Induction of NFAT-mediated Transcription by Gq-coupled Receptors in Lymphoid and Non-lymphoid Cells

Boss, Valerie; Talpade, Deepa J.; Murphy, Thomas J.

doi:10.1074/jbc.271.18.10429

Cited by 69 publications

(61 citation statements)

References 28 publications

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“…In RIE/GPRP-R cells, BBSmediated transcriptional induction of the Cox-2 gene is also calcium dependent, requiring activation of components of the AP-1 transcription factor complex, such as Fos/Jun proteins (Guo et al, 2001). Moreover, involvement of Gaq-coupled receptors as the GRP-R in the activation of NFAT and in the induction of NFATdependent genes has been described in a variety of cell types (Boss et al, 1996;Horsley and Pavlath, 2002;Liu et al, 2004). Noticeably, recent reports have proposed that NFAT proteins may play an important role in cancer, having shown a direct involvement of NFATmediated transcriptional regulation of different genes, including Cox-2 (Jauliac et al, 2002;Lara-Pezzi et al, 2002;Saurin et al, 2002;Neal and Clipstone, 2003;Holzmann et al, 2004;Yiu and Toker, 2006).…”

Section: Discussionmentioning

confidence: 99%

Bombesin induces cyclooxygenase-2 expression through the activation of the nuclear factor of activated T cells and enhances cell migration in Caco-2 colon carcinoma cells

et al. 2006

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Cyclooxygenase-2 (Cox-2), the gastrin-release peptide (GRP) and its cognate receptor (GRP-R) are overexpressed in a significant percentage of colorectal carcinomas and are associated with cell growth, invasiveness and tumor progression. However, a molecular link between all of them in adenocarcinomas has not been established. Here, we show that bombesin (BBS), a GRP homolog, stimulates the expression of Cox-2 mRNA and protein in human colon adenocarcinoma Caco-2 cells, resulting in enhanced release of prostaglandin E 2 . These effects were markedly inhibited by the specific BBS antagonist RC-3940-II. BBS promotes the activation of the nuclear factor of activated T cells (NFAT) through a Ca 2 þ /calcineurin (Cn)-linked pathway. Upon BBS stimulation, the NFATc1 isoform translocates into the nucleus with a concomitant increase in NFATc1 binding to two specific recognition sites in the promoter region of the Cox-2 gene. Furthermore, inhibition of Cn activity by the immunosuppressive drug cyclosporin A impaired NFAT activation and diminished Cox-2 expression in BBSstimulated cells. Interestingly, BBS pretreatment strongly enhances the invasive capacity of carcinoma cells, effect which was inhibited by a Cox-2-specific inhibitor. These findings provide the first evidence for the involvement of the Ca 2 þ /Cn/NFAT pathway in BBS-mediated induction of genes involved in colon carcinoma invasiveness such as Cox-2. Oncogene (2007) 26, 958-969.

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Section: Discussionmentioning

confidence: 99%

Bombesin induces cyclooxygenase-2 expression through the activation of the nuclear factor of activated T cells and enhances cell migration in Caco-2 colon carcinoma cells

et al. 2006

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“…Jurkat cells cotransfected with the human GPR103 cDNA and a luciferase reporter driven by nuclear factor of activated T cells (NFAT) were used to monitor the ligand activities. NFAT acts as a downstream effecter of G␣q protein-coupled receptors in lymphoid cells (5). This system exhibited very low background signals; Jurkat cells appear to express a relatively limited number of GPCRs that are activated by substances in the crude tissue extracts.…”

Section: Resultsmentioning

confidence: 99%

A neuropeptide ligand of the G protein-coupled receptor GPR103 regulates feeding, behavioral arousal, and blood pressure in mice

Takayasu

Sakurai

Iwasaki

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

165

355

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Here, we report the isolation and characterization of an endogenous peptide ligand of GPR103 from rat brains. The purified peptide was found to be the 43-residue RF-amide peptide QRFP. We also describe two mouse homologues of human GPR103, termed mouse GPR103A and GPR103B. QRFP binds and activates the human GPR103, as well as mouse GPR103A and GPR103B, with nanomolar affinities in transfected cells. Systematic in situ hybridization analysis in mouse brains showed that QRFP is expressed exclusively in the periventricular and lateral hypothalamus, whereas the two receptor mRNAs are distinctly localized in various brain areas without an overlap to each other. When administered centrally in mice, QRFP induced feeding behavior, accompanied by increased general locomotor activity and metabolic rate. QRFPinduced food intake was abolished by preadministration of BIBP3226, a specific antagonist for the Y1 neuropeptide Y receptor. Hypothalamic prepro-QRFP mRNA expression was up-regulated upon fasting and in genetically obese ob͞ob and db͞db mice. Central QRFP administration also evoked highly sustained elevation of blood pressure and heart rate. Our findings suggest that QRFP and GPR103A͞B may regulate diverse neuroendocrine and behavioral functions and implicate this neuropeptide system in metabolic syndrome.grooming ͉ hypothalamus ͉ QRFP ͉ wakefulness ͉ metabolic syndrome G protein-coupled receptors (GPCRs) are members of a large protein family that share common structural motifs, including seven transmembrane helices, and play pivotal roles in cell-to-cell communications and in the regulation of cell functions. A large number of GPCRs still remain as ''orphan receptors'' whose cognate ligands have yet to be identified. Identification of ligands for orphan GPCRs provides a basis for understanding the physiological roles of those GPCRs and their ligands, which can involve the central nervous, endocrine, reproductive, cardiovascular, immune, inflammatory, digestive, and metabolic systems.GPR103 (also referred to as SP9155 or AQ27) is an orphan GPCR that shows similarities with orexin, neuropeptide FF, and cholecystokinin receptors. Its mRNA has been detected predominantly in the brain including the cerebral cortex, pituitary, thalamus, hypothalamus, basal forebrain, midbrain, and pons in humans (1). Through bioinformatics approaches, two groups reported putative ligands for GPR103 as a part of a directed effort to identify the precursor genes for a novel RF-amide peptide and its receptor (2, 3). They identified a gene encoding a preproprotein that can be processed into several potential peptides, including a 26-aa (termed P518) and a 43-aa RF-amide peptide (termed QRFP) (2, 3). Both of these peptides activate GPR103, but the 43-aa QRFP exhibited more potent agonistic activity. When intravenously injected into rats, QRFP (43-aa) stimulates aldosterone release (3). The 26-aa RF-amide peptide (termed 26RFa) was independently purified from frog brain by monitoring NPFF-like immunoreactivity (4), and it exhibits orexigenic act...

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“…NFAT pathway elements and/or NFAT activity has been reported in a range of nonlymphoid cell types, including arterial endothelial cells (10), smooth muscle cells (4), skeletal muscle cells (7), and neuronal and neuronal accessory cells (5,20,34,38,44). Although an extensive set of NFAT target genes have been confirmed in T lymphocytes (23), it is likely that additional targets in other cell types remain to be identified.…”

Section: Discussionmentioning

confidence: 99%

Nuclear Translocation and Activation of the Transcription Factor NFAT Is Blocked by Herpes Simplex Virus Infection

Scott

Malcomber

O’Hare

2001

J Virol

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Transcription factors of the NFAT (nuclear factor of activated T cells) family are expressed in most immune system cells and in a range of other cell types. Signaling through NFAT is implicated in the regulation of transcription for the immune response and other processes, including differentiation and apoptosis. NFAT normally resides in the cytoplasm, and a key aspect of the NFAT activation pathway is the regulation of its nuclear import by the Ca 2؉ /calmodulin-dependent phosphatase calcineurin. In a cell line stably expressing green fluorescent protein (GFP)-NFAT, this import can be triggered by elevation of intracellular calcium and visualized in live cells. Here we show that the inducible nuclear import of GFP-NFAT is efficiently blocked at early stages of herpes simplex virus (HSV) infection. This is a specific effect, since we observed abundant nuclear accumulation of a test viral protein and no impediment to general nuclear localization signaldependent nuclear import and retention in infected cells. We show that virus binding at the cell surface is not itself sufficient to inhibit the signaling that induces NFAT nuclear translocation. Since the block occurs following infection in the presence of phosphonoacetic acid but not cycloheximide, we infer that the entry of the virion and early gene transcription are required but the effect is independent of DNA replication or late virus gene expression. A consequence of the block to GFP-NFAT import is a reduction in NFAT-dependent transcriptional activation from the interleukin-2 promoter in infected cells. This HSV-mediated repression of the NFAT pathway may constitute an immune evasion strategy or subversion of other NFAT-dependent cellular processes to promote viral replication.Herpesviruses subvert a range of host cellular processes by interference with signal transduction pathways. For example, mitogenic kinase cascades are activated to establish a cellular environment favorable for virus replication (19,33). Apoptotic pathways are repressed during infection to prevent cell death prior to virus release and possibly also to protect latently infected neuronal cells from destruction (9,24,30). Furthermore, to help evade host immune detection, infection disrupts cytokine-mediated signaling networks crucial for cell-mediated immunity (14), and apoptosis is induced in activated T lymphocytes and macrophages (16,46,54).A key aspect of the regulated transcription response to immune stimuli is the Ca 2ϩ /calmodulin-dependent signal cascade which leads to the activation of the NFAT (nuclear factor of activated T cells) family of transcription factors (51). The family encompasses four closely related proteins, NFAT1 to -4, which share structural and functional homology and are expressed in numerous cell types of the immune system as well as in a range of other cells, including muscle, cardiac, and neuronal cells (7,20,37). These proteins have a conserved Nterminal transactivation domain and a central DNA binding domain with homology to the DNA binding domains of Rel/ ...

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Induction of NFAT-mediated Transcription by Gq-coupled Receptors in Lymphoid and Non-lymphoid Cells

Cited by 69 publications

References 28 publications

Bombesin induces cyclooxygenase-2 expression through the activation of the nuclear factor of activated T cells and enhances cell migration in Caco-2 colon carcinoma cells

Bombesin induces cyclooxygenase-2 expression through the activation of the nuclear factor of activated T cells and enhances cell migration in Caco-2 colon carcinoma cells

A neuropeptide ligand of the G protein-coupled receptor GPR103 regulates feeding, behavioral arousal, and blood pressure in mice

Nuclear Translocation and Activation of the Transcription Factor NFAT Is Blocked by Herpes Simplex Virus Infection

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