Glycosylation regulates turnover of cyclooxygenase‐2

Sevigny, Mary B.; Li, Chai-Fei; Alas, Monika; Hughes‐Fulford, Millie

doi:10.1016/j.febslet.2006.10.073

Cited by 32 publications

(30 citation statements)

References 31 publications

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“…To explain the lack of reduction on PGE 2 production in the presence of mPGES-1 siRNA, the authors speculate that COX-2 might be the rate-limiting enzyme responsible for the production of PGE 2 , as suggested also by others (Degousee et al, 2003;Mancini et al, 2007;Sevigny et al, 2006). More important, the authors also demonstrated that MK-886, a compound reported to decrease mPGES-1 activity, reduces the expression of mPGES-1 but upregulates COX-2 (B˚age et al, 2007).…”

Section: Discussionmentioning

confidence: 85%

Regulation of prostaglandin E₂ synthase expression in activated primary rat microglia: Evidence for uncoupled regulation of mPGES‐1 and COX‐2

Oliveira

Candelario‐Jalil

Bhatia

et al. 2008

Glia

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Prostaglandin E2 (PGE2) is among the most important mediators involved in neuroinflammatory processes. The final step of its synthesis is regulated by enzymes termed prostaglandin E2 synthases (PGES). Three PGES are known, cytosolic (c)PGES, membrane-associated (m)PGES-1 and mPGES-2. The expression of mPGES-1 is induced by inflammatory stimuli such as lipopolysaccharide (LPS), interleukin (IL)-1beta, and tumor necrosis factor (TNF)-alpha. Although some roles of mPGES-1 have already been suggested, its function in the CNS and the signaling pathways involved in its upregulation are poorly understood. In this study, we examined the regulation of mPGES-1 in primary rat microglia and the signaling pathways involved in its expression. Whereas the expression of cPGES and mPGES-2 was not stimulated by LPS, low doses of LPS (0.1-1 ng/mL) sufficiently stimulated mPGES-1 mRNA expression. A corresponding protein synthesis, however, was obtained only with higher doses (10-100 ng/mL). The LPS-induced increase of mPGES-1 was inhibited by different signaling pathway inhibitors, such as SP600125, LY294002, GF109203X, and SC-514, suggesting the involvement of c-Jun N-terminal kinase (JNK), phosphatidylinositol 3-kinase (PI-3K)/Akt, protein kinase C (PKC) pathways, and the nuclear factor (NF)-kappaB, respectively. In contrast to other reports, LPS-induced mPGES-1 synthesis was not invariably coupled to the synthesis of COX-2, since inhibition of PI-3K with LY294002 decreased mPGES-1 but increased COX-2 levels. This detailed view of the intracellular signaling pathways involved in mPGES-1 expression in activated microglia opens a new avenue in the search for novel potential therapeutic targets to reduce neuroinflammation, and demonstrates that mPGES-1 expression is not strictly coupled to the expression of COX-2.

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Section: Discussionmentioning

confidence: 85%

Regulation of prostaglandin E₂ synthase expression in activated primary rat microglia: Evidence for uncoupled regulation of mPGES‐1 and COX‐2

Oliveira

Candelario‐Jalil

Bhatia

et al. 2008

Glia

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“…Previous studies have suggested that Asn-67, Asn-144, and Asn-410 are primarily co-translationally N-glycosylated and that glycosylation of these sites facilitates COX-2 maturation in the ER (37) through a process that probably involves the ER chaperones calnexin and/or calreticulin (38). Asn-594, the fourth N-glycosylation site of COX-2, is variably glycosylated (37,39,40) and does not need to be glycosylated for the enzyme to achieve a catalytically competent conformation (37). Instead, we have found that post-translational N-glycosylation of Asn-594 is important for the degradation of huCOX-2 expressed in HEK293 cells (18).…”

Section: Discussionmentioning

confidence: 99%

Two Distinct Pathways for Cyclooxygenase-2 Protein Degradation

Mbonye

Yuan

Harris

et al. 2008

Journal of Biological Chemistry

103

130

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Cyclooxygenases (COX-1 and COX-2) are N-glycosylated, endoplasmic reticulum-resident, integral membrane proteins that catalyze the committed step in prostanoid synthesis. COX-1 is constitutively expressed in many types of cells, whereas COX-2 is usually expressed inducibly and transiently. The control of COX-2 protein expression occurs at several levels, and overexpression of COX-2 is associated with pathologies such as colon cancer. Here we have investigated COX-2 protein degradation and demonstrate that it can occur through two independent pathways. One pathway is initiated by post-translational N-glycosylation at Asn-594. The N-glycosyl group is then processed, and the protein is translocated to the cytoplasm, where it undergoes proteasomal degradation. We provide evidence from site-directed mutagenesis that a 27-amino acid instability motif (27-IM) regulates posttranslational N-glycosylation of Asn-594. This motif begins with Glu-586 8 residues upstream of the N-glycosylation site and ends with Lys-612 near the C terminus at Leu-618. Key elements of the 27-IM include a helix involving residues Glu-586 to Ser-596 with Asn-594 near the end of this helix and residues Leu-610 and Leu-611, which are located in an apparently unstructured downstream region of the 27-IM. The last 16 residues of the 27-IM, including Leu-610 and Leu-611, appear to promote N-glycosylation of Asn-594 perhaps by causing this residue to become exposed to appropriate glycosyl transferases. A second pathway for COX-2 protein degradation is initiated by substrate-dependent suicide inactivation. Suicide-inactivated protein is then degraded. The biochemical steps have not been resolved, but substrate-dependent degradation is not inhibited by proteasome inhibitors or inhibitors of lysosomal proteases. The pathway involving the 27-IM occurs at a constant rate, whereas degradation through the substrate-dependent process is coupled to the rate of substrate turnover.

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“…The transcriptional activity of NF-κB can be regulated by O-GlcNAcylation [139], which is known to be upregulated in multiple cancer types [45]. Similarly, the pro-inflammatory molecule COX2 is also regulated by glycosylation [140], and the efficiency of some COX2 inhibitors is thought to be dependent on COX2 glycosylation state [141]. Interestingly, a diet derived sialic acid called N-glycolylneuraminic acid (Neu5Gc, found primarily in red meat) can be incorporated in human tissues.…”

Section: Tumour Promoting Inflammationmentioning

confidence: 99%

Hallmarks of glycosylation in cancer

2016

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Aberrant glycosylation plays a fundamental role in key pathological steps of tumour development and progression. Glycans have roles in cancer cell signalling, tumour cell dissociation and invasion, cell-matrix interactions, angiogenesis, metastasis and immune modulation. Aberrant glycosylation is often cited as a ‘hallmark of cancer’ but is notably absent from both the original hallmarks of cancer and from the next generation of emerging hallmarks. This review discusses how glycosylation is clearly an enabling characteristic that is causally associated with the acquisition of all the hallmark capabilities. Rather than aberrant glycosylation being itself a hallmark of cancer, another perspective is that glycans play a role in every recognised cancer hallmark.

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Glycosylation regulates turnover of cyclooxygenase‐2

Cited by 32 publications

References 31 publications

Regulation of prostaglandin E₂ synthase expression in activated primary rat microglia: Evidence for uncoupled regulation of mPGES‐1 and COX‐2

Regulation of prostaglandin E₂ synthase expression in activated primary rat microglia: Evidence for uncoupled regulation of mPGES‐1 and COX‐2

Two Distinct Pathways for Cyclooxygenase-2 Protein Degradation

Hallmarks of glycosylation in cancer

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Glycosylation regulates turnover of cyclooxygenase‐2

Cited by 32 publications

References 31 publications

Regulation of prostaglandin E2 synthase expression in activated primary rat microglia: Evidence for uncoupled regulation of mPGES‐1 and COX‐2

Regulation of prostaglandin E2 synthase expression in activated primary rat microglia: Evidence for uncoupled regulation of mPGES‐1 and COX‐2

Two Distinct Pathways for Cyclooxygenase-2 Protein Degradation

Hallmarks of glycosylation in cancer

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Product

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Regulation of prostaglandin E₂ synthase expression in activated primary rat microglia: Evidence for uncoupled regulation of mPGES‐1 and COX‐2

Regulation of prostaglandin E₂ synthase expression in activated primary rat microglia: Evidence for uncoupled regulation of mPGES‐1 and COX‐2