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Results for “Signal Transduction”

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At least 577 records · Page 32Linked to original sources

PubMed1999

Transcriptional activation of gonadotropin-releasing hormone (GnRH) receptor gene by GnRH: involvement of multiple signal transduction pathways.

Previous studies have shown that GnRH activates transcriptional activity of its own receptor (GnRHR) gene in part through the cAMP signal transduction pathway. In the present study we explored the possible involvement of multiple signal transduction pathways in GnRH regulation of GnRHR gene transcription; these studies relied upon a luciferase reporter gene vector (GnRHR-pXP2) containing a 1226-bp promoter fragment (-1164 to +62, relative to the major transcription start site) of the mouse GnRHR gene in GGH3 cells (GH3 cells stably expressing rat GnRHR). Activation of protein kinase C (PKC) by phorbol myristic acid significantly stimulated GnRHR-luciferase reporter gene (GnRHR-Luc) activity, but did not potentiate the stimulation of GnRHR-Luc activity by the GnRH agonist, buserelin (GnRH-A). Inhibition of PKC by PKC inhibitor (GF 109203X) or depletion of PKC blocked phorbol myristic acid- or GnRH-A-stimulated GnRHR-Luc activity, but did not affect (Bu)2cAMP-stimulated GnRHR-Luc activity. In addition, GnRH-A-stimulated GnRHR-Luc activity was inhibited by preventing external Ca2+ influx with the external Ca2+ chelator EGTA or the Ca2+ ion channel antagonist, D600. Surprisingly, overexpression of the mitogen-activated protein kinase (MAPK) kinase kinase (Raf-1) inhibited GnRHR-Luc activity and partially blocked GnRH-A-stimulated GnRHR-Luc activity. In contrast, inhibition of MAPK activity by MAPK kinase inhibitor (PD 98059) or by overexpression of kinase-deficient MAPKs activated basal and GnRH-A-stimulated GnRHR-Luc activity. These results suggested that PKC- and Ca2+-dependent signal transduction pathways participate in the GnRH activation of GnRHR promoter activity, and that the MAPK cascade is involved in the negative regulation of basal and GnRH-stimulated GnRHR transcriptional activity conferred by the 1226-bp promoter fragment.

Animals↗

PubMed2003

Calmodulin is involved in heat shock signal transduction in wheat.

The involvement of calcium and calcium-activated calmodulin (Ca(2+)-CaM) in heat shock (HS) signal transduction in wheat (Triticum aestivum) was investigated. Using Fluo-3/acetoxymethyl esters and laser scanning confocal microscopy, it was found that the increase of intracellular free calcium ion concentration started within 1 min after a 37 degrees C HS. The levels of CaM mRNA and protein increased during HS at 37 degrees C in the presence of Ca(2+). The expression of hsp26 and hsp70 genes was up-regulated by the addition of CaCl(2) and down-regulated by the calcium ion chelator EGTA, the calcium ion channel blockers LaCl(3) and verapamil, or the CaM antagonists N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide and chlorpromazine. Treatment with Ca(2+) also increased, and with EGTA, verapamil, chlorpromazine, or trifluoperazine decreased, synthesis of HS proteins. The temporal expression of the CaM1-2 gene and the hsp26 and hsp70 genes demonstrated that up-regulation of the CaM1-2 gene occurred at 10 min after HS at 37 degrees C, whereas that of hsp26 and hsp70 appeared at 20 min after HS. A 5-min HS induced expression of hsp26 after a period of recovery at 22 degrees C after HS at 37 degrees C. Taken together, these results indicate that Ca(2+)-CaM is directly involved in the HS signal transduction pathway. A working hypothesis about the relationship between upstream and downstream of HS signal transduction is presented.

Calcium↗

PubMed2004

Regulation of apoptotic signal transduction pathways by the heat shock proteins.

The study about apoptotic signal transductions has become a project to reveal the molecular mechanisms of apoptosis. Heat shock proteins (hsps), which play an important role in cell growth and apoptosis, have attracted great attentions. A lot of researches have showed there is a hsps superfamily including hsp90, hsp70, hsp60 and hsp27, etc., which regulates the biological behaviors of cells, particularly apoptotic signal transduction in Fas pathway, JNK/SAPK pathway and caspases pathway at different levels, partly by the function of molecular chaperone.

Animals↗

PubMed1991

Penetration of CD4 T cells by HIV-1. The CD4 receptor does not internalize with HIV, and CD4-related signal transduction events are not required for entry.

Receptor binding of HIV to the CD4 molecule is required for efficient infection of T cells, but the post-binding steps that result in penetration of HIV are not well understood. CD4 is induced to internalize upon T cell activation, and mAb to CD4 modify signal transduction and T cell activation as does HIV in some systems. It is not known whether HIV binding triggers CD4 endocytosis or whether signal transduction events are required for penetration. Selected inhibitors of signal transduction were evaluated for their effects on penetration using two assays that are dependent on penetration. After short term exposure to inhibitor and HIV, cells were analyzed for reverse-transcribed HIV DNA (DNA amplification assay), or productive infection is monitored (infectivity assay). Viral penetration was tested in the presence of H7 (protein kinase C inhibition), EGTA (extracellular Ca2+ chelation), cyclosporine A (inhibition of Ca2+/calmodulin-dependent activation), or pertussis toxin (inhibition of G protein function). All agents were used at concentrations that were inhibitory for their respective signal transduction pathways. None of the inhibitors affected viral penetration. We tracked the CD4 molecule with fluorescent probes that do not interfere with HIV binding in a system where CD4 T cells were saturated with HIV and the penetration event was relatively synchronized. Under conditions where detection of CD4 was more sensitive than the detection of HIV, HIV internalization was readily detected but CD4 internalization was not.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed2004

The golli-myelin basic protein negatively regulates signal transduction in T lymphocytes.

Protein kinase C (PKC) plays a critical role in signal transduction controlling T lymphocyte activation. Both positive and negative regulation of signal transduction is needed for proper control of T lymphocyte activation. We have found that a golli product of the myelin basic protein (MBP) gene can serve as a negative regulator of signaling pathways in the T lymphocyte, particularly the PKC pathway. Increased expression of golli BG21 in Jurkat T cells strongly inhibits anti-CD3-induced IL-2-luciferase activity, an indicator of T lymphocyte activation. Golli BG21 can be phosphorylated by PKC in vitro and its phosphorylation increases in PMA-activated Jurkat cells. BG21 inhibits the PMA-induced increase in AP-1 or NF-kappaB activation, consistent with golli acting in a PKC-mediated cellular event. Golli BG21 inhibition of the PKC pathway is not due to a direct action on PKC activation but in the cascade following PKC activation, since BG21 neither reduces PKC enzyme activity nor blocks the membrane association of PKCtheta brought on by T lymphocyte activation. The inhibitory function of BG21 is independent of its phosphorylation by PKC because a mutant BG21, in which the PKC sites have been mutated, is as effective as the wild type BG21 in inhibiting the PMA-induced AP-1 activation. Structure-function assays indicate that BG21 inhibitory activity resides in the golli domain rather than in MBP domain of the molecule. These results reveal a novel role for MBP gene products in T lymphocytes within the immune system.

Amino Acid Sequence↗

PubMed2006

Delineating signal transduction pathways in smooth muscle through focused proteomics.

This review will outline examples of the authors' focused proteomics approaches to studying signal transduction pathways in smooth muscle. By focusing the use of traditional proteomics techniques with hypothesis-driven selection methods, this approach efficiently addresses the identification of novel elements in a signal transduction pathway of interest. However, focused proteomics serves only as a starting point in the investigation of novel signaling proteins. While focused proteomics studies can suggest the involvement and general biochemical function of a protein in a signaling pathway, these findings must be further investigated and validated. Through the integrated use of focused proteomics with complementary approaches such as genetics, biochemistry and cell physiology, a complete and detailed mechanism of signal transduction can be determined.

Animals↗

PubMed2002

Two-component and phosphorelay signal-transduction systems as therapeutic targets.

Two-component and phosphorelay signal-transduction systems of pathogenic bacteria control the expression of genes encoding virulence factors and essential functions. Recent systematic gene inactivation studies have confirmed the integral role of two-component systems in the pathogenesis of diseases caused by several microorganisms and highlighted the validity of using these systems as targets for therapeutic intervention. Structural studies of signal-transduction proteins have recently revealed common features that may allow rational drug design for therapeutic intervention. In particular, the conserved domains of response regulators may represent the best targets for inhibition.

Amino Acid Sequence↗

PubMed2002

A dipalmitoyl peptide that binds SH3 domain, disturbs intracellular signal transduction, and inhibits tumor growth in vivo.

The Src homology 3 (SH3) domain plays a crucial role in protein-protein interactions during intracellular signal transduction. Blocking the SH3-mediated protein binding may inhibit the corresponding signal transduction, and thus, block the cellular functions. In this study, a peptide that specifically binds to SH3 domain could be introduced into the intracellular region when the peptides were conjugated with dipalmitic acid and appeared to disturb intracellular signaling. The dipalmitoyl peptide appeared to inhibit the phosphorylation of ZAP-70, Lck, and T-cell antigen receptor zeta in Jurkat. Mobilization of the intracellular free calcium induced by anti-CD3 antibody was reduced after treatment with the dipalmitoyl peptide. It was also observed that the dipalmitoyl peptide inhibited cancer cell growth both in vitro and in vivo. These results suggest that the dipalmitoyl peptide that presumably disturbs SH3-mediated signal transduction may have a potent anti-proliferative activity, which would be useful as a potential anti-tumor agent.

Animals↗

PubMed1997

Aging-related regulation of myo-inositol 1,4,5-trisphosphate signal transduction pathway in the rat striatum.

To determine the effects of the aging process on the regulation of phosphoinositide signal transduction pathway, inositol 1,4,5-trisphosphate and inositol 1,4,5-trisphosphate receptor-associated parameters were examined in the striatum of brains removed from young (3 months), adult (12 months) and senescent (25 months) male Fischer 344 rats. Inositol 1,4,5-trisphosphate content was significantly increased (P < or = 0.01) at 25 months of age compared to 3 and 12 months. No age-related differences in phosphatidylinositol 4,5-bisphosphate hydrolysis were found in striatal slices after stimulation with trans-(1S,3R)-1-aminocyclopentane-1,3-dicarboxylate, a metabotropic glutamatergic receptor agonist. Phosphatidylinositol 4,5-bisphosphate hydrolysis following stimulation with (R,S)-alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid, a glutamatergic/quisqualate agonist, showed a significantly increased accumulation of net [3H]inositol 1,4,5-trisphosphate in senescent striatum whereas the muscarinic cholinergic agonist carbachol induced highest response in the young striatum. In each case, agonist-stimulated response was significantly reduced in the presence of the receptor-associated antagonist. The density of inositol 1,4,5-trisphosphate receptor in the particulate membranes derived from 12- and 25-month-old rats was decreased (P < 0.01) compared to that from young rats. Binding affinity of inositol 1,4,5-trisphosphate receptor for [3H]inositol 1,4,5-trisphosphate was increased (P = 0.05) only at 25 months of age when compared with 3 months of age. Incubation of partially purified inositol 1,4,5-trisphosphate receptor with striatal cytosol in the presence of Ca2+ showed an age-dependent susceptibility to proteolytic degradation of this receptor that was completely inhibited by calpain I inhibitor peptide. Paradoxically, the quantity of inositol 1,4,5-trisphosphate receptor mRNA-encoding transcripts was increased (P < or = 0.01) at 25 months of age, suggesting an age-dependent change in either transcriptional rate, stability or processing of inositol 1,4,5-trisphosphate receptor mRNAs in the striatum. The activity of inositol 1,4,5-trisphosphate3-kinase decreased (P < or = 0.01) with age whereas the activity of soluble inositol 1,4,5-trisphosphate 5-phosphatase was highest at 3 months but significantly decreased at 12 months of age. However, the activity of inositol 1,4,5-trisphosphate 5-phosphatase remained unchanged between 12 and 25 months of age, suggesting possible developmental modulation of the activity of the enzyme. Taken together with the established 'cross-talk' between signal transduction systems, the present data suggest that molecular/cellular changes in striatal inositol 1,4,5-trisphosphate/Ca2+ signal transduction pathway along with neuronal cell loss may contribute to aging-related decrease in striatal functioning.

Aging↗

PubMed1994

Intracellular signal transduction systems do not regulate Na channel in frog ventricular cells.

The regulation of sodium channel activity through intracellular signal transduction systems was studied on isolated frog ventricular cells using a whole cell patch-clamp technique. Special care was exercised in evaluating the stability of the voltage-clamp condition by observing shifts in the steady-state inactivation curve (h infinity curve) and changes in series resistance. We applied the following reagents: isoproterenol (Iso; 0.1-10 microM) and forskolin (Fsk; 0.1-10 microM) to activate protein kinase A. 1-Oleoyl-2-acetyl-sn-glycerol (40 microM) and 12-O-tetradecanoylphorbol-13-acetate (80-800 nM) were used to activate protein kinase C, and phenylephrine (0.1-10 microM), dopamine (0.1-10 microM), and histamine (10 microM) were used to stimulate alpha-adrenergic, dopaminergic, and histaminergic receptors, respectively. The current-voltage relationship and the h infinity curve for the sodium channel remained unchanged regardless of the application of these reagents. Iso and Fsk did not affect the sodium current but substantially increased the calcium current, suggesting that the intracellular signal transduction systems remained intact. Therefore, it is concluded that sodium channel in frog ventricular cells is not regulated by intracellular signal transduction systems.

Animals↗

PubMed2000

CGRP-RCP, a novel protein required for signal transduction at calcitonin gene-related peptide and adrenomedullin receptors.

It is becoming clear that receptors that initiate signal transduction by interacting with G-proteins do not function as monomers, but often require accessory proteins for function. Some of these accessory proteins are chaperones, required for correct transport of the receptor to the cell surface, but the function of many accessory proteins remains unknown. We determined the role of an accessory protein for the receptor for calcitonin gene-related peptide (CGRP), a potent vasodilator neuropeptide. We have previously shown that this accessory protein, the CGRP-receptor component protein (RCP), is expressed in CGRP responsive tissues and that RCP protein expression correlates with the biological efficacy of CGRP in vivo. However, the function of RCP has remained elusive. In this study stable cell lines were made that express antisense RCP RNA, and CGRP- and adrenomedullin-mediated signal transduction were greatly reduced. However, the loss of RCP did not effect CGRP binding or receptor density, indicating that RCP did not behave as a chaperone but was instead coupling the CGRP receptor to downstream effectors. A candidate CGRP receptor named calcitonin receptor-like receptor (CRLR) has been identified, and in this study RCP co-immunoprecipitated with CRLR indicating that these two proteins interact directly. Since CGRP and adrenomedullin can both signal through CRLR, which has been previously shown to require a chaperone protein for function, we now propose that a functional CGRP or adrenomedullin receptor consists of at least three proteins: the receptor (CRLR), the chaperone protein (RAMP), and RCP that couples the receptor to the cellular signal transduction pathway.

3T3 Cells↗

PubMed2004

[Effect of protein kinase C-nuclear factor-kappa B signal transduction pathway on proliferation and expression of vascular endothelial growth factor in human pulmonary artery smooth muscle cells].

OBJECTIVE: To investigate the effect of protein kinase C (PKC)-nuclear factor-kappa B (NF-kappaB) signal transduction pathway on proliferation and expression of vascular endothelial growth factor (VEGF) in human pulmonary artery smooth muscle cells (HPASMCs). METHODS: Cultured HPASMCs in normoxia or hypoxia conditions were divided into three groups and stimulated with or without phorbol 12-myristate 13-acetate (PMA) and pyrrolidine dithiocarbamate (PDTC) in vitro. The three groups were the control group, the PMA group and the PMA + PDTC group. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to detect VEGF mRNA expression, and the expression of VEGF protein and the inhibitor protein IkappaBalpha were observed by Western blot, while the location and expression of NF-kappaB p65 were observed by immunocytochemical staining, and cell cycle phases were analyzed by flow cytometry. RESULTS: (1) As for the positive rate of nucleolar staining for NF-kappaB p65, the relative expression of IkappaBalpha protein, and the percentage of G(2)/M phases of cell cycle, there were significant differences between the PMA group and the control group or PMA + PDTC group, both in normoxia and hypoxia conditions (P < 0.05, respectively), and there was also a significant difference between the normoxia and hypoxia PMA groups (P < 0.05). (2) There were no significant differences in VEGF mRNA and protein expression among the three groups (P > 0.05, respectively) in normoxia, but the expression was higher in hypoxia PMA group than in hypoxia control and hypoxia PMA + PDTC or normoxia PMA group (P < 0.05, respectively). (3) There was a positive correlation between the positive rate of nucleolar staining for NF-kappaB p65, the relative expression of VEGF protein and the percentage of G(2)/M phases of cell cycle in hypoxia PMA group (r = 0.587 - 0.710, P < 0.05, respectively). CONCLUSIONS: There is a signal transduction pathway of PKC-NF-kappaB in HPASMCs. The activity of PKC can be enhanced in hypoxia, concomitant NF-kappaB activation or VEGF overexpression to be involved in the proliferation. These results suggest that the activation of NF-kappaB can be considered as a downstream of PKC signal transduction pathway, and the activation of PKC-NF-kappaB signal transduction pathway and VEGF overexpression may contribute to the process of hypoxic pulmonary hypertension.

Cell Cycle↗

PubMed1996

Prolactin signal transduction mechanisms in the mammary gland: the role of the Jak/Stat pathway.

Prolactin signal transduction in mammary epithelial cells is mediated by a novel, direct signalling system that links the activation of the prolactin receptor at the cell surface to changes in gene transcription in the nucleus. This recently identified pathway is a variant of the Jak/Stat (for Janus kinase/signal transducer and activator of transcription) pathway used by many other growth factors and cytokines. Current data suggest that the key intracellular components of the prolactin signalling pathway are the kinase Jak2 and the transcription factor Stat5. This discovery has exciting implications for the interaction between prolactin and other extracellular signals in both the mammary gland and other tissues. Here we review work that began with attempts to understand the regulation of milk protein gene expression and ultimately demonstrated the central role of the Jak/Stat pathway in prolactin signal transduction in the mammary gland.

Animals↗

PubMed1999

Neurotrophin-3 contributes to the initiation of behavioral sensitization to cocaine by activating the Ras/Mitogen-activated protein kinase signal transduction cascade.

These experiments were designed to assess the role of neurotrophins and the Ras/mitogen-activated protein kinase (MAP) signal transduction cascade in behavioral sensitization to cocaine. The first experiments evaluated the effect of three daily intra-ventral tegmental area (VTA) microinjections of neurotrophin-3 (NT-3) or brain-derived neurotrophic factor (BDNF) on the behavioral-activating effects of a subsequent challenge injection of cocaine in rats. Results indicated that, although NT-3 did not influence behavior across the three microinjection days, animals displayed a sensitized behavioral response to the subsequent cocaine challenge injection. In contrast, BDNF microinjections resulted in a progressive increase in behavioral activity but did not influence the subsequent behavioral response to cocaine. A second series of experiments assessed the effect of inhibiting the MAP kinase signal transduction cascade on the initiation of behavioral sensitization to cocaine. The MAP kinase kinase inhibitor PD98059, or its vehicle, was microinjected into the VTA before three daily cocaine injections. Although PD98059 did not influence the acute behavioral response to cocaine, it blocked sensitization. Finally, the effects of acute and repeated cocaine injections on NT-3 and BDNF mRNA levels in the VTA, substantia nigra, and hippocampus were assessed. Results indicated that an acute cocaine injection resulted in a transient increase in NT-3 mRNA levels in the VTA. Collectively, these results suggest that NT-3 contributes to the initiation of behavioral sensitization to cocaine by activating the Ras/MAP kinase signal transduction system. The present data also indicate that BDNF itself produced a progressive augmentation in behavioral activation with repeated administration.

Animals↗

PubMed1999

Antigen receptor-induced signal transduction imbalances associated with the negative selection of immature B cells.

Signals transduced through the B cell Ag receptor (BCR) drive B cell development. However, BCR-induced responses are developmentally regulated; immature B cells are tolerized following antigenic exposure while mature B cells are triggered to proliferate and differentiate. This differential responsiveness allows for the negative selection of self-reactive immature B cells while simultaneously allowing for clonal expansion of mature B cells in response to foreign Ags. Intrinsic differences in BCR-induced signal transduction at various stages of development may account for this functional dichotomy. We had previously demonstrated that the BCR-induced proliferation of mature B cells is accompanied by an increase in intracellular calcium levels and polyphosphoinositide bis phosphate (PIP2) hydrolysis. In contrast, immature B cells that undergo BCR-induced apoptosis increase intracellular calcium in the relative absence of PIP2 hydrolysis. Since PIP2 hydrolysis leads to the generation of diacylglycerol, a cofactor for protein kinase C (PKC) activation, these data suggested that an "imbalance" in BCR-induced signal transduction resulting from a relative inability to activate PKC may play a role in the susceptibility of immature B cells to BCR-induced apoptosis. In support of this hypothesis, we demonstrate that PKC activation can rescue immature B cells from BCR-induced apoptosis. Furthermore, the susceptibility of immature B cells to BCR-induced apoptosis is recapitulated in mature B cells that are either PKC depleted or are stimulated in the presence of PKC inhibitors, suggesting that an uncoupling of PKC activation from BCR-induced signaling is responsible for the apoptotic response of immature B cells.

Animals↗

PubMed1995

Interactions of human immunodeficiency virus type 1 transactivator of transcription protein with signal transduction pathways.

The current state of knowledge investigating Tat interactions with signal transduction pathways is still in its infancy but has made significant progress toward understanding HIV pathology. This area is of great interest because Tat is among a small group of newly discovered RNA-based regulators of transcription. What is more important, however, are the implications of understanding these interactions concerning HIV-infected individuals. With the failure to develop effective HIV vaccines after years of development, it is becoming more feasible to conjecture therapies that target Tat as a means to keep HIV in its quiescent state rather than to eliminate the virus. In either case, the intense study of Tat and signal transduction pathways promises to provide a wealth of information about transcriptional control as well as the regulation of immune cell activation.

Animals↗

PubMed1991

A signal transduction through a unique rat T cell specific antigen, 8H3.

A signal transduction was detected in various rat T cells by cross-linking of 8H3 antigen by 8H3 antibody. A rat T cell proliferative response induced by 8H3 antibody is dependent on the presence of adherent cells. When spleen cells were cultured in the presence of 8H3 antibody, only CD4-positive T cell proliferation was induced. These proliferative CD4-positive T cells express rat interleukin 2 receptor, alpha chain. Cross-linking of 8H3 antigen resulted in an increase in cytoplasmic free Ca2+ in T cells and phosphorylation of a 120 kDa component of the 8H3 antigen. It should be noted that cross-linking of 8H3 antigen together with CD4 antigen but not with CD8 antigen by suboptimal doses of 8H3 and corresponding antibodies initiated the mobilization of [Ca2+]i. Furthermore, physical association of 8H3 antigen with TCR was demonstrated by comodulation of these two molecular complexes in some T cells. Thus, 8H3 antigen is involved in rat T cell transmembrane signal transduction.

Animals↗

PubMed2001

Evidence for a role of protein kinase C in FGF signal transduction in the developing chick limb bud.

In developing limbs, numerous signaling molecules have been identified but less is known about the mechanisms by which such signals direct patterning. We have explored signal transduction pathways in the chicken limb bud. A cDNA encoding RACK1, a protein that binds and stabilizes activated protein kinase C (PKC), was isolated in a screen for genes induced by retinoic acid (RA) in the chick wing bud. Fibroblast growth factor (FGF) also induced RACK1 and such induction of RACK1 expression was accompanied by a significant augmentation in the number of active PKC molecules and an elevation of PKC enzymatic activity. This suggests that PKCs mediate signal transduction in the limb bud. Application of chelerythrine, a potent PKC inhibitor, to the presumptive wing region resulted in buds that did not express sonic hedgehog (Shh) and developed into wings that were severely truncated. This observation suggests that the expression of Shh depends on PKCs. Providing ectopic SHH protein, RA or ZPA grafts overcome the effects of blocking PKC with chelerythrine and resulted in a rescue of the wing morphology. Taken together, these findings suggest that the responsiveness of Shh to FGF is mediated, at least in part, by PKCs.

Alkaloids↗