Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Granulin-epithelin precursor (GEP/progranulin) is an autocrine growth factor for ovarian cancer. We examined the production and function of GEP and report that: (1) GEP production is regulated by endothelin (ET-1), lysophosphatidic acid (LPA), and cAMP; (2) cAMP signals GEP production through exchange protein activated by cAMP (EPAC); (3) ET-1 and cAMP/EPAC induce GEP through ERK1/2; and (4) neutralization of GEP results in apoptosis. Exposure of HEY-A8 and OVCAR3 ovarian cancer cells to LPA and ET-1 yielded GEP production and secretion in a dose- and time-dependent fashion; neither stimulated significant concentrations of cAMP directly. Stimulation of cAMP production with pertussis and cholera toxin, or forskolin induced GEP in a PKA-independent fashion. EPAC, an intracellular cAMP receptor, is activated specifically by the cAMP analog, 8-CPT-2'-O-Me-cAMP (8-CPT); 8-CPT treatment stimulated GEP production and secretion. The MEK inhibitor, U0126, abrogated GEP production in response to ET-1 and 8-CPT, confirming involvement of MAPK. A partial inhibition of basal and stimulated GEP production was observed when cells were treated with a internal calcium chelator, BAPTA. Neutralizing anti-GEP antibody reversed basal as well as LPA, ET-1 and 8-CPT-induced ovarian cancer cell growth and induced apoptosis as demonstrated by caspase-3 and PARP cleavage, DNA fragmentation, and nuclear condensation. These results indicate that GEP is a growth and survival factor for ovarian cancer, induced by LPA and ET-1 and cAMP/EPAC through ERK1/2.
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PMID:Lysophosphatidic acid and endothelin-induced proliferation of ovarian cancer cell lines is mitigated by neutralization of granulin-epithelin precursor (GEP), a prosurvival factor for ovarian cancer. 1604 62

There is increased staining of endothelins (ET-1, -2, and -3) and receptors (ET-RA and -RB) in invasive breast tumors compared to nonneoplastic tissue, and ETs stimulate MCF-7 cell invasion in vitro. We analyzed ETstimulation of benign and transformed mammary epithelial cells, and whether expression of ETs is sufficient to induce invasiveness. In breast cancer patient serum, ET-1 was increased in those patients with lymph node metastases compared to those with no lymph node involvement; ETs, however, had no mitogenic effect on breast tumor cell lines in vitro. The benign mammary epithelial cell line, hTERT-HME1, and the poorly invasive breast tumor cell line MCF-7 secreted low levels of ET-1, while the invasive cell lines SKBR3 and MDAMB231 secreted high levels. Expression of the ETs and receptors by the cell lines broadly correlated with their in vitro invasiveness; overexpression of ETs in MCF-7 cells increased basal invasion. ET-mediated invasion involved both receptors and a calcium influx to induce a pertussis toxin-sensitive MAPK pathway. MMP-14 activity was induced via ET-RA in an autocrine manner. In contrast to transformed cells, ET stimulation or overexpression did not induce an invasive phenotype in benign cells. Benign cells do not respond to ETs, and ET expression is not sufficient to induce invasion; however, the level of ET production by tumor cells correlates with their invasiveness, and increasing expression of the ET axis promotes breast tumor cell invasion via both receptors, while MMP-14 is induced via ET-RA.
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PMID:Expression of endothelins and their receptors promotes an invasive phenotype of breast tumor cells but is insufficient to induce invasion in benign cells. 1627 97

Gap junctions contribute to important functions of communicating glial cells in brain physiology and pathology. Endothelins (ETs), a vasoactive family of peptides present in the brain, have been described as potent inhibitors of astrocyte gap junctional communication. Through dye-coupling studies we demonstrate here that this inhibition occurs rapidly and then successively reverses and returns to control levels after 90 min of continuous ET1 or ET3 exposure. In addition, long-term exposure of cells to ET3, which acts mainly on ETB receptors, also desensitized the acute action of ET1, which was previously shown to act through either ETA or ETB receptor sites, or both. The gap junction blocker carbenoxolone did not show any time-dependent desensitization and was fully effective also in cultures treated with ETs for prolonged times. The ETs inhibitory effects were partially prevented when blocking pertussis toxin-sensitive G-proteins, chelating intracellular Ca2+, or omitting extracellular Ca2+. We further show that ETs modulate gap junction-mediated transfer of 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-Y1)amino]-2-deoxyglucose (2-NBDG), a fluorescent glucose molecule, indicating a role of astrocyte gap junction coupling in metabolic trafficking and suggesting the importance of these peptides in the control of intercellular diffusion of energetic compounds. These findings might have particular relevance in early tissue reactions after various cerebral injuries, which commonly involve increased cerebral ET levels.
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PMID:Kinetics of endothelin-induced inhibition and glucose permeability of astrocyte gap junctions. 1660 58

Our previous work showed that ET-1 induced a concentration-dependent increase of cytosolic Ca2+ ([Ca]c) and nuclear Ca2+ ([Ca]n) in human aortic vascular smooth muscle cells (hVSMCs). In the present study, using hVSMCs and 3-dimensional confocal microscopy coupled to the Ca2+ fluorescent probe Fluo-3, we showed that peptidic antagonists of ETA and ETB receptors (BQ-123 (10(-6) mol/L) and BQ-788 (10(-7) mol/L), respectively) prevented, but did not reverse, ET-1-induced sustained increase of [Ca]c and [Ca]n. In contrast, nonpeptidic antagonists of ETA and ETB (respectively, BMS-182874 (10(-8)-10(-6) mol/L) and A-192621 (10(-7) mol/L)) both prevented and reversed ET-1-induced sustained increase of [Ca]c and [Ca]n. Furthermore, activation of the ETB receptor alone using the specific agonist IRL-1620 (10(-9) mol/L) induced sustained increases of [Ca]c and [Ca]n, and subsequent administration of ET-1 (10(-7) mol/L) further increased nuclear Ca2+. ET-1-induced increase of [Ca]c and [Ca]n was completely blocked by extracellular application of the Ca2+ chelator EGTA. Pretreatment with the G protein inhibitors pertussis toxin (PTX) and cholera toxin (CTX) also prevented the ET-1 response; however, strong membrane depolarization with KCl (30 mmol/L) subsequently induced sustained increase of [Ca]c and [Ca]n. Pretreatment of hVSMCs with either the PKC activator phorbol-12,13-dibutyrate or the PKC inhibitor bisindolylmaleimide did not affect ET-1-induced sustained increase of intracellular Ca2+. These results suggest that both ETA- and ETB-receptor activation contribute to ET-1-induced sustained increase of [Ca]c and [Ca]n in hVSMCs. Moreover, in contrast to the peptidic antagonists of ET-1 receptors, the nonpeptidic ETA-receptor antagonist BMS-182874 and the nonpeptidic ETB-receptor antagonist A-192621 were able to reverse the effect of ET-1. Nonpeptidic ETA- and ETB-receptor antagonists may therefore be better pharmacological tools for blocking ET-1-induced sustained increase of intracellular Ca2+ in hVSMCs. Our results also suggest that the ET-1-induced sustained increase of [Ca]c and [Ca]n is not mediated via activation of PKC, but via a PTX- and CTX-sensitive G protein calcium influx through the R-type Ca2+ channel.
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PMID:Nonpeptidic antagonists of ETA and ETB receptors reverse the ET-1-induced sustained increase of cytosolic and nuclear calcium in human aortic vascular smooth muscle cells. 1875 3

The objective of this work was to verify whether, as in the case of the plasma membrane of human vascular smooth muscle cells (hVSMCs), cytosolic ET-1-induced increase of nuclear calcium is mediated via the activation of calcium influx through the steady-state R-type calcium channel. Pharmacological tools to identify the R-type calcium channels, as well as real 3-D confocal microscopy imaging techniques coupled to calcium fluorescent probes, were used to study the effect of cytosolic ET-1 on nuclear calcium in isolated nuclei of human hepatocytes and plasma membrane perforated hVSMCs. Our results showed that pre-treatment with pertussis toxin (PTX) or cholera toxin (CTX) prevented cytosolic ET-1 (10(-9) mol/L) from inducing a sustained increase in nuclear calcium. Furthermore, the L-type calcium channel blocker nifedipine did not prevent cytosolic ET-1 from inducing an increase in nuclear calcium, as opposed to the dual L- and R-type calcium channel blocker isradipine (PN200-110) (in the presence of nifedipine). In conclusion, the preventative effect with PTX and CTX, and the absence of an effect with nifedipine, as well as the blockade by isradipine on cytosolic ET-1-induced increase in nuclear calcium, suggest that this nuclear calcium influx in hVSMCs is due to activation of the steady-state R-type calcium channel. The sarcolemmal and nuclear membrane R-type calcium channels in hVSMCs are involved in ET-1 modulation of vascular tone in physiology and pathology.
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PMID:Nuclear membrane R-type calcium channels mediate cytosolic ET-1-induced increase of nuclear calcium in human vascular smooth muscle cells. 2574 85


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