Transcriptional Control of COX-2 via C/EBPβ

Abstract

Abstract-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. Key Words: aspirin Ⅲ C/EBP Ⅲ COX-2 Ⅲ inflammation Ⅲ NF-B C yclooxygenase (COX, also known as prostaglandin [PG] H synthase or PGHS) occupies a pivotal position in PG and thromboxane A 2 (TXA 2 ) synthesis. It is a bifunctional enzyme containing a cyclooxygenase catalytic center, which adds 2 oxygen (bisoxygenation) to arachidonic acid (AA) to form a peroxide, PGG 2 , and a peroxidase active site, which reduces PGG 2 to PGH 2 . 1 PGH 2 is a common precursor for synthesis of biologically active prostanoids, including PGE 2 , PGI 2 (prostacyclin), TXA 2 , PGD 2 , and PGF 2␣ . 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 DiseasesUnder 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 A 2 is translocated and colocalized with COX-2 and prostacyclin (PGI 2 ) synthase to endoplasmic reticulum and...

CCAAT/enhancer binding protein β deficiency provides cerebral protection following excitotoxic injury

“…Therefore, the suppression of both COX2 and IL1β expression in neurons and glial cells, respectively, in response to tissue injury in C/EBPβ -/-mice may be directly responsible for the observed reduction in hippocampal neuronal loss. Consistent with this idea, it has been shown previously that the promoter of both genes is directly regulated by C/EBPβ Shirakawa et al, 1993;Sirois and Richards, 1993;Wadleigh et al, 2000;Wu et al, 2005;Yang et al, 2000;Zhang and Rom, 1993). The C/EBPβ-deficient animals in this study displayed a dramatic reduction in neuronal degeneration in the CA1 and CA3 subfields of the hippocampus (Fig.…”

Chemopreventive effect of saikosaponin-d on diethylinitrosamine-induced hepatocarcinogenesis: Involvement of CCAAT/enhancer binding protein�β and cyclooxygenase-2

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Pathogenesis of Aryl Hydrocarbon Receptor-Mediated Development of Lymphoma Is Associated with Increased Cyclooxygenase-2 Expression

“…It has been shown to regulate COX-2 transcriptional activation in murine and human cells induced by diverse inflammatory stimuli 31 and chemicals. 32,33 COX-2 is an important enzyme in regulation of cell growth, differentiation, and apoptosis.…”