Gi-coupled prostanoid receptors are the likely targets for COX-1-generated prostanoids in rat pheochromocytoma (PC12) cells

Yung, H.S.; Chow, Kevin B.S.; Lai, K.H.; Wise, Helen

doi:10.1016/j.plefa.2009.04.010

Cited by 4 publications

(4 citation statements)

References 31 publications

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“…However, limited information concerning the function of COX-1, such as for the mucosal protection of the stomach and blood flow maintenance, has been available (39). Recently, COX-1, but not COX-2, was reported to show involvement in brain inflammation (40,41), and, importantly, COX-1 expression is regulated in PC12 cells in response to NGF stimulation (42,43), suggesting that COX-1 is associated with neuronal differentiation. In our study, down-regulation of COX-1 using COX-1 siRNA rescued the abnormal phenotypes observed in NF1-KD cells; thus, COX-1 may be a candidate clinical target for NF1-related disease pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Integrated Proteomics Identified Novel Activation of Dynein IC2-GR-COX-1 Signaling in Neurofibromatosis Type I (NF1) Disease Model Cells

Hirayama

Kobayashi

Mizuguchi

et al. 2013

Molecular & Cellular Proteomics

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Neurofibromatosis type 1 (NF1) tumor suppressor gene product, neurofibromin, functions in part as a Ras-GAP, and though its loss is implicated in the neuronal abnormality of NF1 patients, its precise cellular function remains unclear. To study the molecular mechanism of NF1 pathogenesis, we prepared NF1 gene knockdown (KD) PC12 cells, as a NF1 disease model, and analyzed their molecular (gene and protein) expression profiles with a unique integrated proteomics approach, comprising iTRAQ, 2D-DIGE, and DNA microarrays, using an integrated protein and gene expression analysis chart (iPEACH). In NF1-KD PC12 cells showing abnormal neuronal differentiation after NGF treatment, of 3198 molecules quantitatively identified and listed in iPEACH, 97 molecules continuously up-or down-regulated over time were extracted. Pathway and network analysis further revealed overrepresentation of calcium signaling and transcriptional regulation by glucocorticoid receptor (GR) in the up-regulated protein set, whereas nerve system development was overrepresented in the down-regulated protein set. The novel up-regulated network we discovered, "dynein IC2-GR-COX-1 signaling," was then examined in NF1-KD cells. Validation studies confirmed that NF1 knockdown induces altered splicing and phosphorylation patterns of dynein IC2 isomers, up-regulation and accumulation of nuclear GR, and increased COX-1 expression in NGF-treated cells. Moreover, the neurite retraction phenotype observed in NF1-KD cells was significantly recovered by knockdown of the dynein IC2-C isoform and COX-1. In addition, dynein IC2 siRNA significantly inhibited nuclear translocation and accumulation of GR and up-regulation of COX-1 expression. These results suggest that dynein IC2 up-regulates GR nuclear translocation and accumulation, and subsequently causes increased COX-1 expression, in this NF1 disease model. Our integrated proteomics strategy, which combines multiple approaches, demonstrates that NF1-related neural abnormalities are, in part, caused by upregulation of dynein IC2-GR-COX-1 signaling, which may be a novel therapeutic target for NF1. Neurofibromatosis type 1 (NF1)1 is an autosomal dominantly inherited disorder with an estimated prevalence of 1 in 3000 people (1). The hallmarks of NF1 include development of benign tumors of the peripheral nervous system and increased risk of malignancies. The phenotype of NF1 is highly variable, with several organ systems affected including the skin, bones, irises, and central and peripheral nervous systems. The effects on the nervous system are manifested in multiple neurofibroma, gliomas, and learning disabilities.The NF1 gene is located on chromosome 17q11.2 and encodes a large protein of 2818 amino acids, neurofibromin (2). Because the great majority of NF1 gene mutations frequently found in NF1 patients disturb the expression of intact neurofibromin, functional disruption of neurofibromin is potentially relevant to the expression of some or all of the abnormalities that occur in NF1 patients (3). A region centered 1...

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Section: Discussionmentioning

confidence: 99%

Integrated Proteomics Identified Novel Activation of Dynein IC2-GR-COX-1 Signaling in Neurofibromatosis Type I (NF1) Disease Model Cells

Hirayama

Kobayashi

Mizuguchi

et al. 2013

Molecular & Cellular Proteomics

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“…Arachidonic acid is produced in neurons by phospholipases A 2 family members and is converted to PGE 2 by cyclooxygenase (COX)-1 and -2. It was reported that NGF induced COX-1 expression and enzymatic activity in PC12 cells . PGE 2 can enhance neuronal differentiation expressed by stimulation of neurite outgrowth in neuroblastoma cell lines such as mouse NG108-15 cells and mouse DRG neurons .…”

Section: Resultsmentioning

confidence: 97%

“…It was reported that NGF induced COX-1 expression and enzymatic activity in PC12 cells. 39 PGE 2 can enhance neuronal differentiation expressed by stimulation of neurite outgrowth in neuroblastoma cell lines such as mouse NG108-15 cells 40 and mouse DRG neurons. 41 Therefore, to evaluate the possibility that HU-MCA-13 affects the PGE 2 production in PC12 cells, we treated the cultures for 24 h with either different concentrations of HU-MCA-13 or 1 μg/mL LPS, the lipopolysaccharide bacterial product known to increase PGE 2 production, cultures’ media was collected and PGE 2 was measured by ELISA ( Figure 6 A).…”

Section: Resultsmentioning

confidence: 99%

Neurotropic activity and safety of methylene-cycloalkylacetate (MCA) derivative 3-(3-allyl-2-methylenecyclohexyl) propanoic acid

Lahiani

Haham-Geula

Lankri

et al. 2020

ACS Chem. Neurosci.

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Polyneuropathy is a disease involving multiple peripheral nerves injuries. Axon regrowth remains the major prerequisite for plasticity, regeneration, circuit formation, and eventually functional recovery and therefore, regulation of neurite outgrowth might be a candidate for treating polyneuropathies. In a recent study, we synthesized and established the methylene-cycloalkylacetate (MCAs) pharmacophore as a lead for the development of a neurotropic drug (inducing neurite/axonal outgrowth) using the PC12 neuronal model. In the present study we extended the characterizations of the in vitro neurotropic effect of the derivative 3-(3-allyl-2-methylenecyclohexyl) propanoic acid (MCA-13) on dorsal root ganglia and spinal cord neuronal cultures and analyzed its safety properties using blood biochemistry and cell counting, acute toxicity evaluation in mice and different in vitro “off-target” pharmacological evaluations. This MCA derivative deserves further preclinical mechanistic pharmacological characterizations including therapeutic efficacy in in vivo animal models of polyneuropathies, toward development of a clinically relevant neurotropic drug.

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“…During studies to assess the role of prostaglandins during PC12 cell differentiation [11] , we noted a marked increase in forskolin-stimulated adenylyl cyclase (AC) activity over a 6-day treatment period with NGF. Forskolin directly activates AC and can amplify cAMP-dependent signaling activated by G s -coupled receptors [12] .…”

Section: Introductionmentioning

confidence: 99%

Nerve Growth Factor-Induced Differentiation of PC12 Cells Is Accompanied by Elevated Adenylyl Cyclase Activity

Yung

Lai²,

Chow³

et al. 2010

Neurosignals

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Rat pheochromocytoma (PC12) cells characteristically undergo differentiation when cultured with nerve growth factor (NGF). Here we show that NGF dramatically increased the adenylyl cyclase-activating property of forskolin in PC12 cells. This effect of NGF was well maintained even when NGF was removed after 4 days, even though the morphological features of neuronal differentiation were rapidly lost on removal of NGF. The enhanced cAMP production in response to forskolin could be due to a synergistic interaction between forskolin and endogenously released agonists acting on G_s-coupled receptors. However, responses to forskolin were not attenuated by antagonists of adenosine A2 receptors or pituitary adenylate cyclase-activating polypeptide (PACAP) receptors, suggesting that adenosine and PACAP were not involved. Adenylyl cyclases 3, 6 and 9 were the predominant isoforms expressed in PC12 cells, but we found no evidence for NGF-induced changes in expression levels of any of the 9 adenylyl cyclase isoforms, nor in the expression of Gα_s. These findings highlight that NGF has a subtle influence on adenylyl cyclase activity in PC12 cells which may influence more than the neurite extension process classically associated with neuronal differentiation.

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Gi-coupled prostanoid receptors are the likely targets for COX-1-generated prostanoids in rat pheochromocytoma (PC12) cells

Cited by 4 publications

References 31 publications

Integrated Proteomics Identified Novel Activation of Dynein IC2-GR-COX-1 Signaling in Neurofibromatosis Type I (NF1) Disease Model Cells

Integrated Proteomics Identified Novel Activation of Dynein IC2-GR-COX-1 Signaling in Neurofibromatosis Type I (NF1) Disease Model Cells

Neurotropic activity and safety of methylene-cycloalkylacetate (MCA) derivative 3-(3-allyl-2-methylenecyclohexyl) propanoic acid

Nerve Growth Factor-Induced Differentiation of PC12 Cells Is Accompanied by Elevated Adenylyl Cyclase Activity

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