Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P20366 (substance P)
21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The neuropeptide substance P (SP) regulates many biological processes through binding to and activating the SP receptor (NK-1 subtype). Activation of the SP receptor induces mitogenesis in several cell types. In this study, we characterized the mitogenic response induced by SP peptide in the U-373MG astrocytoma cell line and showed that activation of the SP receptor induces [3H]thymidine incorporation into DNA. We also found that SP potently induces c-myc mRNA and protein in the U-373MG cells. Tyrphostin A25, which blocks activity of tyrosine kinases, significantly inhibited SP-induced mitogenesis, suggesting that the mitogenic response induced by SP peptide involves phosphorylation by tyrosine kinases. Furthermore, stimulation of the SP receptor activates tyrosine phosphorylation and enzymatic activity of extracellular signal-regulated kinases (Erk1 and Erk2), also called the mitogen-activated protein kinases (MAPKs). This result suggests that MAPKs participate in the SP peptide-induced signaling pathway. The addition of CP 96,345 ([(2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1 -azabicyclo[2.2.2]octan-3-amine]; an NK-1 receptor antagonist) or PD 098059 (MEK1 inhibitor) inhibited both DNA synthesis and activation of the MAPK pathway, substantiating that SP stimulates mitogenesis by activating the MAPK pathway through receptors of the NK-1 subtype. Our results demonstrate that SP peptide is a strong mitogen in the U-373MG astrocytoma cell line and establish a clear correlation between SP-induced mitogenesis and activation of MAPK signaling pathway.
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PMID:Substance P-induced mitogenesis in human astrocytoma cells correlates with activation of the mitogen-activated protein kinase signaling pathway. 889 54

Protein kinase C (PKC) designates a family of kinases that regulate many essential functions including cell growth and differentiation. The tight regulation of PKC activity is crucial for maintaining normal cellular proliferation and excessive activity leads to abnormal or uncontrolled cell growth. Recent reports indicate that malignant glioma cell lines express 100 to 1000-fold higher PKC activity when compared to non-neoplastic astrocytes. This high activity correlates well with the proliferation of tumor cells in vitro. We recently reported on the anti-proliferative properties of selective PKC inhibitors on the growth of U-373MG human astrocytoma cell line, and their ability to block mitogen-activated protein (MAP) kinase pathway activated by substance P (SP) neuropeptide receptor signaling via a PKC-dependent mechanism. Therefore, inhibiting PKC activity by selective PKC inhibitors may present a promising approach for improving astroglial brain tumor therapy. For this purpose, we constructed a high throughput model cell system to evaluate the efficacy of PKC inhibitors. This system is based on the measurement of light production in U-373MG cells stably transfected with the luciferase reporter gene whose expression depends on the transcriptional activation of GAL4-Elk1 fusion protein by enzyme components of the MAP kinase pathway and the upstream activation of PKC (PKC activation-->MAP kinases-->GAL4-Elk1 phosphorylation-->luciferase expression-->luciferase activity). In brief, we have demonstrated that the PKC activator 12-O-tetradecanoyl phorbol 13-acetate (TPA)-induced luciferase activity in this cell system is mediated via the MAP kinase pathway and can be blocked in the presence of MEK1 selective inhibitors (PD 098059 or U0126). We also demonstrated that TPA-induced luciferase activity in U-373MG stable clones can be blocked by PKC inhibitors (CGP 41251, Go 6976, and GF 109203X) in a concentration dependent manner. In contrast, epidermal growth factor (EGF)-induced luciferase activity, which is independent of PKC activation (Ras-->Raf-1-->MEK1-->MAP kinases-->GAL4-Elk1 phosphorylation-->luciferase expression-->luciferase activity) can only be blocked using a selective EGF receptor inhibitor (AG 1478). In conclusion, we have constructed a model cell system for the high throughput screening and identification of PKC inhibitors potentially active against astrocytoma cells in culture.
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PMID:A high throughput system for the evaluation of protein kinase C inhibitors based on Elk1 transcriptional activation in human astrocytoma cells. 991 10

A synthetic peptide, (D-Phe(6), beta-Ala(11), Phe(13), Nle(14))bombesin-(6-14) was used to investigate the signal transduction mechanisms of bombesin receptor subtype-3. Using NCI-1299#5 human lung cancer cells stably transfected with bombesin receptor subtype-3, 100 nM (D-Phe(6), beta-Ala(11), Phe(13), Nle(14))bombesin-(6-14) elevated the cytosolic Ca2+ from 150 to 250 nM within 10 s. Addition of (D-Phe(6), beta-Ala(11), Phe(13), Nle(14))bombesin-(6-14) caused phosphorylation of mitogen activated protein kinase in a time- and concentration-dependent manner. The mitogen activated protein kinase phosphorylation caused by (D-Phe(6), beta-Ala(11), Phe(13), Nle(14))bombesin-(6-14) was inhibited by 2'-amino-3'-methyoxyflavone (PD98059), a mitogen activated protein kinase kinase (MEK-1) inhibitor. Using a luciferase reporter gene construct, (D-Phe(6), beta-Ala(11), Phe(13), Nle(14))bombesin-(6-14) caused Elk-1 activation after 10 min and the increase in Elk-1 activation caused by (D-Phe(6), beta-Ala(11), Phe(13), Nle(14))bombesin-(6-14) was inhibited by PD98059 as well as a dominant-negative MEK-1. (D-Phe(6), beta-Ala(11), Phe(13), Nle(14))bombesin-(6-14) caused increased c-fos as well as c-jun mRNAs 1 h after addition to NCI-H1299#5 cells. The 47-fold increase in c-fos mRNA caused by 100 nM (D-Phe(6), beta-Ala(11), Phe(13), Nle(14))bombesin-(6-14) was inhibited by PD98059, a dominant-negative MEK-1 and a substance P antagonist but not (3-phenylpropanoyl-D-Ala(24), Pro(26), Psi(26,27), Phe(27))GRP-(20-27) (BW2258U89), a GRP receptor antagonist. These results indicate that (D-Phe(6), beta-Ala(11), Phe(13), Nle(14))bombesin-(6-14) caused increased nuclear oncogene expression and upstream events include mitogen activated protein kinase phosphorylation and Elk-1 activation.
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PMID:A bombesin receptor subtype-3 peptide increases nuclear oncogene expression in a MEK-1 dependent manner in human lung cancer cells. 1116 31

Tolerance to opiates reduces their effectiveness in the treatment of severe pain. Although the mechanisms are unclear, overactivity of pro-nociceptive systems has been proposed to contribute to this phenomenon. We have reported that the development of morphine tolerance significantly increased calcitonin-gene-related-peptide-like immunoreactivity (CGRP-IR) in primary sensory afferents of the spinal dorsal horn, suggesting that changes in pain-related neuropeptides in the dorsal root ganglion (DRG) neurons may be involved (Menard et al., 1996, J. Neurosci., 16, 2342-2351). Recently, we have shown that repeated morphine treatments induced increases in CGRP- and substance P (SP)-IR in cultured DRG, mimicking the in vivo effects (Ma et al., 2000, Neuroscience, 99, 529-539). In this study, we investigated the intracellular signal transduction pathways possibly involved in morphine-induced increases in CGRP- and SP-IR in DRG neurons. Repeated morphine exposure (10-20 microm) for 6 days increased the number of neurons expressing phosphorylated (p) mitogen-activated protein (MAP) kinases, including the extracellular signal-regulated kinase (pERK), c-jun N-terminal kinase (pJNK) and P38 (pP38 MAPK). The number of neurons expressing phosphorylated cAMP responsive element binding protein (pCREB) was also markedly increased in morphine-exposed cultured DRG neurons. pERK-, pP38-, pJNK- and pCREB-IR were colocalized with CGRP-IR in cultured DRG neurons. Naloxone effectively blocked these actions of morphine, whereas a selective MEK1 inhibitor, PD98059, inhibited the morphine-induced increase in the phosphorylation of ERK and CREB, and the expression of CGRP and SP. Moreover, in morphine-tolerant rats, the number of pCREB-, CGRP- and SP-IR neurons in the lumbar DRG was also significantly increased. These in vitro and in vivo data suggest that the phosphorylation of MAP kinases and CREB plays a role in the morphine-induced increase in spinal CGRP and SP levels in primary sensory afferents, contributing to the development of tolerance to opioid-induced analgesia.
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PMID:Chronic morphine exposure increases the phosphorylation of MAP kinases and the transcription factor CREB in dorsal root ganglion neurons: an in vitro and in vivo study. 1168 1

Substance P (SP) released from sensory nerve endings in the airways induces several responses including cell proliferation. However, the mechanisms were not completely understood in tracheal smooth muscle cells (TSMCs). We therefore investigated the effect of SP on cell proliferation and activation of p42/p44 mitogen-activated protein kinase (MAPK) in these cells. SP stimulated [3H]thymidine incorporation and p42/p44 MAPK phosphorylation in a time- and concentration-dependent manner in TSMCs. Both DNA synthesis and phosphorylation of MAPK in response to SP were attenuated by pretreatment with pertussis toxin, genistein, D609, U73122, staurosporine, removal of Ca(2+) by BAPTA/AM plus EGTA, PD98059, and SB202190. Furthermore, overexpression of dominant negative mutants, H-Ras-15A and Raf-N4, significantly suppressed p42/p44 MAPK activation induced by SP and PDGF-BB. These results conclude that the mitogenic effect of SP was mediated through the activation of Ras/Raf/MEK/MAPK pathway, which was modulated by PC-PLC, PI-PLC, Ca(2+), and PKC in cultured human TSMCs.
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PMID:Substance P-induced activation of p42/44 mitogen-activated protein kinase associated with cell proliferation in human tracheal smooth muscle cells. 1222 Jun 17

Substance P is a member of the tachykinin family of neuropeptides that plays an important role in pain transmission, neurogenic inflammatory diseases and the adaptive response to stress. Substance P exerts its biological activities via binding to a G-protein coupled receptor of the neurokinin (NK) receptor family. Here, we show by Western blot experiments that substance P induced a transient synthesis of the zinc finger transcriptional regulator Egr-1 in human glioma cells. Substance P-induced stimulation of Egr-1 biosynthesis was completely inhibited by the mitogen-activated protein kinase kinase inhibitor PD98059 and by AG1487, an epidermal growth factor (EGF) receptor-specific tyrosine kinase inhibitor. These results indicate that transactivation of the EGF receptor as well as stimulation of the mitogen activated/extracellular signal-regulated protein kinase (ERK) are essential for substance P/NK-1 receptor-induced activation of Egr-1 biosynthesis. Moreover, we show that the signaling cascade initiated by substance P or EGF are indistinguishable, including the activation of the EGF receptor, the activation of ERK, and the final stimulation of Egr-1 biosynthesis. The synthesis of Egr-1 in glioma cells as a result of substance P stimulation suggests that substance P exerts long-term effects in glioma cells via Egr-1-mediated gene transcription.
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PMID:Substance P induced biosynthesis of the zinc finger transcription factor Egr-1 in human glioma cells requires activation of the epidermal growth factor receptor and of extracellular signal-regulated protein kinase. 1238 23

Workplace related standard settings for solvents are based in a remarkable extent on information about sensory irritations. However, data from controlled human exposure studies are seldom available. Therefore, the aim of this study was to present the association of self-reported symptoms and physiological processes leading to sensory irritations. Three series of laboratory experiments each with 24 young male subjects were performed. Ethyl benzene (EB), 2-butanone (methyl ethyl ketone or MEK), isopropyl alcohol (IPA), 1-octanol (OCT), and 2-ethylhexanol (EHEX) were investigated in low and high concentrations. Ratings for sensory irritations (eyes and nose), olfactory symptoms, and annoyance were assessed repeatedly before, during and after the 4-h-exposures. The anterior active rhinomanometry (AAR) was employed measuring the nasal flow. The nasal lavage was used for the analysis of the neuropeptide substance P as indicator of nasal chemosensory irritations. Goodness-of-fit was calculated for non-linear regression analyses by fitting the sine function on the data of the ratings given during the 4-h-exposure. In general, ratings for annoyance and odor symptoms were fitted on a higher level than those for sensory irritations. However, a high fit could be shown for nasal irritations due to EHEX. In these experiments, a significant reduction of the nasal flow and a significant increase of substance P could be proved.
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PMID:Physiological and psychological approaches to chemosensory effects of solvents. 1267 73

In the present study, we investigated whether activation of protease-activated receptor type 2 (PAR-2) with SLIGRL (SL)NH2, a short mimetic agonistic peptide, directly stimulates pepsinogen secretion from gastric-isolated, pepsinogen-secreting (chief) cells. Immunostaining of gastric-dispersed chief cells with a specific anti-PAR-2 antibody demonstrated expression of PAR-2 receptors on membrane and cytoplasm. SL-NH2 and trypsin potently stimulated pepsinogen secretion (EC50 = 0.3 nM) and caused Ca2+ mobilization (EC50 = 0.6 nM). In contrast to SL-NH2, the scramble peptide LSIGRL-NH2 failed to stimulate pepsinogen release. Exposure to SL-NH2 also resulted in ERK1/2 phosphorylation and activation. Exposure of chief cells to phosphotyrosine kinase inhibitors and 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one, a selective MEK inhibitor, significantly reduced secretion induced by SL-NH2. Pepsinogen secretion induced by SL-NH2 was desensitized by pretreating the cells with the mimetic peptide and trypsin, and exposure to SL-NH2 abrogates pepsinogen secretion induced by carbachol and CCK-8, but not secretion induced by secretin and vasointestinal peptide. Exposure to Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 (substance P) but not to calcitonin gene-related peptide increased pepsinogen release. The neurokinin-1 receptor antagonist, N-acetyl-l-tryptophan 3,5-bis(trifluoromethyl)benzyl ester, inhibited substance P-stimulated pepsinogen secretion, whereas it did not affect secretion induced by SL-NH2. Collectively, these data indicate that PAR-2 is expressed on gastric chief cells and that its activation causes a Ca2+-ERK-dependent stimulation of pepsinogen secretion.
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PMID:PAR-2 modulates pepsinogen secretion from gastric-isolated chief cells. 1274 62

Programmed cell death (pcd) may take the form of apoptosis or of nonapoptotic pcd. Whereas cysteine aspartyl-specific proteases (caspases) mediate apoptosis, the mediators of nonapoptotic cell death programs are much less well characterized. Here we report that alternative, nonapoptotic pcd induced by the neurokinin-1 receptor (NK(1)R) activated by its ligand Substance P, is mediated by a MAPK phosphorylation cascade recruited by the scaffold protein arrestin 2. The activation of the protein kinases Raf-1, MEK2, and ERK2 is essential for this form of nonapoptotic pcd, leading to the phosphorylation of the orphan nuclear receptor Nur77. NK(1)R-mediated cell death was inhibited by a dominant negative form of arrestin 2, Raf-1, or Nur77, by MEK1/2-specific inhibitors, and by RNA interference directed against ERK2 or MEK2 but not ERK1 or MEK1 and against Nur77. The MAPK pathway is also activated in neurons in primary culture undergoing NK(1)R-mediated death, since the MEK inhibitor PD98059 inhibited Substance P-induced death in primary striatal neurons. These results suggest that Nur77, which is regulated by a MAPK pathway activated via arrestin 2, modulates NK(1)R-mediated nonapoptotic pcd.
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PMID:Alternative, nonapoptotic programmed cell death: mediation by arrestin 2, ERK2, and Nur77. 1476 94

Substance P (SP) participates in acute intestinal inflammation via binding to the G-protein-coupled neurokinin-1 receptor (NK-1R) and release of proinflammatory cytokines from colonic epithelial cells. SP also stimulates cell proliferation, a critical event in tissue healing during chronic colitis, via transactivation of the epidermal growth factor (EGF) receptor (EGFR) and activation of mitogen-activated protein kinase (MAPK). Here we examined the mechanism by which SP induces EGFR and MAPK activation. We used non-transformed human NCM460 colonocytes stably transfected with the human NK-1R (NCM460-NK-1R cells) as well as untransfected U373 MG cells expressing high levels of endogenous NK-1R. Exposure of both cell lines to SP (10(-7) m) stimulated EGFR activation (1 min) followed by extracellular signal-regulated protein kinase (ERK1/2) activation (2-5 min). SP-induced ERK1/2 activation was blocked by pretreatment with the metalloproteinase inhibitor Batimastat/GM6001, the EGFR phosphorylation inhibitor AG1478, and the tumor necrosis factor-alpha-converting enzyme (TACE) inhibitor TAPI-1. Pretreatment with antibodies against potential EGFR ligands suggested that transforming growth factor-alpha (TGFalpha), but not the other EGFR ligands EGF, heparin-binding EGF, or amphiregulin, mediates SP-induced EGFR transactivation. SP stimulated TGFalpha release into the extracellular space that was measurable within 2 min, and this release was inhibited by metalloproteinase inhibitors and the TACE inhibitor TAPI-1. SP also induced MAPK-mediated cell proliferation that was inhibited by TACE, matrix metalloproteinase (MMP), EGFR, and MEK1 inhibitors. Thus, in human colonocytes, NK-1R-induced EGFR and MAPK activation and cell proliferation involve matrix metalloproteinases (most likely TACE) and the release of TGFalpha. These signaling mechanisms may be involved in the protective effects of NK-1R in chronic colitis.
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PMID:Metalloproteinases and transforming growth factor-alpha mediate substance P-induced mitogen-activated protein kinase activation and proliferation in human colonocytes. 1531 41


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