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At least 505 records · Page 28Linked to original sources
PubMed1998

A histone deacetylase corepressor complex regulates the Notch signal transduction pathway.

The Delta-Notch signal transduction pathway has widespread roles in animal development in which it appears to control cell fate. CBF1/RBP-Jkappa, the mammalian homolog of Drosophila Suppressor of Hairless [Su(H)], switches from a transcriptional repressor to an activator upon Notch activation. The mechanism whereby Notch regulates this switch is not clear. In this report we show that prior to induction CBF1/RBP-Jkappa interacts with a corepressor complex containing SMRT (silencing mediator of retinoid and thyroid hormone receptors) and the histone deacetylase HDAC-1. This complex binds via the CBF1 repression domain, and mutants defective in repression fail to interact with the complex. Activation by Notch disrupts the formation of the repressor complex, thus establishing a molecular basis for the Notch switch. Finally, ESR-1, a Xenopus gene activated by Notch and X-Su(H), is induced in animal caps treated with TSA, an inhibitor of HDAC-1. The functional role for the SMRT/HDAC-1 complex in CBF1/RBP-Jkappa regulation reveals a novel genetic switch in which extracellular ligands control the status of critical nuclear cofactor complexes.

3T3 Cells↗
PubMed2002

The neurobiology of bipolar disorder: focus on signal transduction pathways and the regulation of gene expression.

OBJECTIVE: This article presents an overview of signal transduction pathways and reviews the research undertaken to study these systems in clinically relevant samples from patients with bipolar disorder (BD). METHOD: We reviewed the published findings from studies of postmortem brain tissue and blood samples from patients with BD. RESULTS: Although the exact biochemical abnormalities have yet to be identified, the presented findings strongly suggest that BD may be due, at least in part, to abnormalities in signal transduction mechanisms. In particular, altered levels or function, or both, of G-protein alpha subunits and effector molecules such as protein kinase A (PKA) and protein kinase C (PKC) have consistently been associated with BD both in peripheral cells and in postmortem brain tissue, while more recent studies implicate disruption in novel second-messenger cascades, such as the ERK/MAPK pathway. CONCLUSIONS: Despite the difficulties inherent in biochemical studies of clinically relevant tissue samples, numerous investigations have illuminated the signal transduction mechanisms in patients with BD. These studies also suggest that BD may be due to the interaction of many abnormalities. In this context, novel techniques enabling the study of gene expression promise to assist in untangling these complex interactions, through visualizing the end result of these changes at the level of gene transcription.

Bipolar Disorder↗
PubMed2003

Cyclin D-Cdk4 and cyclin E-Cdk2 regulate the Jak/STAT signal transduction pathway in Drosophila.

The JAK/STAT signal transduction pathway regulates many developmental processes in Drosophila. However, the functional mechanism of this pathway is poorly understood. In this report, we identify the Drosophila cyclin-dependent kinase 4 (Cdk4), which exhibits embryonic mutant phenotypes identical to those in the Hopscotch/JAK kinase and stat92E/STAT mutations. Specific genetic interactions between Cdk4 and hop mutations suggest that Cdk4 functions downstream of the HOP tyrosine kinase. We further show that Cyclin D-Cdk4 (as well as Cyclin E-Cdk2) binds and regulates STAT92E protein stability. STAT92E regulates gene expression for various biological processes, including the endocycle S phase. These data suggest that Cyclin D-Cdk4 and Cyclin E-Cdk2 play more versatile roles in Drosophila development.

Animals↗
PubMed1997

PDK1, one of the missing links in insulin signal transduction?

The initial steps in insulin signal transduction occur at the plasma membrane and lead to the activation of phosphatidylinositide (PtdIns) 3-kinase and the formation of PtdIns(3,4,5,)P3 in the inner leaflet of the plasma membrane which is then converted to PtdIns(3,4)P2 by a specific phosphatase. Inhibitors of PtdIns 3-kinase suppress nearly all the metabolic actions of insulin indicating that PtdIns(3,4,5)P3 and/or PtdIns(3,4)P2 are key 'second messengers' for this hormone. A major effect of insulin is its ability to stimulate the synthesis of glycogen in skeletal muscle. By 'working backwards' from glycogen synthesis, we have dissected an insulin-stimulated protein kinase cascade which is triggered by the activation of PtdIns 3-kinase. The first enzyme in this cascade is termed 3-phosphoinositide-dependent protein kinase (PDK1), because it is only active in the presence of PtdIns(3,4,5)P3 or PtdIns(3,4)P2. PDK1 then activates protein kinase B (PKB) which, in turn, inactivates glycogen synthase kinase-3 (GSK3), leading to the dephosphorylation and activation of glycogen synthase and hence to an acceleration of glycogen synthesis. We review the evidence which indicates that the phosphorylation of other proteins by PKB and GSK3 is likely to mediate many of the intracellular actions of insulin.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed2006

Thermodynamic basis for redox regulation of the Yap1 signal transduction pathway.

The Yap1 oxidative stress signal transduction pathway found in Saccharomyces cerevisiae is redox-regulated. We have examined the thermodynamic basis of the disulfide/dithiol couples that are involved in the regulation of this pathway. The oxidized form of the Yap1 redox domain (Yap1-RD) fragment, derived from the Yap1 transcription factor, contains two disulfide bonds, one between Cys303 and Cys598 and one between Cys310 and Cys629. Oxidation-reduction titrations reveal the presence of two separate two-electron redox couples in Yap1-RD, with redox midpoint potentials (E(m)) of -155 and -330 mV, respectively, at pH 7.0. We measured E(m) values of -275 and -265 mV for the two cytoplasmic S. cerevisiae thioredoxins, Trx1 and Trx2, respectively, both at pH 7.0. Last, we measured an E(m) value of -255 mV for the Cys36-Cys82 disulfide bond at pH 6.0 in the glutathione peroxidase-like enzyme, oxidant receptor protein (Orp1). We were unable to obtain satisfactory redox titration data for Orp1 at pH 7.0, but if the redox-active disulfide of Orp1 exhibits the -59 mV per pH unit dependence for E(m) typical of protein disulfides in this pH region, an E(m) value of -315 mV can be estimated for Orp1 at pH 7.0 by extrapolation. Together, these data suggest that, at physiological ratios of Trx(ox)/Trx(red), the reduction of both the E(m) = -315 mV disulfide of Orp1 and the E(m) = -330 mV disulfide of Yap1 by either Trx1 or Trx2 would be thermodynamically possible.

Amino Acid Sequence↗
PubMed1994

Involvement of JAK-family tyrosine kinases in hematopoietin receptor signal transduction.

A variety of cytokines, hormones and hematopoietic growth factors signal through the hematopoietin family of membrane receptors, which share several structural features, including a Trp-Ser-X-Trp-Ser motif and four paired cysteine residues. The signal transduction mechanisms utilized by these receptors have remained elusive, although tyrosine kinase activation has been one common element. Recently, a role for the cytoplasmic tyrosine kinases of the Janus kinase (JAK) family has been implicated in signalling by these receptors. There are currently three known JAK family kinases, including JAK1, JAK2 and TYK2. This review will focus on the role of such tyrosine kinases in hematopoietin receptor signal transduction, and address the possibility of the involvement also of unidentified Janus kinases.

Amino Acid Sequence↗
PubMed2005

Modeling and simulation in signal transduction pathways: a systems biology approach.

Modeling, the heart of systems biology, of complex processes (example: signal transduction) is a wide scientific discipline where many approaches from different areas are confronted with the aim of better understanding, identifying and modeling of complex data coming from various sources. The purpose of this paper is to introduce the basic steps of systems biology view towards signaling pathways, which mainly deals with the computational tools. The paper emphasizes the modeling and simulation approach in the signal transduction pathways using the topologies of the biochemical reactions with an overview of the different types of software platforms. Finally, we demonstrated the epidermal growth factor receptor signaling pathway model as an example to study the growth factor mediated signaling system with biological experiments. This paper will enables new comers to underline the strengths of the computational approaches towards signal transduction, as well as to highlight the systems biology research directions.

Animals↗
PubMed1994

Pharmacological dissociation of glutamatergic metabotropic signal transduction pathways in cortical astrocytes.

Using cultured cortical astrocytes we demonstrate differential activation of metabotropic signal transduction pathways with 1-aminocyclopentane-trans-1S3R-dicarboxylic acid (1S3R-ACPD) and the glutamate transport inhibitor trans-2,4-pyrrolidine dicarboxylic acid (trans-2,4-PDC). Phosphoinositide hydrolysis was more potently stimulated by 1S3R-ACPD than by L-trans-2,4-PDC; however, L-trans-2,4-PDC was far more efficacious than 1S3R-ACPD at inhibiting cyclic AMP accumulation. The metabotropic receptor antagonist (+)-alpha-methyl-4-carboxyphenylglycine ((+)-MCPG) inhibited 1S3R-ACPD stimulation of phosphoinositide hydrolysis but not its ability to inhibit cyclic AMP accumulation thereby demonstrating a means to pharmacologically dissociate these two metabotropic signal transduction pathways in astrocytes. (+)-MCPG produced similar antagonism of the metabotropic agonist properties of L-trans-2,4-PDC. The metabotropic effects of L-trans-2,4-PDC could not be reduced with enzymatic treatment of the cultures to remove extracellular glutamate, suggesting that these effects are not secondary to the ability of this compound to inhibit glutamate uptake. Taken together the findings indicate the presence of multiple glutamatergic signal transduction pathways in astrocytes and suggest a similarity in the pharmacophores for metabotropic receptors and glutamate transporters.

Animals↗
PubMed2006

Involvement of the AtoS-AtoC signal transduction system in poly-(R)-3-hydroxybutyrate biosynthesis in Escherichia coli.

The AtoS-AtoC signal transduction system in E. coli, which induces the atoDAEB operon for the growth of E. coli in short-chain fatty acids, can positively modulate the levels of poly-(R)-3-hydroxybutyrate (cPHB) biosynthesis, a biopolymer with many physiological roles in E. coli. Increased amounts of cPHB were synthesized in E. coli upon exposure of the cells to acetoacetate, the inducer of the AtoS-AtoC two-component system. While E. coli that overproduce both components of the signal transduction system synthesize higher quantities of cPHB (1.5-4.5 fold), those that overproduce either AtoS or AtoC alone do not display such a phenotype. Lack of enhanced cPHB production was also observed in cells overexpressing AtoS and phosphorylation-impaired AtoC mutants. The results were not affected by the nature of the carbon source used, i.e., glucose, acetate or acetoacetate. An E. coli strain with a deletion in the atoS-atoC locus (delta atoSC) synthesized lower amounts of cPHB compared to wild-type cells. When the delta atoSC strain was transformed with a plasmid carrying a 6.4-kb fragment encoding the AtoS-AtoC system, cPHB biosynthesis was restored to the level of the atoSC+ cells. Introduction of a multicopy plasmid carrying a functional atoDAEB operon, but not one with a promoterless operon, resulted in increased cPHB synthesis only in atoSC+ cells in the presence of acetoacetate. These results indicate that the presence of both a functional AtoS-AtoC two-component signal transduction system and a functional atoDAEB operon is critical for the enhanced cPHB biosynthesis in E. coli.

Acetoacetates↗
PubMed1992

Dissociation of human cytokine receptor expression and signal transduction.

We have examined the relationship between granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) receptor expression and signal transduction in populations of HL-60 cells differing in proliferative capacity to these cytokines. GM-CSF or IL-3 stimulation of HL-60 cells pretreated with either dimethyl sulfoxide (DMSO) or retinoic acid results in increases in proliferative response as well as both tyrosine and serine phosphorylation. In contrast, neither GM-CSF or IL-3 stimulation of parental HL-60 cells (those not treated with DMSO or retinoic acid) produced any changes in either proliferation or protein phosphorylation. Thus, although parental HL-60 cells expressed both GM-CSF and IL-3 receptors, treatment with either DMSO or retinoic acid was necessary to confer the capacity for signal transduction as assessed by both a biologic and biochemical response. Pretreatment of cells with genistein, a protein tyrosine kinase inhibitor, resulted in inhibition of GM-CSF-induced protein tyrosine phosphorylation as well as proliferation. These data show a strong correlation between cytokine-induced increases in protein phosphorylation and subsequent biologic responses. Further, this work demonstrates that cytokine receptor expression and signal transduction can be disassociated and suggests the potential for independent regulation of these two components of signal transduction.

Cell Division↗
PubMed1995

A comparison of the effects of signal transduction inhibitors on oxidative burst and degranulation in IL-I beta stimulated bovine neutrophils.

There is little information available on IL-1 mediated signal transduction in neutrophils from species other than humans. In this study, signal transduction pathway inhibitors were used to compare signaling pathways for the oxidative burst and degranulation in bovine neutrophils stimulated with rBoIL-1 beta. Protein kinase C inhibitors (staurosporine and chelerythine), DL-propranolol, pertussis toxin (PT), genistein and verapamil significantly inhibited rBoIL-1 beta (10 ng/ml) stimulated luminol-dependent chemiluminescence (LDCL) in a dose-dependent manner, while indomethacin and zileuton had no effect. Propranolol significantly decreased both primary and secondary granule release in response to rBoIL-1 beta. Staurosporine enhanced secondary but not primary granule release, and PT increased primary and secondary granule release. In addition, propranolol inhibited the shape change induced by rBoIL-1 beta and zymosan-activated serum, whereas PT markedly decreased the response induced by zymosan-activated serum, but not rBoIL-1 beta. These findings suggest that rBoIL-1 beta stimulation of the oxidative burst, degranulation, and shape change of bovine neutrophils are mediated through distinct signal transduction pathways.

Animals↗
PubMed2004

Advances in NF-kappaB signaling transduction and transcription.

The molecular mechanisms for NF-kappaB signaling transduction and transcription have been the most attractive subjects for both basic research and pharmaceutical industries due to its important roles in both physiological and pathogenesis, particularly the close association of dysregulated NF-kappaB with tumorgenesis and inflammation. Several novel intracellular molecular events that regulate NF-kappaB activity have been described recently, including the discovery of an alternative signaling pathway that appears inducing a specific subset genes involved in adoptive immune response. Multi-level and multi-dimensional regulation of NF-kappaB activity by phosphorylation and acetylation modifications have unveiled and became the hottest targets for potentially tissue specific molecular interventions. Another emerging mechanism for NF-kappaB-responsive gene's regulation where NF-kappaB participates the transcriptional regulation independent of its cognate regulatory binding site within the target gene's promoter but facilitating the transaction activity of other involved transcription factors, that implicated an novel transcriptional activities for NF-kappaB. Thus, the current review will focus on these recent progresses that have been made on NF-kappaB signaling transduction and transcription.

Acetylation↗
PubMed1996

Multiple intracellular signal transduction pathways mediating inward current produced by the neuropeptide, achatin-I.

The effects of intracellular signal transduction system inhibitors on the inward current (Iin) caused by achatin-I (Gly-D-Phe-Ala-Asp), an Achatina endogenous tetrapeptide having a D-phenylalanine residue, applied locally onto the neurone tested, were examined under voltage clamp using two identifiable Achatina giant neurone types, v-RCDN (ventral-right cerebral distinct neurone) and PON (periodically oscillating neurone). H-89 (N-[2-(p-bromocinnamylamino)-ethyl]-5-isoquinolinesulfonamide) (adenosine-3',5'-cyclic monophosphate (cyclic AMP)-dependent protein kinase inhibitor) markedly suppressed the achatin-I-induced Iin on PON, whereas this drug was ineffective on the Iin of v-RCDN. Dose (pressure duration)-response study of achatin-I on PON in a physiological solution and in the presence of H-89, and Lineweaver-Burk plot of these data, indicated that H-89 inhibited the Iin in a noncompetitive manner. KT5823 (N-methyl-(8R*,9S*,11S*)-(-)-9-methoxy-9-methoxycarbonyl-8-methyl-2,3,9, 10-tetrahydro-8,11-epoxy-1H,8H,11H-2, 7b,11a-triazadibenzo[a,g]cycloocta[c,d,e]-trinden-1-on e) (guanosine-3',5'-cyclic monophosphate (cyclic GMP)-dependent protein kinase inhibitor) suppressed the achatin-I-induced Iin of v-RCDN in mainly noncompetitive and partly uncompetitive manners, but this drug had no effect on the Iin of PON. W-7 (N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide) (calmodulin inhibitor) suppressed noncompetitively the Iin of PON, but this drug had no effect on the Iin of v-RCDN. IBMX (3-isobutyl-1-methylxanthine) (cyclic nucleotide phosphodiesterase inhibitor) enhanced the achatin-I-induced Iin of v-RCDN, but this drug was ineffective on the Iin of PON. However, IBMX might have effects on the achatin-I receptor sites on v-RCDN. These findings suggest multiple intracellular signal transduction pathways mediating the achatin-I-induced Iin: the Iin of PON is via cyclic AMP-dependent and probably Ca2+/calmodulin-dependent protein kinases, and that of v-RCDN via cyclic GMP-dependent protein kinase. Other signal transduction system inhibitors including calphostin C (2-[12-[2-(benzyloxy)-propyl]-3, 10-dihydro-4,9-dihydroxy-2,6,7,11-tetramethoxy-3,10-dioxo-1-per yleny]-1 -methylethyl carbonic acid 4-hydroxyphenyl ester) (protein kinase C inhibitor) did not significantly affect the Iin of both v-RCDN and PON.

1-Methyl-3-isobutylxanthine↗
PubMedDate not supplied

Signal transduction pathways controlling multicellular development in Dictyostelium.

The importance of signal transduction pathways in regulating developmental processes in a number of organisms has become evident in recent years. This is exceptionally clear for Dictyostelium, which uses soluble factors to regulate morphogenesis and cellular differentiation. It is now known that many of these processes are controlled by signal transduction pathways mediated by cyclic AMP through cell surface receptors coupled to G proteins, and that others are mediated by the morphogen DIF.

Animals↗
PubMed1994

Ligation of MHC class I and class II molecules can lead to heterologous desensitization of signal transduction pathways that regulate homotypic adhesion in human lymphocytes.

Engagement of lymphocyte MHC class I and class II Ags activates an array of intracellular signal transduction pathways that up-regulates the activity of cell-surface adhesion receptors, resulting in homotypic cell-cell aggregation. In this study, engagement of MHC class I and class II molecules with specific mAbs was shown to also inhibit lymphocyte homotypic adhesion. Two mAbs reactive with class II Ag, homotypic adhesion blocking mAb (HAB)-2, and HAB-3, and one mAb reactive with class I Ag, HAB-4, were generated that inhibited homotypic adhesion of activated lymphocytes and B and T cell lines at concentrations as low as 0.1 microgram/ml. Binding of these mAbs resulted in heterologous desensitization of other surface signal transduction molecules as homotypic adhesion induced through class I, class II, CD19, CD20, CD39, CD40, Leu-13, and PMA was also inhibited. The spontaneous adhesion exhibited by some cell lines was also abrogated by binding of these mAbs. Abs that either induced, blocked, or had no effect on adhesion bound to distinct epitopes on class I, whereas the anti-class II mAbs recognized either distinct or overlapping epitopes. Thus, engagement of distinct epitopes on MHC molecules can result in homologous or heterologous desensitization of cell-surface signaling molecules. The induction or inhibition of homotypic adhesion through class I molecules did not require the presence of the cytoplasmic domain, as deletion of this portion of the class I molecule had no effect. In contrast, the transmembrane region was essential for signal transduction as the mAbs binding to a chimeric molecule in which the transmembrane and cytoplasmic domains of class I were exchanged with those of the HB15 molecule did not induce or inhibit homotypic adhesion. Although this report is the first demonstration that homotypic adhesion can be influenced in a negative manner through MHC molecules, these findings demonstrate a considerable level of cross-talk between MHC molecules and other cell-surface receptor systems and their signal transduction pathways, and suggests that MHC class I and class II molecules may serve important roles in the regulation of adhesive events during lymphocyte activation.

Animals↗
PubMed2001

[PI-3 kinase/AKT/PKB signal transduction pathway in kidneys mediates angiotensin II-induced hypertension].

INTRODUCTION: The activation of PI-3 kinase/AKT/PKB signal transduction pathway has implicated in the cell growth regulation and proliferation. AIM: To determine a role of PI-3 kinase/AKT/PKB signal transduction pathway in the kidney of Angiotensin II-induced hypertensive rats. METHODS: NZW (New Zealand White) rats have been infused by Angiotensin II using osmotic minipump for six days (n = 8). Control group was untreated rats (n = 6). PI-3 inase and AKT/PKB activities were measured in the presence or absence of different inhibitors. RESULTS: Angiotensin II elevated mean arterial blood pressure (MABP) to 182 +/- 2 mm Hg (p < 0.001) vs untreated control rats (95 +/- 3 mm Hg). Ras-GTPase and PI-3 Kinase activities were elevated in angiotensin II-treated group. Ras inhibitors FPT III and BMS/191563 attenuated MABP to 122 +/- 2 and 127 +/- 4 mm Hg (p < 0.05) and abolished Ras-GTPase and PI-3 Kinase activities. AKT/PKB activity followed the PI-3 kinase activity. CONCLUSION: PI-3 kinase/AKT/PKB signal transduction pathway in the kidney is activated and mediates Angiotesin II-induced hypertension.

Angiotensin II↗
PubMed1999

Dissecting the VanRS signal transduction pathway with specific inhibitors.

The VanRS two-component signal transduction pathway from Enterococcus faecium was reconstituted in vitro from partially purified components and shown to be inhibited by the halophenyl isothiazolone LY-266,400, inhibitor A, a compound shown previously to reduce expression of the AlgR1-AlgR2 two-component signal transduction pathway in Pseudomonas aeruginosa (S. Roychoudhury, N. A. Zielinski, A. J. Ninfa, N. E. Allen, L. N. Jungheim, T. I. Nicas, and A. M. Chakrabarty, Proc. Natl. Acad. Sci. USA 90:965-969, 1993). Inhibitor A attenuates phosphoryl transfer from VanS approximately P to VanR by its action on the ability of VanR to accept. We observed an apparent stimulatory effect of inhibitor A on VanS autophosphorylation which is attributable to the accumulation of VanS approximately P as an intermediate unable to transfer Pi to the inhibited VanR. Thus, inhibitor A acts on the second of two sequential steps which lead to transcriptional activation of the VanHAXYZ gene cluster and the resultant expression of vancomycin resistance.

Bacterial Proteins↗