Cyclooxygenase‐deficient Mice: A Summary of Their Characteristics and Susceptibilities to Inflammation and Carcinogenesis

Langenbach, Robert; Loftin, Charles D.; Lee, Christopher; Tiano, Howard F.

doi:10.1111/j.1749-6632.1999.tb08723.x

Cited by 148 publications

(99 citation statements)

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“…The serum-starved cells were then washed three times with DMEM, including 0.2% FBS, to remove the aspirin and then were serum-stimulated by incubation in DMEM, including 20% FBS, to induce muCOX-2 protein. After 3 h, the medium was removed and replaced with 2 ml of MEM containing 10% FBS and 10 nmol of [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]arachidonic acid (ϳ300,000 cpm) and incubated for 10 min at room temperature. Subsequently, 1 N citric acid and 10% butylated hydroxytoluene were added to stop the reaction (21), and prostaglandins were extracted from cell suspension by adding 8 ml of hexane/ethyl acetate (1:1, v/v) and centrifuged to separate the phases for 10 min at 4°C.…”

Section: Methodsmentioning

confidence: 99%

Two Pathways for Cyclooxygenase-2 Protein Degradation in Vivo

Wada

Saunders

Morrow

et al. 2009

Journal of Biological Chemistry

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COX-2, formally known as prostaglandin endoperoxide H synthase-2 (PGHS-2), catalyzes the committed step in prostaglandin biosynthesis. COX-2 is induced during inflammation and is overexpressed in colon cancer. In vitro, an 18-amino acid segment, residues 595-612, immediately upstream of the C-terminal endoplasmic reticulum targeting sequence is required for N-glycosylation of Asn 594 , which permits COX-2 protein to enter the endoplasmic reticulum-associated protein degradation system. To determine the importance of this COX-2 degradation pathway in vivo, we engineered a del595-612 PGHS-2 (⌬18 COX-2) knock-in mouse lacking this 18-amino acid segment. ⌬18 COX-2 knock-in mice do not exhibit the renal or reproductive abnormalities of COX-2 null mice. ⌬18 COX-2 mice do have elevated urinary prostaglandin E 2 metabolite levels and display a more pronounced and prolonged bacterial endotoxin-induced febrile response than wild type (WT) mice. Normal brain tissue, cultured resident peritoneal macrophages, and cultured skin fibroblasts from ⌬18 COX-2 mice overexpress ⌬18 COX-2 relative to WT COX-2 expression in control mice. These results indicate that COX-2 can be degraded via the endoplasmic reticulum-associated protein degradation pathway in vivo. Treatment of cultured cells from WT or ⌬18 COX-2 mice with flurbiprofen, which blocks substrate-dependent degradation, attenuates COX-2 degradation, and treatment of normal mice with ibuprofen increases the levels of COX-2 in brain tissue. Thus, substrate turnover-dependent COX-2 degradation appears to contribute to COX-2 degradation in vivo. Curiously, WT and ⌬18 COX-2 protein levels are similar in kidneys and spleens from WT and ⌬18 COX-2 mice. There must be compensatory mechanisms to maintain constant COX-2 levels in these tissues.

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Section: Methodsmentioning

confidence: 99%

Two Pathways for Cyclooxygenase-2 Protein Degradation in Vivo

Wada

Saunders

Morrow

et al. 2009

Journal of Biological Chemistry

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“…PGE 2 is one of the mostestablished key players in the initiation and progression of inflammation [38], and NSAIDs exert their beneficial effects in vivo essentially by repressing PGE 2 formation [13]. Animals deficient in COX-2 or mPGES-1 clearly show reduced inflammatory symptoms [19,39].…”

Section: Page 21 Of 39mentioning

confidence: 99%

Identification of 5-lipoxygenase and microsomal prostaglandin E2 synthase-1 as functional targets of the anti-inflammatory and anti-carcinogenic garcinol

Koeberle

Northoff

Werz

2009

Biochemical Pharmacology

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To cite this version:Andreas Koeberle, Hinnak Northoff, Oliver Werz. Identification of 5-lipoxygenase and microsomal prostaglandin E synthase-1 as functional targets of the anti-inflammatory and anti-carcinogenic garcinol. Biochemical Pharmacology, Elsevier, 2009, 77 (9) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 Ca 2+ -ionophore (A23187)-induced arachidonic acid release in neutrophils nor COX-2 activity in A549 cells or whole blood, measured as formation of 6-keto PGF 1α , or isolated human recombinant COX-2 were significantly affected by garcinol (≤ 30 µM). Together, the high potency of garcinol to selectively suppress PGE 2 synthesis and 5-lipoxygenase product formation provides a molecular basis for the anti-inflammatory and anti-carcinogenic effects of garcinol and rationalizes its therapeutic use.

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“…12 In addition to inflammation and cell growth regulation, COX-2 expression has been associated with carcinogenesis and tumor development. 3,6 Several population-based studies have detected a 40% to 50% decrease in relative risk for colorectal cancer in persons who regularly use aspirin and other NSAIDs. Moreover, studies in a variety of animal models (both genetic and carcinogen induced) of colon cancer and in human colon cancer cells have also indicated a significant reduction in tumor multiplicity and metastatic potential by NSAID treatment.…”

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Expression of cyclooxygenase-2 promotes the release of matrix metalloproteinase-2 and -9 in fetal rat hepatocytes

Callejas

2001

Hepatology

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Treatment of primary cultures of fetal hepatocytes with proinflammatory cytokines, lipopolysaccharide (LPS), and hepatocyte growth factor promoted the expression of cyclooxygenase-2 (COX-2) and the synthesis of high amounts of prostaglandins (PGs). Under these conditions, the active forms of the matrix metalloproteinases-2 and -9 (MMPs) were released to the extracellular medium. This process was inhibited when the synthesis of PGs was suppressed pharmacologically with COX-2 inhibitors. Addition to the cell cultures of PGE 2 promoted the release of MMPs through a mechanism that involved the expression of COX-2 and the synthesis of additional PGs. Kinetic analysis of the secretion of MMPs in response to LPS and PGE 2 showed a similar time course, with a lag period of 6 hours, which suggests that PGE 2 does not act directly on the mechanism of MMP processing and release. Inhibitors of protein kinase A, p38 MAP kinase, phosphatidylinositol-3-kinase, and nuclear factor B Prostaglandin H synthase, also known as cyclooxygenase (COX), catalyzes the synthesis of prostaglandin H 2 from arachidonate and constitutes a key regulatory step in the biosynthesis of prostanoids. 1-3 Two distinct isoforms of COX are known: COX-1 and COX-2. The two isoenzymes are encoded by different genes, and the control of their expression, regulation of enzyme activity, and physiologic functions are very different. 1,4 COX-1 seems to be involved in the house keeping function of prostaglandins (PGs) 4 and is expressed constitutively. In contrast, COX-2 is inducible, is expressed as an immediate early gene, and is involved in the onset of inflammation and mitogenic responses. 1,3,5,6 COX-2 expression is positively regulated by lipopolysaccharide (LPS), interleukin 1␤, tumor necrosis factor ␣, and reactive oxygen intermediates in different cells. 7,8 In addition to these stimuli, it has been described that hepatocyte growth factor (HGF) and epidermal growth factor (EGF) triggered the expression of COX-2 in rat gastric epithelial cells, in human amnion-derived WISH cells, and in human gingival fibroblasts, and this effect was mediated through the activation of the ERK2 signaling pathway. [9][10][11] Our previous results showed that adult hepatocytes failed to express COX-2 regardless of the proinflammatory factors used. However, fetal hepatocytes, which exhibit a liver phenotype distinct from the adult counterpart, were able to express COX-2 upon challenge with LPS and proinflammatory cytokines. 8 Regarding the mechanism responsible for the suppression of COX-2 inducibility in adult hepatocytes, our data suggest the existence of a close relationship between COX-2 induction and the decrease of C/EBP␣ levels that bind to the nuclear factor-interleukin 6 site of the COX-2 promoter. 12 In addition to inflammation and cell growth regulation, COX-2 expression has been associated with carcinogenesis and tumor development. 3,6 Several population-based studies have detected a 40% to 50% decrease in relative risk for colorectal cancer in persons who regularl...

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Cyclooxygenase‐deficient Mice: A Summary of Their Characteristics and Susceptibilities to Inflammation and Carcinogenesis

Cited by 148 publications

References 58 publications

Two Pathways for Cyclooxygenase-2 Protein Degradation in Vivo

Two Pathways for Cyclooxygenase-2 Protein Degradation in Vivo

Identification of 5-lipoxygenase and microsomal prostaglandin E2 synthase-1 as functional targets of the anti-inflammatory and anti-carcinogenic garcinol

Expression of cyclooxygenase-2 promotes the release of matrix metalloproteinase-2 and -9 in fetal rat hepatocytes

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