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

Transforming growth factor-beta 1 (TGF-beta 1) regulates the expression of the carcinoembryonic antigen (CEA) gene family in the human colon carcinoma cell line Moser. The mechanisms through which it acts, however, are unknown. In this communication, several lines of evidence are presented to show that the induction of CEA expression and secretion (collectively called CEA responses) by TGF-beta 1 is associated with protein kinase C (PKC) pathway of signal transduction. Treatment of intact cells with the PKC-specific inhibitor calphostin C down-modulated cellular PKC phosphotransferase activity and blocked the induction of the CEA responses by TGF-beta 1. Depletion of PKC by treatment of intact cells with phorbol ester also blocked the action of TGF-beta 1. The induction of the CEA responses by TGF-beta 1 was also blocked by the protein kinase inhibitor 1-(isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7), which also inhibited cellular PKC activity. However, TGF-beta 1 did induce the CEA responses in intact cells treated with the calmodulin antagonist N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride (W-7), the calmodulin-dependent phosphodiesterase inhibitor calmidazolium, the diacylglycerol kinase inhibitor R59 022, and the G-protein inhibitors cholera toxin and pertussis toxin. Treatment of intact cells with TGF-beta 1 induced a rapid and transient increase in PKC phosphotransferase activity. TGF-beta 1, however, was unable to induce PKC enzymatic activity in cells pretreated with calphostin C. Therefore, it is concluded that TGF-beta 1 regulates the CEA responses through a signal transducing pathway associated with PKC.
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PMID:Role of protein kinase C in transforming growth factor-beta 1 induction of carcinoembryonic antigen in human colon carcinoma cells. 138 May 12

STa, the heat-stable enterotoxin of Escherichia coli, stimulates membrane-bound guanylate cyclase in enterocytes, elevates cyclic GMP, and results in intestinal secretion of ions and fluid. Using the T84 colon carcinoma cell line as a model. Weikel et al. reported that phorbol esters enhance STa-stimulated cyclic GMP production by 60-140% [(1990) Infect. Immun. 58, 1402-1407]. In the present report we demonstrate that the acetylcholine analog carbachol enhanced toxin-stimulated cyclic GMP accumulation in intact T84 cells by 50-100% and that this effect was blocked by 10 microM atropine and 10 microM sphingosine. Pertussis toxin treatment of the T84 cells did not affect the subsequent response to carbachol. Carbachol, which elevates intracellular calcium in these cells, may act through protein kinase C to enhance cyclic GMP production.
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PMID:Carbachol mimics phorbol esters in its ability to enhance cyclic GMP production by STa, the heat-stable toxin of Escherichia coli. 217 3

The heat-stable enterotoxin (STa) of Escherichia coli causes intestinal secretion by stimulating guanylate cyclase, an enzyme believed to be distinct from the STa receptor. Pertussis toxin (PT) has been reported to block the ability of STa to stimulate guanylate cyclase in rat intestinal mucosa (S. A. Epstein, R. A. Giannella, and H. J. Brandwein, FEBS Lett. 203:44-48, 1986). This suggested that a guanine nucleotide regulatory protein (G protein) coupled the STa receptor to guanylate cyclase, a function not previously recognized for G proteins. We sought to explore this phenomenon and, if possible, to identify this G protein. Initial experiments with the human colon carcinoma cell line T84 revealed that higher-than-expected concentrations (1 micrograms/ml) of PT were needed to intoxicate cells, as assessed by ADP-ribosylation of endogenous PT substrate, but that 99 to 100% intoxication could be achieved. Homogenates made from fully intoxicated cells did not differ from controls in basal or STa-stimulated guanylate cyclase activity, and cyclic GMP accumulation in intact T84 cells was not changed by PT treatment. We conclude that a PT-sensitive G protein is not involved in the stimulation of cyclic GMP production by the enterotoxin STa.
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PMID:Failure of pertussis toxin to inhibit activation of guanylate cyclase by the heat-stable enterotoxin of Escherichia coli (STa) in the T84 cell line. 256 75

Previous studies have established that the human colon carcinoma cell line HT29 expresses an alpha 2-adrenergic receptor of the alpha 2A subtype, which is negatively coupled to adenylate cyclase. The purpose of the present study was to examine the mechanisms of alpha 2-adrenergic signal transduction in these cells. [32P]ADP-ribosylation with pertussis toxin and immunoblots using antibodies specific for the Gi alpha-subunits indicated that two distinct Gi-proteins (Gi2 and Gi3) were present in HT29-cell membranes. Treatment of intact cells with pertussis toxin resulted in a time-dependent decrease in the amount of [32P]ADP-ribosylatable Gi2 and Gi3, which coincided with a diminution in the number of alpha 2-adrenergic receptors in high-affinity state for agonists and with a progressive loss of ability of UK14304 to inhibit forskolin-stimulated accumulation of cyclic AMP. When membranes were [32P]ADP-ribosylated with cholera toxin in the absence of exogenous added guanine nucleotides, radioactivity was incorporated into a 45 kDa polypeptide representing Gs, as well as into 40-41 kDa polypeptides corresponding to Gi3 and Gi2. The amount of radioactivity incorporated into the two GiS under basal conditions was decreased by addition of the alpha 2-antagonist RX821002. It was not significantly affected by addition of clonidine (partial alpha 2-agonist), but was doubled by the addition of UK14304 (full alpha 2-agonist). This effect was blocked by RX821002. Study of adenylate cyclase activity indicated that preincubation of HT29 membranes with the antibody AS/7 (anti-alpha i1/alpha i2), but not with the antibody EC/2 (anti-alpha i3), attenuated the inhibitory effect of UK14304 on forskolin-stimulated adenylate cyclase. These data demonstrate that the alpha 2A-adrenergic receptor is coupled to both Gi2 and Gi3, and identify Gi2 as the major mediator of inhibition of adenylate cyclase in HT29 cells.
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PMID:Coupling of the alpha 2-adrenergic receptor to the inhibitory G-protein Gi and adenylate cyclase in HT29 cells. 809 79

The effect of purinergic receptor agonists on arachidonic acid release was investigated in [3H]arachidonic acid-prelabeled human airway epithelial cells. Exposure of bronchial epithelial BEAS39 cells to extracellular ATP resulted in a marked release of unesterified [3H]arachidonic acid with maximal effect observed within 60-90 s. [3H]diacylglycerol and [3H]phosphatidic acid accumulated in parallel with [3H]arachidonic acid. ATP-stimulated [3H]arachidonic acid release with a K0.5 of 9 +/- 2 microM and UTP was equipotent; no effect was observed with P2Y- or P2X-purinergic receptor agonists or with adenosine. Similar results were obtained with primary cultures of normal human nasal epithelium, CF/T43 and HBE1 airway epithelial cell lines derived from a cystic fibrosis patient and from a normal donor, respectively, and HT-29 human colon carcinoma cells. ATP stimulated inositol phosphate formation in BEAS39 cells with a concentration dependence identical to that for [3H]arachidonic acid release. The effect of ATP on both [3H]arachidonic acid release and inositol phosphate formation was equally inhibited by pertussis toxin. The Ca2+ ionophore A-23187 mimicked the effects of ATP or UTP on arachidonic acid release, and a marked inhibitory effect was observed with thapsigargin. The protein kinase C inhibitor staurosporine partially inhibited ATP-stimulated [3H]arachidonic acid release. These data are consistent with the hypothesis that phospholipase A2 activation is secondary to P2U-purinergic receptor stimulation of D-myoinositol 1,4,5-trisphosphate production and calcium mobilization from intracellular stores.
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PMID:Calcium-dependent release of arachidonic acid in response to purinergic receptor activation in airway epithelium. 814 Dec 54

The P-glycoprotein (Pgp) reversing agent, reserpine, induces MDR1 mRNA and PGP protein in human colon carcinoma cells (Schuetz, E. G., Beck, W. T., and Schuetz, J. D. (1996) Mol. Pharmacol. 49, 311-318) and in H35 rat hepatoma cells. Reserpine's interference with cellular dopamine utilization suggested that dopamine and dopaminergics might be important physiological regulators of PGP expression. Initial studies demonstrated that the H35 cells express the D2 dopamine receptor. Pgp protein and pgp2/mdr1b mRNA was increased (maximum of 10- and 8-fold, respectively) by the potent D2 dopamine receptor agonists bromocriptine, R(-)-propylnorapomorphine hydrochloride, and quinpirole, and Pgp protein induction was blocked by D2 receptor antagonists spiperone and clozapine. D2 receptor agonist induction of pgp2/mdr1b mRNA was paralleled by transcriptional activation of the pgp2/mdr1b promoter but blocked by pretreatment with the D2 dopamine receptor antagonists, spiperone, eticlopride, and clozapine. Co-transfection of a D2 dopamine receptor expression vector enhanced bromocriptine's transcriptional activation of the pgp2/mdr1b promoter. The G-protein, Galphai2, is required for bromocriptine transcriptional activation because the G-protein inhibitor, pertussis toxin, suppressed bromocriptine's activation of pgp2/mdr1b transcription and co-transfection of a dominant negative Galphai2 abrogated bromocriptine activation of pgp2/mdr1b. Gi proteins can transduce signals by activation of mitogen-activated protein kinases (MAPKs), and because Raf-1 is a known activator of MDR1, we tested for Raf-1 involvement. Co-transfection of a dominant negative Raf-1 failed to block bromocriptine induction of pgp2/mdr1b, and bromocriptine treatment caused no phosphorylation of the MAP kinase kinase substrates p42 and p44, demonstrating that the MAP kinase pathway was not involved. These are the first studies demonstrating transcriptional activation of an MDR gene by dopamine receptor agonists and that this activation occurs by a signal transduction pathway requiring the D2 dopamine receptor coupled to a functional G-protein.
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PMID:Bromocriptine transcriptionally activates the multidrug resistance gene (pgp2/mdr1b) by a novel pathway. 911 Oct 66

It is now clearly established that alpha-2 adrenergic receptors can be subdivided in three pharmacological subtypes (alpha-2A, alpha-2B and alpha-2C) encoded by distinct genes (alpha 2C10, alpha 2C2 and alpha 2C4, respectively, in humans). Whereas the study of the regulation of the human alpha-2A adrenergic receptor and of the promoter region of the alpha 2C10 gene has being greatly helped by the availability of the colon carcinoma cell line HT29, the study of the other human receptor subtypes has thus far been limited to homologous desensitization/down-regulation in transfected cells, because of the lack of human cellular models constitutively-expressing alpha-2B or alpha-2C adrenergic receptors. Several human cell lines were thus screened, in an attempt to find such models. Radioligand binding studies with [3H]RX821002 and [3H]MK912, reverse transcription-polymerase chain reactions and RNase mapping experiments with pairs of primers and riboprobes specific for each subtype demonstrated that the hepatoma cell line HepG2 and the neuroblastoma cell line SK-N-MC possess alpha-2 adrenergic receptors of the alpha-2C subtype. However, whereas HepG2 expresses exclusively alpha-2C receptors (55 +/- 7 fmol of [3H]MK912 binding sites/mg of protein), SK-N-MC expresses both alpha-2A and alpha-2C subtypes in fairly similar amounts (20 +/- 8 and 23 +/- 3 fmol of [3H]MK912 binding sites/mg of protein, respectively). The study of the inhibition of 3H-labeled antagonist binding by UK14304 demonstrated that a fraction of the receptor population was coupled to pertussis toxin-sensitive G-proteins, which were identified as Gi2 and Gi3 by immunoblotting. The alpha-2 agonist was, moreover, able to decrease forskolin-stimulated cAMP production by 47% in HepG2 and 23% in SK-N-MC, demonstrating that inhibition of adenylyl cyclase is one of the primary mechanisms of signal transduction in both cell lines. HepG2 and SK-N-MC are the first human cell lines unquestionably shown to natively express alpha-2C adrenergic receptors. The discovery of these two models may be useful for future study of the regulation of alpha 2C4 gene expression in cells of different origins and investigation of the reciprocal regulation of alpha-2A and alpha-2C subtype in single cells.
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PMID:HepG2 and SK-N-MC: two human models to study alpha-2 adrenergic receptors of the alpha-2C subtype. 915 9

CXCR4, the receptor for the chemokine stromal cell-derived factor (SDF)-1 (CXCL12), is involved in lymphocyte trafficking. We have demonstrated previously that it is required for invasion of lymphoma cells into tissues and therefore essential for lymphoma metastasis. CXCR4 is also expressed by carcinoma cells, and CXCR4 antibodies were recently shown to reduce metastasis of a mammary carcinoma cell line. This was also ascribed to impaired invasion. We have blocked CXCR4 function in CT-26 colon carcinoma cells by transfection of SDF-1, extended with a KDEL sequence. The SDF-KDEL protein is retained in the endoplasmic reticulum by the KDEL-receptor and binds CXCR4, which is thus prevented from reaching the cell surface. We found that metastasis of these cells to liver and lungs was greatly reduced and often completely blocked. Surprisingly, however, our observations indicate that this was not attributable to inhibition of invasion but rather to impairment of outgrowth of micrometastases: (a) in contrast to the lymphoma cells, metastasis was not affected by the transfected S1 subunit of pertussis toxin. S1 completely inhibited Gi protein signaling, which is required for SDF-1-induced invasion; (b) CXCR4 levels were very low in CT-26 cells grown in vitro but strongly up-regulated in vivo. Strong up-regulation was not seen in the lungs until 7 days after tail vein injection. CXCR4 can thus have no role in initial invasion in the lungs; and (c) CXCR4-deficient cells did colonize the lungs to the same extent as control cells and survived. However, they did not expand, whereas control cells proliferated rapidly after a lag period of > or = 7 days. We conclude that CXCR4 is up-regulated by the microenvironment and that isolated metastatic cells are likely to require CXCR4 signals to initiate proliferation. Our results suggest that CXCR4 inhibitors have potential as anticancer agents to suppress outgrowth of micrometastases.
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PMID:The chemokine receptor CXCR4 is required for outgrowth of colon carcinoma micrometastases. 1283 81