LIP suppresses gene transcription.43,44 We observed LIP but not LAP binding to C/EBP site of COX-2 promoter in resting cells, and PMA enhanced LIP and induced LAP binding, without altering the cellular LIP or LAP protein levels.38 LIP is a dominant-negative mutant of LAP, and its overexpression in human cells abrogates PMA-induced LAP binding and COX-2 promoter activity.38 LIP controls basal and PMA-induced COX-2 transcriptional activation and may play an important role in limiting the extent and duration of COX-2 expression.

C/EBPß (FL and LAP) in resting cells does not bind to C/EBP enhancer element because C/EBPß harbors an intramolecular bipartite inhibitory element located between the N-terminal transactivating domain and C-terminal DNA-binding and leucine zipper (dimerization) region.45 This intramolecular inhibitory element is abolished by phosphorylation of serine or threonine residues adjacent to this element. It has been shown that phosphorylation of C/EBPß at Thr-235 by p42/p44 mitogen-activated protein kinase (ERK1/2), Thr-266 by p90 ribosomal S6 kinase (RSK), Ser-288 by protein kinase A, and Ser-325 by calmodulin-dependent kinase IV enhance C/EBPß binding activity.46–49 The signaling pathway via which proinflammatory mediators activate C/EBPß has not been reported. Identification of kinases that activate C/EBPß should be valuable for providing specific target for drug discovery.

C/EBPß plays an important role in mediating vascular diseases. It is involved in mediating transcription of COX-2 as well as inducible nitric oxide synthase50 and cytokines.51,52 The results of a recent study have shown that administration of a C/EBP decoy oligonucleotide into a balloon-injured carotid artery of a rabbit atherosclerosis model reduced intimal hyperplasia and attenuated vascular inflammation accompanied by a complete inhibition of C/EBP protein binding to a consensus C/EBP sequence.53 Taken together, these findings underscore the importance of C/EBPß and C/EBP{delta} in regulating COX-2 promoter activity induced by proinflammatory stimuli. The extent and duration of COX-2 expression are regulated by several inter-related molecular events, including C/EBP{delta} degradation, C/EBPß activation and binding, and competitive inhibition of LIP. These events are likely to influence the extent of vascular lesions and are potential targets for developing new therapeutic strategies.

Aspirin and Salicylate Suppress COX-2 Expression by Blocking C/EBPß Activation
Aspirin has several therapeutic indications including prevention of myocardial infarction and ischemic stroke, treatment of pain, and inflammatory disorders.54 The mechanism by which it prevents myocardial infarction and stroke proves to be caused by irreversible inhibition of platelet COX-1 activity, thereby suppressing TXA2 production and TXA2-mediated secondary platelet aggregation.55,56 Its anti-inflammatory effect cannot be explained by COX-1 inhibition but the mechanism was unclear. Aspirin has a short half-life ({approx}20 minutes) and is rapidly converted to salicylate in vivo. Thus, salicylate is considered to be an active metabolite of aspirin.57 It, therefore, attracted considerable interests when it was reported that salicylate was capable of inhibiting NF-{kappa}B (P50/RelA) activation.58 It was subsequently shown that salicylate blocks NF-{kappa}B by inhibiting I{kappa}B kinase, through which salicylate inhibits I{kappa}B phosphorylation and dissociation from NF-{kappa}B.59 However, salicylate inhibited I{kappa}B kinase and NF-{kappa}B at very high concentrations (>5 mmol/L) considered to be suprapharmacological, and it was pointed out that salicylate at such high concentrations has broad, nonspecific inhibitory effects on many kinases.60 Thus, the therapeutic effect of aspirin on inflammation is unlikely caused by inhibition of NF-{kappa}B. Results from our studies indicate that aspirin and sodium salicylate at therapeutic concentrations (10–6 M to 10–3 M) selectively inhibit C/EBPß activation, thereby suppressing the expression of COX-2 induced by PMA, IL-1ß, and lipopolysaccharide (LPS), but not TNF{alpha}. We have shown that aspirin and sodium salicylate equipotently inhibited PMA-induced and IL-1ß–induced COX-2 protein, mRNA, and promoter activity in a concentration-dependent manner and aspirin inhibited LPS-induced COX-2 in murine peritoneal macrophages in vivo.61 Aspirin and sodium salicylate at 10–5 M selectively inhibited C/EBPß binding to COX-2 promoter without an effect on p50/RelA NF-{kappa}B binding.35 We have recently shown that salicylate (10–5 M) inhibited COX-2 and inducible nitric oxide synthase (iNOS) expression in murine RAW 264.7 cells stimulated with LPS/interferon-{gamma} for 4 hours by inhibiting C/EBPß binding but not NF-{kappa}B binding.62 Besides inhibiting COX-2 and iNOS expression, salicylate at therapeutic concentrations has been shown to inhibit IL-463 and IL-6 expressions (unpublished data). Because the expressions of both cytokines require C/EBPß, it is likely that aspirin and sodium salicylate inhibit their expressions by suppressing C/EBPß binding. It may be further speculated that aspirin and its in vivo metabolite are capable of inhibiting the expression of C/EBPß-mediated proinflammatory genes, thereby suppressing vascular inflammation and vascular lesions. A recent report has provided evidence for control by low-dose aspirin of atherosclerotic lesions, vascular inflammation, and plaque stability in a low-density lipoprotein receptor-deficient mouse model.64 However, it remains to be investigated whether the protective actions of aspirin are mediated by control of C/EBPß-dependent expression of COX-2 and proinflammatory genes. The mechanism by which aspirin and salicylate inhibit C/EBPß binding remains to be elucidated. One potential target is RSK, which is activated by several signaling pathways, including the Ras-Raf-MEK-1-ERK1/2 pathway65 and inhibited by salicylate.66 RSK phosphorylates human C/EBPß at Thr-266 thereby activating C/EBPß. Salicylate may selectively inhibit RSK activation, thereby suppressing C/EBPß-mediated gene expression (Figure 2).



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  		Figure 2. Proposed mechanism by which salicylates inhibit C/EBPß activation, thereby suppressing COX-2 transcriptional activation indicated by proinflammatory mediators.

Aspirin and Salicylate Inhibit COX-2 Expression in a Cell Cycle-Dependent Manner
Inhibition of COX-2 transcriptional activation by salicylates was made in serum-starved human fibroblasts and endothelial cells. However, after the serum-starved cells had been treated with fetal bovine serum for 4 hours, COX-2 expression stimulated by PMA or IL-1ß was no longer blocked by aspirin or sodium salicylate.35 A more detailed time course analysis revealed that COX-2 expression was suppressible only for the first 2 hours after addition of serum. Similarly, COX-2 expression in cells treated with platelet-derived growth factor (PDGF) for 4 hours became resistant to salicylates. These results suggest a cell cycle-dependent effect of salicylates. Human fibroblasts have been extensively established as a cell model for studying cell cycle.67 It was shown by flow cytometry that >90% of serum-starved fibroblasts are in G0. After addition of 2.5% fetal bovine serum, the S phase cells start to increase at 16 hours and reach maximal at 24 hours.68 PDGF exerted a similar progression in cell cycle. Thus, COX-2 expression becomes resistant to salicylates at early G1 phase of cell cycle. The reason for this is unclear but may be related to an inherent control of COX-2 expression in cycling cells. Kinetics analysis of COX-2 mRNA and protein expressions in cells at various phases of cell cycle reveals a progressive decline of COX-2 expressions in response to PMA stimulation as the cell cycle progresses from G1 to S to G2/M.68 COX-2 promoter activity in proliferating cells (24 hours after fetal bovine serum treatment) stimulated with PMA is markedly reduced when compared with that in quiescent cells.68 PDGF induces G0 cells into cell cycle in a manner similar to fetal bovine serum.68 Serum-starved cells treated with PDGF for 24 hours expressed a lower level of COX-2 in response to PMA than the serum-starved cells without addition of PDGF. These results suggest an endogenous control mechanism of COX-2 expression that is tied to the cell cycle machinery. Cell cycle-dependent control of COX-2 expression may occur at the level of (1) transactivator activation, such as blocking of kinases that activate a large number of transactivators; (2) transactivator expression and degradation; (3) transcriptional coactivator activity; or (4) chromatin remodeling. Because salicylates lose their inhibitory action in cycling cells, it may be speculated that C/EBPß activation may be one of the factors that are shut down by the endogenous control mechanism. Because TNF{alpha}-induced COX-2 expression, which is independent of C/EBPß, is also suppressed in cycling cells, it is likely that the control mechanism is not restricted to C/EBPß activation.

COX-2 Expression Is Controlled by an Endogenous Factor
It has been shown that COX-2 expression in proliferating fibroblasts is attributable to a factor that is released into the extracellular milieu after the cells have entered S phase.69 Deng et al, from our laboratory, reported that addition of conditioned medium collected from proliferating fibroblasts (serum-starved fibroblasts treated with fetal bovine serum or PDGF for 24 hours) inhibited COX-2 expression in serum-starved quiescent cells stimulated with PMA, IL-1ß, TNF{alpha}, LPS, or vascular endothelial growth factors.69 Control medium collected from serum-starved quiescent cells had a minimal effect on COX-2 expression. The chemical nature of this factor, which we called cytoguardin, is being characterized.


*    Conclusion
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 up arrowAbstract
 up arrowIntroduction
 *Conclusion
down arrowReferences
 
COX-2 expression in response to stimulation by proinflammatory mediators is transcriptionally regulated through activation of NF-{kappa}B, C/EBPß, AP-1, and CREB-2. C/EBPß has emerged as a major driver of COX-2 transcriptional activation and is a potential target for transcription-guided therapy. This is illustrated by selective inhibition of C/EBPß binding by aspirin and its in vivo metabolite, salicylate. Salicylates at pharmacological concentrations inhibit C/EBPß binding by blocking C/EBPß phosphorylation catalyzed by a number of kinases, notably RSK. It remains unclear whether salicylates directly inhibit RSK. Further studies are needed to identify the direct kinase target of salicylates, which should be a useful target for screening drugs.

COX-2 expression is robust in quiescent cells and the level of expression in response to exogenous stimuli declines progressively after the cells enter proliferating phase. It has been suggested that decline in COX-2 expression in proliferating cells is caused by a factor released from these cells. This proposal is being tested by research work to isolate, identify, and characterize this factor and to elucidate the mechanism by which COX-2 expression is suppressed. Nevertheless, these reports shed light on the differential function of quiescent versus proliferating cells. The so-called quiescent cells appear to be capable of expressing a high level of COX-2 in response to challenge by proinflammatory mediators. They may be considered as the front-line cells in response to exogenous insults. By contrast, the key function of cycling cells is to perform DNA replication and cell division. Because their chromatin structure is open and DNA is vulnerable to damage by oxidants,70 they have developed an endogenous mechanism to control the expression of proinflammatory and oxidative genes so that DNA damage may be prevented. COX-2 may be considered as a prototype of the proinflammatory genes that impose threat to DNA integrity when they are overexpressed. In addition to producing biologically active prostanoids, COX-2 generates reactive oxygen species and oxidative metabolites such as malondialdehyde,71 which have been shown to contribute to DNA oxidation damage and cell apoptosis.72 The molecular processes that the proliferating cell develops to protect its DNA and cell function are largely unknown. The COX-2 transcriptional control serves as an excellent model for unraveling the molecular mechanisms, and the results should have a great impact on understanding fundamental cytoprotection program and developing transcription-targeted therapeutic strategies.


*    Acknowledgments
 
We thank Susan Mitterling for editorial assistance. This work was supported by National Institutes of Health grants (R01 HL-50675 and P50 NS-23327).

Received June 6, 2004; accepted January 18, 2005.


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