cPGES/p23 Is Required for Glucocorticoid Receptor Function and Embryonic Growth but Not Prostaglandin E<sub>2</sub> Synthesis

Lovgren, Alysia Kern; Kovářová, Martina; Koller, Beverly H.

doi:10.1128/mcb.02314-06

Cited by 70 publications

(59 citation statements)

References 82 publications

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“…Cells were seeded at a low density (about 20%) to allow for vigorous growth over a period of several days. In the absence of GA, p23-null cells grew slightly more slowly than wild-type cells as previously reported by others (31). However, in the presence of a relatively low dose of GA, p23-null cells rapidly stopped growing and died, whereas wild-type p23 cells even continued to grow for about 2 days and survived much longer (Fig.…”

Section: Resultssupporting

confidence: 85%

p23/Sba1p Protects against Hsp90 Inhibitors Independently of Its Intrinsic Chaperone Activity

Forafonov

Toogun

Grad

et al. 2008

Molecular and Cellular Biology

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The molecular chaperone Hsp90 assists a subset of cellular proteins and is essential in eukaryotes. A cohort of cochaperones contributes to and regulates the multicomponent Hsp90 machine. Unlike the biochemical activities of the cochaperone p23, its in vivo functions and the structure-function relationship remain poorly understood, even in the genetically tractable model organism Saccharomyces cerevisiae. The SBA1 gene that encodes the p23 ortholog in this species is not an essential gene. We found that in the absence of p23/Sba1p, yeast and mammalian cells are hypersensitive to Hsp90 inhibitors. This protective function of Sba1p depends on its abilities to bind Hsp90 and to block the Hsp90 ATPase and inhibitor binding. In contrast, the protective function of Sba1p does not require the Hsp90-independent molecular chaperone activity of Sba1p. The structure-function analysis suggests that Sba1p undergoes considerable structural rearrangements upon binding Hsp90 and that the large size of the p23/Sba1p-Hsp90 interaction surface facilitates maintenance of high affinity despite sequence divergence during evolution. The large interface may also contribute to preserving a protective function in an environment in which Hsp90 inhibitory compounds can be produced by various microorganisms.

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Section: Resultssupporting

confidence: 85%

p23/Sba1p Protects against Hsp90 Inhibitors Independently of Its Intrinsic Chaperone Activity

Forafonov

Toogun

Grad

et al. 2008

Molecular and Cellular Biology

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“…A study of mPGES-2-deficient mice demonstrated that mPGES-2 was not essential for PGE 2 biosynthesis in peritoneal macrophages (32). Similar to mPGES-2, analysis of cPGES/p23-deleted mice suggests that cPGES is not required for PGE 2 synthesis (33). Taken together, these data suggest that increases in the level of mPGES-1 and its product, PGE 2 , in the spinal cord play a significant role in at least some of the sequential disturbances of motor performance in G93A mice.…”

Section: Discussionmentioning

confidence: 99%

Expression of Microsomal Prostaglandin E Synthase-1 in the Spinal Cord in a Transgenic Mouse Model of Amyotrophic Lateral Sclerosis

et al. 2012

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Abstract. Prostaglandin E 2 (PGE 2 ) is a key molecule involved in the neuroinflammatory processes that characterize amyotrophic lateral sclerosis (ALS). Although PGE 2 synthesis is regulated by PGE 2 synthases (PGESs), the pathological role of PGESs in ALS still remains unknown. Experiments were performed to elucidate the expression of PGESs and the localization of microsomal PGES-1 (mPGES-1) in neurons and glial cells in the spinal cord of ALS model (G93A) mice. Neurological symptom was observed in G93A mice from 14 weeks by the tail suspension test, and rotarod performances were decreased at 16 weeks and older. Western blotting revealed that the level of mPGES-1 was increased in G93A mice at 15 weeks and older. In contrast, the levels of cytosolic PGES and mPGES-2 did not change at any age. Immunohistochemical analysis demonstrated that age-dependent expression of mPGES-1 was found in motor neurons in G93A mice at 11 and 15 weeks. Immunoreactivity of mPGES-1 was also co-localized in Iba1-positive microglia in G93A mice at 15 weeks. These results suggest that mPGES-1 in motor neurons may play a role in the pathogenesis of ALS and that mPGES-1 may work sequentially in motor neurons and activated microglia to produce ALS symptoms in G93A mice.

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“…However, membrane prostaglandin E synthase-2 may contribute to the augmentation of endothelium-dependent contractions in the aorta of the aging rat. Recent gene knockout studies demonstrated that cytosolic prostaglandin E synthase is not required for the generation of prostaglandin E 2 in the mouse embryonic heart and liver, but it is required for the generation of prostaglandin E 2 in the embryonic mouse lung (18,24).…”

Section: Discussionmentioning

confidence: 99%

Gene expression changes of prostanoid synthases in endothelial cells and prostanoid receptors in vascular smooth muscle cells caused by aging and hypertension

Tang

Vanhoutte

2008

Physiological Genomics

155

173

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The present study was designed to assess whether or not changes in genomic expression of cyclooxygenases (COX-1, COX-2), endothelial nitric oxide synthase (eNOS), and prostanoid synthases in the endothelium and of prostanoid receptors in vascular smooth muscle contribute to the occurrence of endothelium-dependent contractions during aging and hypertension. Gene expression was quantified by real-time PCR using isolated endothelial cells and smooth muscle cells (SMC) from the aorta of Wistar-Kyoto and spontaneously hypertensive rats. Genes for all known prostanoid synthases and receptors were present in endothelial cells and SMC, respectively. Aging caused overexpression of eNOS, COX-1, COX-2, thromboxane synthase, hematopoietic-type prostaglandin D synthase, membrane prostaglandin E synthase-2, and prostaglandin F synthase in endothelial cells and COX-1 and prostaglandin E 2 (EP)4 receptors in SMC. Hypertension augmented the expression of COX-1, prostacyclin synthase, thromboxane synthase, and hematopoietic-type prostaglandin D synthase in endothelial cells and prostaglandin D 2 (DP), EP3, and EP4 receptors in SMC. The increase in genomic expression of endothelial COX-1 explains why in aging and hypertension the endothelium has greater propensity to release cyclooxygenase-derived vasoconstrictive prostanoids. The expression of prostacyclin synthase was by far the most abundant, explaining why the majority of the COX-1-derived endoperoxides are transformed into prostacyclin, substantiating the role of prostacyclin as an endothelium-derived contracting factor. The expression of thromboxane synthase was increased in the cells of aging or hypertensive rats, explaining why the prostanoid can contribute to endothelium-dependent contractions. It is uncertain whether the gene modifications caused by aging and hypertension directly contribute to endotheliumdependent contractions or rather to vascular aging and the vascular complications of the hypertensive process. endothelium-dependent contractions; endothelium-derived contracting factors; prostacyclin synthase; prostacyclin; real-time quantitative polymerase chain reaction THE OCCURRENCE of endothelium-dependent contractions is accelerated by aging and hypertension (13,17,19,39,42). Thus such contractions are observed readily in aortas from adult spontaneously hypertensive rats (SHR) and aged normotensive Wistar-Kyoto rats (WKY) (17,19,42). The mediators of endothelium-dependent contractions are produced by endothelial cyclooxygenase (7,12,33) and have been termed endothelium-derived contracting factors (EDCFs). EDCF is unlikely to be a single substance but rather is constituted of a mixture of prostanoids, the formation of which depends on the vascular bed, the age, and the condition of the species studied. Thus prostacyclin (9, 10, 27), endoperoxides (7, 14), and thromboxane A 2 (10, 11, 29) have been proposed as EDCFs. Cyclooxygenase breaks down arachidonic acid to form endoperoxides, which are subsequently converted into prostacyclin, thromboxane A 2 , prostaglandin...

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cPGES/p23 Is Required for Glucocorticoid Receptor Function and Embryonic Growth but Not Prostaglandin E₂ Synthesis

Cited by 70 publications

References 82 publications

p23/Sba1p Protects against Hsp90 Inhibitors Independently of Its Intrinsic Chaperone Activity

p23/Sba1p Protects against Hsp90 Inhibitors Independently of Its Intrinsic Chaperone Activity

Expression of Microsomal Prostaglandin E Synthase-1 in the Spinal Cord in a Transgenic Mouse Model of Amyotrophic Lateral Sclerosis

Gene expression changes of prostanoid synthases in endothelial cells and prostanoid receptors in vascular smooth muscle cells caused by aging and hypertension

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cPGES/p23 Is Required for Glucocorticoid Receptor Function and Embryonic Growth but Not Prostaglandin E2 Synthesis

Cited by 70 publications

References 82 publications

p23/Sba1p Protects against Hsp90 Inhibitors Independently of Its Intrinsic Chaperone Activity

p23/Sba1p Protects against Hsp90 Inhibitors Independently of Its Intrinsic Chaperone Activity

Expression of Microsomal Prostaglandin E Synthase-1 in the Spinal Cord in a Transgenic Mouse Model of Amyotrophic Lateral Sclerosis

Gene expression changes of prostanoid synthases in endothelial cells and prostanoid receptors in vascular smooth muscle cells caused by aging and hypertension

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cPGES/p23 Is Required for Glucocorticoid Receptor Function and Embryonic Growth but Not Prostaglandin E₂ Synthesis