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)

Octreotide (SMS), a somatostatin analogue, is an established antigrowth peptide, but it does not effectively inhibit the growth of insulinoma cells. In order to study the mechanisms that underlie this apparent lack of an antiproliferative effect on insulinoma tumor cells we established the rat insulinoma cell line, RINm5F, in culture. Cells in culture were tested by incubation in media with and without SMS. To study tritiated [3H]-thymidine incorporation into extracted DNA (TTID), 2 muCi/well of 3H was added for 24 hr, and cells were harvested and assayed for TTID (cpm/microgram DNA). Insulin (IRI) and intracellular cAMP (cAMPi) were measured by RIA. To study the effects of SMS on insulin secretion, conditioned media were sampled after 24 hr. To study the effects of cAMPi, conditioned medium was used to extract cAMPi following incubation with SMS for 15 min. Increasing concentrations of SMS had no significant effect on TTID in the presence of 1% FBS. Trypan blue exclusion tests showed > 90% viable cells throughout all stages of these experiments. There were no significant differences in cell numbers and protein content in the presence of SMS. There was a significant decrease in the secretion of insulin and intracellular cAMP levels in response to 50 nM SMS. However, SMS significantly inhibited TTID in RINm5F cells following a 4-hr pretreatment with pertussis toxin (PT) (23553 +/- 1747 vs 20635 [cpm/microgram DNA] +/- 1983 [SEM], P < 0.01). We conclude that the inhibition of insulin secretion by SMS is associated with an attenuation of cAMP formation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanisms of somatostatin action in RINm5F cells in culture: preliminary evidence for possible altered G protein function. 135 94

In the preceding report (Kelvin, D.J., G. Simard, H.H. Tai, T.P. Yamaguchi, and J.A. Connolly. 1989. J. Cell Biol. 108:159-167) we demonstrated that pertussis toxin (PT) blocked proliferation and induced differentiation in BC3H1 muscle cells. In the present study, we have used PT to examine specific growth factor signaling pathways that may regulate these processes. Inhibition of [3H]thymidine by PT in 20% FBS was reversed in a dose-dependent fashion by purified fibroblast growth factor (FGF). In 0.5% FBS, the normally induced increase in creatine kinase (CK) activity was blocked by FGF in both the presence and absence of PT. Similar results were obtained with purified epidermal growth factor (EGF). We subsequently examined the effect of a family of growth factors linked to inositol lipid hydrolysis and found that thrombin, like FGF, would increase [3H]thymidine incorporation and block CK synthesis. However, PT blocked thymidine incorporation induced by thrombin, and blocked the inhibition of CK turn-on in 0.5% FBS by thrombin. The ras oncogene, a G protein homologue, has previously been shown to block muscle cell differentiation in C2 muscle cells (Olson, E.N., G. Spizz, and M.A. Tainsky. 1987. Mol. Cell. Biol. 7:2104-2111); we have characterized a BC3H1 cell line, BCT31, which we transfected with the val12 oncogenic Harvey ras gene. This cell line did not express CK in response to serum deprivation. Whereas [3H]thymidine incorporation was inhibited by 70-80% by increasing doses of PT in control cells, BCT31 cells were only inhibited by 15-20%. ADP ribosylation studies indicate this PT-insensitivity is not because of the lack of a PT substrate in this cell line. Furthermore, PT could not induce CK expression in BCT31 cells as it did in parental cells. We conclude that there are at least two distinct growth factor pathways that play a key role in regulating proliferation and differentiation in BC3H1 muscle cells, one of which is PT sensitive, and postulate that a G protein is involved in transducing signals from the thrombin receptor. We believe that ras functions in the transduction of growth factor signals in the nonPT-sensitive pathway or downstream from the PT substrate in the second pathway.
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PMID:Growth factors, signaling pathways, and the regulation of proliferation and differentiation in BC3H1 muscle cells. II. Two signaling pathways distinguished by pertussis toxin and a potential role for the ras oncogene. 249 22

Cells of the nonfusing muscle cell line BC3H1 stop proliferating and express a family of muscle-specific proteins when the FBS concentration is reduced from 20 to 0.5% (Munson, R., K.L. Caldwell, and L. Glaser. 1982. J. Cell Biol. 92:350-356). Several growth factors have been shown to block differentiation in this cell line. To begin to investigate the potential role of G proteins in signal transducing pathways from these receptors, we have examined the effects of cholera toxin (CT) and pertussis toxin (PT) on proliferation and differentiation in BC3H1 cells. PT specifically ADP ribosylates a protein with an apparent molecular mass of 40 kD in BC3H1 cell membranes, whereas CT specifically ADP ribosylates three proteins of 35-43 kD. When added to exponentially growing cells in 20% FBS, CT and PT inhibited [3H]thymidine incorporation by up to 75% in a dose-dependent fashion. We found the synthesis of creatine kinase (CK) and skeletal muscle myosin light chain was reversibly induced in cells in 20% FBS treated with PT, but no increased synthesis was seen in cells treated with CT or in control cells; Northern analysis indicated this induction was at the level of mRNA. In cells shifted to 0.5% FBS, CT inhibited the normally induced synthesis of CK whereas PT potentiated it by approximately 50%. Forskolin also inhibited growth in 20% FBS and differentiation in 0.5% FBS medium in a dose-dependent fashion. both forskolin and CT elevated cAMP levels compared with control or PT-treated cells, suggesting that CT is blocking proliferation and differentiation by elevating cAMP levels. These results establish that a PT-sensitive pathway is involved in regulating proliferation and differentiation in BC3H1 cells, and we postulate that PT functions by ADP ribosylating a G protein that transduces signals from growth factor receptors in these cells.
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PMID:Growth factors, signaling pathways, and the regulation of proliferation and differentiation in BC3H1 muscle cells. I. A pertussis toxin-sensitive pathway is involved. 253 32

The respiratory burst of phagocytes in an important leukocyte function which results in generation of oxygen species that are both microbicidal and potentially damaging to host tissues. We investigated regulation of the respiratory burst of alveolar macrophages in response to lipopolysaccharide (LPS) derived from gram-negative bacteria, serum proteins, and several modulators of signal transduction. When employed as a single stimulus, LPS (E. coli 055:B5, 10 ng/ml-1 microgram/ml) was a weak stimulus for generation of superoxide anion (O2-) as compared to the potent effect of the protein kinase C activator, phorbol 12-myristate 13-acetate (PMA; 500 ng/ml). However, when LPS was combined with fetal bovine serum (FBS; 0.4-1.0% vol/vol, equivalent to 128-320 micrograms protein/ml), O2- generation was enhanced approximately two-fold over LPS alone. A chromatographically-derived bovine serum fraction which contained bovine lipopolysaccharide-binding protein (bLBP; 0.25-1.0 microgram/ml) was an effective substitute for FBS at a much lower protein concentration than whole FBS, and a similar synergistic effect with LPS on O2- generation was observed. Stimulation of macrophages for generation of O2- either with LPS alone or with LPS plus serum/serum fraction was suppressed by the protein tyrosine kinase inhibitor heribimycin A (0.2 ng/ml), and the calcium chelator BAPTA (12 microM), but not by modulators of G-proteins, including pertussis toxin (10 ng/ml) and cholera toxin (5 micrograms/ml protein). Essentially complete inhibition of O2- synthesis by herbimycin A and BAPTA occurred in the presence of LPS and the bLBP-containing serum fraction (1 microgram/ml protein), but only partial inhibition (46.7% and 64.1%, respectively) was observed in the presence of LPS plus FBS (256 micrograms/ml protein). These results indicate that when LPS is used as a sole stimulus it induces modest respiratory burst activity. However, when LPS is combined with appropriate serum components, it stimulates alveolar macrophages to generate larger amounts of O2-. Cellular signaling pathways important in stimulation of macrophages by LPS and serum components are protein tyrosine kinase- and Ca(++)-dependent, but do not relay on G-protein-mediated signaling.
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PMID:Regulation of superoxide anion generation in bovine alveolar macrophages by bacterial lipopolysaccharide, serum proteins, and modulators of signal transduction. 859 31

Through selective activation of the gonadotropic signal transduction pathway, we have determined the probable site of the antigonadotropic effects of prostaglandin F2alpha (PGF2alpha) in the human granulosa-luteal cell (hGLC). The gonadotropic signal transduction pathway was activated at the level of the receptor (luteinizing hormone and beta-adrenergic), stimulatory G protein (Gs), adenylate cyclase (AC), and protein kinase A (PKA) by human chorionic gonadotropin (hCG) and isoproterenol (Iso), cholera toxin (CTX), forskolin, and dibutryl cAMP (Db cAMP), respectively. Concomitantly, the ability of PGF2alpha to inhibit progesterone production in response to the activation of this cascade at these different levels was examined. hGLCs were obtained from in vitro fertilization patients and were precultured for 8 d in Medium 199 supplemented with fetal bovine serum (M199; 10% FBS). Following the preculture period, cells were treated with either vehicle or one of the above activators of the gonadotropic pathway, either in the absence or presence of PGF2alpha (in M199; No FBS). Following the treatment period, media were collected and assayed for progesterone by RIA. Prostaglandin F2alpha (10(-6) M) significantly inhibited hCG (1 IU/mL), Iso (10(-5) M), CTX (1 microg/mL), and forskolin- (10(-5) M) stimulated progesterone production. Conversely, PGF2alpha did not inhibit progesterone production stimulated by a saturating concentration of Db cAMP (10(-6) M). The ability of PGF2alpha to inhibit hCG- or CTX-stimulated progesterone production was attenuated by pertussis toxin (PTX; 50 ng/mL). In conclusion, through a pertussis toxin-sensitive G protein, PGF2alpha inhibits progesterone production at a level below AC, and above the activation of PKA by cAMP.
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PMID:Stepwise activation of the gonadotropic signal transduction pathway, and the ability of prostaglandin F2alpha to inhibit this activated pathway. 974 35

In CCL39 cells thrombin is a potent growth factor which requires sustained activation of mitogen activated protein kinases (MAPKs) to promote DNA synthesis. Some of the effects of thrombin can be mimicked by peptides based on the new amino terminus of the cleaved receptor; however, these thrombin receptor peptides (TRPs) fail to induce sustained activation of MAPK or DNA synthesis. We have used thrombin, TRP-7 and other agonists which elicit sustained or transient MAPK activation to identify immediate-early and delayed-early genes which are only expressed under conditions of sustained MAPK activation focusing on cyclin D1, p21CiP1 and the AP-1 transcription factor. Of the stimuli tested only FBS and thrombin were able to stimulate a sustained activation of MAPK, expression of cyclin D1, p21Cip1 and cell cycle re-entry. The expression of cyclin D1 was strongly, though not completely, inhibited by the MEK1 inhibitor PD098059. Thrombin stimulated a rapid but transient accumulation of c-Fos whereas the expression of Fra-1, Fra-2, c-Jun and JunB was sustained throughout the G1 phase of the cell cycle. We focussed our analysis on c-Fos (typical of AP-1 genes which are expressed rapidly and transiently) and Fra-1 and JunB (typical of AP-1 genes expressed after a delay but in a sustained manner). The expression of c-Fos, Fra-1 and JunB was dependent upon the activation of MAPK since these responses were inhibited by PD098059. However, a comparison of responses to FBS, thrombin, TRPs, LPA and EGF revealed that Fra-1 and JunB expression required sustained activation of MAPK whereas c-Fos expression was strongly induced even by non-mitogenic stimuli which elicited only transient MAPK activation. The expression of c-Fos (in response to thrombin, TRP or LPA) or Fra-1, JunB and cyclin D1 (thrombin only) was also inhibited by pertussis toxin. This suggests that both early and late AP-1 gene expression is regulated by the same Gi-mediated, MEK-dependent MAPK signalling pathway but that expression of late AP-1 genes and cyclin D1 requires that this pathway be persistently activated. The results suggest that the duration of receptor signalling and therefore MAPK activation is a key determinant of qualitative changes in gene expression during cell cycle re-entry.
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PMID:Sustained MAP kinase activation is required for the expression of cyclin D1, p21Cip1 and a subset of AP-1 proteins in CCL39 cells. 1034 Mar 80

We investigated the chemotactic action of PDGF and urokinase on human airway smooth muscle (HASM) cells in culture. Cells were put in collagen-coated transwells with 8-micro m perforations, incubated for 4 h with test compounds, then fixed, stained, and counted as migrated nuclei by microscopy. Cells from all culture conditions showed some basal migration (migration in the absence of stimuli during the assay), but cells preincubated for 24 h in 10% FBS or 20 ng/ml PDGF showed higher basal migration than cells quiesced in 1% FBS. PDGF(BB), PDGF(AA), and PDGF(AB) were all chemotactic when added during the assay. PDGF chemotaxis was blocked by the phosphatidyl 3'-kinase inhibitor LY-294002, the MEK inhibitor U-0126, PGE(2), formoterol, pertussis toxin, and the Rho kinase inhibitor Y-27632. Urokinase alone had no stimulatory effect on migration of quiescent cells but caused a dose-dependent potentiation of chemotaxis toward PDGF. Urokinase also potentiated the elevated basal migration of cells pretreated in 10% FBS or PDGF. This potentiating effect of urokinase appears to be novel. We conclude that PDGF and similar cytokines may be important factors in airway remodeling by redistribution of smooth muscle cells during inflammation and that urokinase may be important in potentiating the response.
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PMID:Urokinase potentiates PDGF-induced chemotaxis of human airway smooth muscle cells. 1257 95

Prokineticin-1 (PK1) has been identified as a mitogen-specific protein for the endothelium of steroidogenic glands. Here we report a novel function of PK1 in the regulation of multiple myeloma (MM) cells. PK1 activates multiple signals including mitogen-activated protein kinase (MAPK), PI3K-AKT, and Jak-STAT3, sphingosine kinase-1 (SPK1) in MM cells. Treatment of MM cells with PK1 causes a time- and dose-dependent phosphorylation of MAPK, AKT and STAT3 and upregulation of SPK1 expression and cellular activity. We also show that PK1 upregulates Mcl-1 expression in a time- and dose-dependent manner in human MM cell lines and in the cells of patients with MM. Pertussis toxin, a pan-PK1 receptor inhibitor, can block PK1-induced upregulation of Mcl-1, indicating it relates to a G-protein-coupled receptor. We also show that PK1 protects MM cells against apoptosis induced by starvation for fetal calf serum (FBS), or for FBS and IL-6. Taken together, PK1 activates multiple signaling pathways and, upregulates Mcl-1 expression, leading to proliferation and survival of MM cells.
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PMID:Prokineticin-1/endocrine gland-derived vascular endothelial growth factor is a survival factor for human multiple myeloma cells. 2079 91