Signaling by the Cysteinyl-Leukotriene Receptor 2

Thompson, C. S.; Cloutier, Alexandre; Bossé, Ynuk; Poisson, Caroline; Larivée, Pierre; McDonald, Patrick P.; Staňková, Jana; Rola‐Pleszczynski, Marek

doi:10.1074/jbc.m608197200

Cited by 28 publications

(10 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, LTD 4 can up-regulate the mRNA expression of CysLT 2 R in monocytes [43] and epithelial cells [44] and the cytokines IL-4, IL-8 and IFN-γ [28], [45], [46] can up-regulate the mRNA expression of CysLT 2 R in several different cell types. Since a binding site for IRF-7 was present in the putative promoter region of the CysLT 2 R , we hypothesized that the IFN-α would be able to induce CysLT 2 R expression via transcription factor IRF-7.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Cysteinyl Leukotriene Receptor 2 Expression—A Potential Anti-Tumor Mechanism

et al. 2011

View full text Add to dashboard Cite

BackgroundThe cysteinyl leukotrienes receptors (CysLTRs) are implicated in many different pathological conditions, such as inflammation and cancer. We have previously shown that colon cancer patients with high CysLT1R and low CysLT2R expression demonstrate poor prognosis. Therefore, we wanted to investigate ways for the transcriptional regulation of CysLT2R, which still remains to be poorly understood.Methodology/Principal FindingsWe investigated the potential role of the anti-tumorigenic interferon α (IFN-α) and the mitogenic epidermal growth factor (EGF) on CysLT2R regulation using non-transformed intestinal epithelial cell lines and colon cancer cells to elucidate the effects on the CysLT2R expression and regulation. This was done using Western blot, qPCR, luciferase reporter assay and a colon cancer patient array. We found a binding site for the transcription factor IRF-7 in the putative promoter region of CysLT2R. This site was involved in the IFN-α induced activity of the CysLT2R luciferase reporter assay. In addition, IFN-α induced the activity of the differentiation marker alkaline phosphatase along with the expression of mucin-2, which protects the epithelial layer from damage. Interestingly, EGF suppressed both the expression and promoter activity of the CysLT2R. E-boxes present in the CysLT2R putative promoter region were involved in the suppressing effect. CysLT2R signaling was able to suppress cell migration that was induced by EGF signaling.Conclusions/SignificanceThe patient array showed that aggressive tumors generally expressed less IFN-α receptor and more EGFR. Interestingly, there was a negative correlation between CysLT2R and EGFR expression. Our data strengthens the idea that there is a protective role against tumor progression for CysLT2R and that it highlights new possibilities to regulate the CysLT2R.

show abstract

Section: Discussionmentioning

confidence: 99%

Regulation of Cysteinyl Leukotriene Receptor 2 Expression—A Potential Anti-Tumor Mechanism

et al. 2011

View full text Add to dashboard Cite

show abstract

“…59) Thompson et al have reported that the signaling pathway for CysLT2 is involved in the activation of PKC pathway via Gq-proteins. 60) We expected that CysLT2 can sensitize TRPV1 in primary sensory neurons, however one of the doses of LTC4 (8 fmol, 0.8, 80 pmol) affected on heat sensitivity at 10, 30 and 60 min after the injection in normal rats. The data indicate LTC4 does not have a role on thermal hyperalgesia in a normal condition.…”

Section: Functional Consideration Of Cyslt2 In Drg Neuronsmentioning

confidence: 94%

Leukotrienes in Nociceptive Pathway and Neuropathic/Inflammatory Pain

Noguchi

Okubo

2011

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

The purpose of this review is to summarize the recent studies examining the expression of leukotrienes (LTs) and their receptors in nociceptive pathways, and their crucial roles in pathological pain conditions. LTs belong to a large family of lipid mediators, termed eicosanoids, which are derived from arachidonic acids and released from the cell membrane by phospholipases. LTs are known to be important factors in a variety of local and systemic diseases and allergic/inflammatory diseases. We examined whether LTs were implicated in neuropathic pain following peripheral nerve injury. Using the SNI model in rats, we investigated the expression of LT synthases and receptors mRNAs in the spinal cord and the roles on the pain behaviors. We found the expression of 5-lipoxygenase (5-LO), FLAP and the cysteinyl leukotrienes (CysLT1) mRNAs in spinal microglia, LTA4h and LTC4s mRNAs in both spinal neurons and microglia, and BLT1 mRNA in spinal neurons. Administration of the 5-LO inhibitor or the receptor antagonists suppressed mechanical allodynia. Our findings suggest that the increase of LT synthesis in spinal microglia produced via p38 mitogen-activated protein kinase (MAPK) plays a role in the generation of neuropathic pain. We also examined the expression and roles on pain behaviors of LT receptors in the dorsal root ganglion (DRG) using a peripheral inflammation model. The data indicate CysLT2 expressed in DRG neurons may play a role as a modulator of P2X3, and contribute to the potentiation of the neuronal activity following peripheral inflammation. This review summarizes the hypothesis that LTs might work in the spinal cord and primary afferent in pathological pain conditions.

show abstract

“…This lack of visible specific interactions renders the virtual re-docking of arachidonic acid and de novo docking of linoleic acid in the h-5-LOX enzyme active site futile. Therefore, we modeled a bound structure of linoleic acid by manually threading the lipid into the crystal structure of arachidonic acid using PyMOL [51]. The threaded linoleic acid was then minimized using default settings in UCSF Chimera (version 1.6) [52] to produce the final model of linoleic acid bound to the h-5-LOX active site as shown in Figure 11a.…”

Section: Resultsmentioning

confidence: 99%

Discovery of a novel activator of 5-lipoxygenase from an anacardic acid derived compound collection

Wisastra

Kok

Eleftheriadis

et al. 2013

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

Lipoxygenases (LOXs) and cyclooxygenases (COXs) metabolize poly-unsaturated fatty acids into inflammatory signaling molecules. Modulation of the activity of these enzymes may provide new approaches for therapy of inflammatory diseases. In this study, we screened novel anacardic acid derivatives as modulators of human 5-LOX and COX-2 activity. Interestingly, a novel salicylate derivative 23a was identified as a surprisingly potent activator of human 5-LOX. This compound showed both non-competitive activation towards the human 5-LOX activator adenosine triphosphate (ATP) and non-essential mixed type activation against the substrate linoleic acid, while having no effect on the conversion of the substrate arachidonic acid. The kinetic analysis demonstrated a non-essential activation of the linoleic acid conversion with a KA of 8.65 μM, αKA of 0.38 μM and a β value of 1.76. It is also of interest that a comparable derivative 23d showed a mixed type inhibition for linoleic acid conversion. These observations indicate the presence of an allosteric binding site in human 5-LOX distinct from the ATP binding site. The activatory and inhibitory behavior of 23a and 23d on the conversion of linoleic compared to arachidonic acid are rationalized by docking studies, which suggest that the activator 23a stabilizes linoleic acid, whereas the larger inhibitor 23d blocks the enzyme active site.

show abstract

Signaling by the Cysteinyl-Leukotriene Receptor 2

Cited by 28 publications

References 63 publications

Regulation of Cysteinyl Leukotriene Receptor 2 Expression—A Potential Anti-Tumor Mechanism

Regulation of Cysteinyl Leukotriene Receptor 2 Expression—A Potential Anti-Tumor Mechanism

Leukotrienes in Nociceptive Pathway and Neuropathic/Inflammatory Pain

Discovery of a novel activator of 5-lipoxygenase from an anacardic acid derived compound collection

Contact Info

Product

Resources

About