CommentariesCyclooxygenase knockout mice: Models for elucidating isoform-specific functions
Section snippets
General characteristics of COX-1 and COX-2 null mice
The DNA manipulations used to disrupt the genes coding for COX-1 and COX-2 have been reported 38, 39, 40. Both COX-1 and COX-2 deficient mice lacked the respective normal size message and immunoreactive protein. Mice heterozygous for Ptgs-1 or Ptgs-2 expressed the respective messages and proteins at about 50% of the levels observed in wild-type mice. In the tissues examined (stomach, colon, kidney, testes), COX-1 null mice did not compensate by up-regulating the expression of COX-2, nor did
Effects of COX deficiency on carcinogenesis
One of our original goals for making the COX null mice was to investigate the roles of COX-1 and COX-2 in carcinogenesis. Two types of cancers, colon cancer and skin cancer, had been chosen for study. The rationales for the COXs having roles in colon cancer development are based on both rodent and human epidemologic data. Reddy and colleagues [56 and references therein] had conducted many studies indicating that NSAIDs reduce carcinogen-induced intestinal cancer in rodents. Furthermore,
Effects of COX deficiency on female reproductive processes
Prostaglandins are known to have important roles in the female reproductive processes, and understanding of the contributions of the individual COX isoforms in female reproduction has been facilitated by the development of COX deficient mice 82, 83, 84, 85.
In initial studies, we observed that COX-1 null female mice produced litters of normal size, but had difficulty with parturition, and most pups were born dead or died shortly after birth [38]. Other aspects of the female reproductive
Effects of COX deficiency on the inflammatory response
Inflammation is a complex biological response modulated by various chemical mediators with which prostaglandins have a synergistic role 45, 88. Since the recent discovery of COX-2, a significant number of studies have associated this isoform with the inflammatory process, and, therefore, considerable effort has gone into developing NSAIDs that selectively inhibit this isoform 22, 23, 24, 25, 26, 27, 28, 29. To better understand the relative contributions of the COX isoforms in the inflammatory
Effects of COX deficiency on spontaneous and induced gastric ulceration
The current hypothesis about the medicinal usage of NSAIDs is that inhibition of COX-2 is responsible for their beneficial effects, whereas the inhibition of COX-1 is responsible for their adverse effects, the most common of which is gastric ulceration. Therefore, it was surprising that COX-1 deficient mice did not spontaneously develop gastric ulcers [38]. Measurement of gastric PG levels in the COX-1 null mice indicated a greater than 99% reduction, and this reduction in gastric PGs was
Development of mice deficient in both COX isoforms
Because both COX-1 and COX-2 null mice independently showed reasonable survival 38, 39, 40, we thought that it might be possible to develop a mouse line deficient in both isoforms, i.e. COX-1(−/−)-COX-2(−/−). A COX-1 and COX-2 double null mouse could offer a model to elucidate the essential physiological functions of PGs. In the course of generating double null mice, COX-1(+/−)-COX-2(+/−), COX-1(+/−)-COX-2(−/−), and COX-1(−/−)-COX-2(+/−) mice also would be produced. As gene dosage effects have
Relevance of COX-deficient mice to humans
Humans with platelets deficient in COX-1 activity have been identified [105]. Western analyses of three human cases have indicated two distinct types of defects. In two cases, no detectable COX-1 protein was observed, similar to the targeted disruption of the Ptgs-1 gene in mice [38]. In the second defect type, COX-1 protein was present, but the protein lacked catalytic activity. The characteristics of the three patients were: mild bleeding disorders, reduced platelet aggregation, and reduced
Conclusion
Data obtained with the COX-1 and COX-2 null mice have contributed to a clearer understanding of the physiological roles of the two COX isoforms. A summary of the phenotypes of the COX null mice is shown in Table 1. Based on pathologies observed in the null mice, it appears that deficiency of COX-2 has more severe effects than does deficiency of COX-1. No doubt, additional effects of COX deficiency will be obtained as these mice are studied further.
The mechanisms by which PGs originating from
References (108)
- et al.
Isolation and characterization of the complementary DNA for sheep seminal vesicle prostaglandin endoperoxide synthase (cyclooxygenase)
J Biol Chem
(1988) - et al.
A serum- and glucocorticoid-regulated 4-kilobase mRNA encodes a cyclooxygenase-related protein
J Biol Chem
(1991) - et al.
TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue
J Biol Chem
(1991) - et al.
Hormonal regulation of messenger ribonucleic acid encoding a novel isoform of prostaglandin endoperoxide H synthase in rat preovulatory follicles. Induction in vivo and in vitro
J Biol Chem
(1992) - et al.
Prostaglandin endoperoxide H synthases-1 and -2
Adv Immunol
(1996) - et al.
Differentiation of monocytoid THP-1 cells with phorbol ester induces expression of prostaglandin endoperoxide synthase-1 (COX-1)
Biochem Biophys Res Commun
(1993) - et al.
Effects of transforming growth factor-β and interleukin-1 β on expression of cyclooxygenase 1 and 2 and phospholipase A2 mRNA in lung fibroblasts and endothelial cells in culture
Biochem Biophys Res Commun
(1993) - et al.
Selective induction of prostaglandin G/H synthase I by stem cell factor and dexamethasone in mast cells
J Biol Chem
(1995) - et al.
Expression of a mitogen-inducible cyclooxygenase in brain neuronsRegulation by synaptic activity and glucocorticoids
Neuron
(1993) - et al.
Constitutive expression of prostaglandin endoperoxide G/H synthetase (PGHS)-2 but not PGHS-1 in human tracheal epithelial cells in vitro
Prostaglandins
(1996)
Different intracellular locations for prostaglandin endoperoxide H synthase-1 and -2
J Biol Chem
Prostaglandin endoperoxide H synthases (cyclooxygenases)-1 and -2
J Biol Chem
Molecular mechanisms of diverse actions of prostanoid receptors
Biochim Biophys Acta
Prostaglandin synthase-1 and prostaglandin synthase-2 are coupled to distinct phospholipases for the generation of prostaglandin D2 in activated mast cells
J Biol Chem
Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs
J Biol Chem
Cyclooxygenase-2 inhibitorsA new class of anti-inflammatory agents that spare the gastrointestinal tract
Gastroenterol Clin North Am
Mechanism of action of nonsteroidal anti-inflammatory drugs
Am J Med
Staiano Coico L, Shiff SI and Rigas B, Effects of nonsteroidal anti-inflammatory drugs on proliferation and on induction of apoptosis in colon cancer cells by a prostaglandin-independent pathway
Biochem Pharmacol
Peroxisome proliferator-activated receptors α and γ are activated by indomethacin and other non-steroidal anti-inflammatory drugs
J Biol Chem
Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin- induced gastric ulceration
Cell
Prostaglandin synthase 2 gene disruption causes severe renal pathology in the mouse
Cell
Self-promotion? Intimate connections between APC and prostaglandin H synthase-2
Cell
Prostaglandin synthase 2
Biochim Biophys Acta
Cyclooxygenase-2Regulation and relevance in inflammation
Biochem Pharmacol
Nonsteroidal anti-inflammatory drugs and gastroenteropathyThe second hundred years
Gastroenterology
Cytoprotection by prostaglandins
Gastroenterology
Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas
Gastroenterology
Increased cyclooxygenase-2 levels in carcinogen-induced rat colonic tumors
Gastroenterology
Suppression of intestinal polyposis in ApcΔ716 knockout mice by inhibition of cyclooxygenase 2 (COX-2)
Cell
Studies of neoplasia in the Min mouse
Biochim Biophys Acta
Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2
Cell
Cyclooxygenase regulates angiogenesis induced by colon cancer cells
Cell
Tumorigenic transformation of immortalized ECV endothelial cells by cyclooxygenase-1 overexpression
J Biol Chem
Multiple female reproductive failures in cyclooxygenase 2-deficient mice
Cell
Multiple controls in inflammation. Extracellular and intracellular phospholipase A2, inducible and constitutive cyclooxygenase, and inducible nitric oxide synthase
Biochem Pharmacol
NS-398, a new anti-inflammatory agent, selectively inhibits prostaglandin G/H synthase/cyclooxygenase (COX-2) activity in vitro
Prostaglandins
Cyclooxygenase 1 contributes to inflammatory responses in rats and miceImplications for gastrointestinal toxicity
Gastroenterology
Induction of cyclooxygenase 2 in gastric mucosal lesions and its inhibition by the specific antagonist delays healing in mice
Gastroenterology
Importance of gastric acid in gastric ulcer formation in rabbits with antibody-induced prostaglandin deficiency
Gastroenterology
Primary structure of prostaglandin G/H synthase from sheep vesicular gland determined from the complementary DNA sequence
Proc Natl Acad Sci USA
Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing
Proc Natl Acad Sci USA
Prostacyclin synthesis in ovine pulmonary artery is developmentally regulated by changes in cyclooxygenase-1 gene expression
J Clin Invest
Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction
J Clin Invest
Differential activation of adipogenesis by multiple PPAR isoforms
Genes Dev
Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors α and γ
Proc Natl Acad Sci USA
Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs
Nat New Biol
Mitogen-inducible prostaglandin G/H synthaseA new target for nonsteroidal antiinflammatory drugs
Drug Dev Res
Towards a better aspirin
Nature
Induction of cyclo-oxygenase-2 by cytokines in human pulmonary epithelial cellsRegulation by dexamethasone
Br J Pharmacol
Aspirin-like molecules that covalently inactivate cyclooxygenase-2
Science
Cited by (205)
PGE2 vs PGF2α in human parturition
2021, PlacentaProstaglandins and bone metabolism
2019, Principles of Bone BiologyBioactive lysolipids in cancer and angiogenesis
2019, Pharmacology and Therapeutics