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PubMed1998

A model for early events in the assembly pathway of cyanobacterial phycobilisomes.

Biological self-assembly is remarkable in its fidelity and in the efficient production of intricate molecular machines and functional materials from a heterogeneous mixture of macromolecules. The phycobilisome, a light-harvesting structure of cyanobacteria, presents the opportunity to study an in vivo assembly process in detail. The phycobilisome molecular architecture is defined, and crystal structures are available for all major proteins, as are a large sequence database (including a genome sequence) and effective genetic systems exist for some cyanobacteria. Recent studies on subunit interaction, covalent modification, and protein stability suggest a model for the earliest events in the phycobilisome assembly pathway. Partitioning of phycobilisome proteins between degradation and assembly is proposed to be controlled by the interaction equilibria between phycobilisome assembly partners, processing enzymes and chaperones. The model provides plausible explanations for existing observations and makes predictions that are amenable to direct experimental investigation.

Bacterial Proteins↗
PubMed1999

Transport and trafficking: Toxoplasma as a model for Plasmodium.

Like Plasmodium, the protozoan parasite Toxoplasma gondii is a member of the phylum Apicomplexa, and an obligate intracellular pathogen. Unlike Plasmodium, however, Toxoplasma is highly amenable to experimental manipulation in the laboratory. The development of molecular transformation protocols for T. gondii has provided both scientific precedent and practical selectable markers for Plasmodium. Beyond the feasibility of molecular biological experimentation now possible in both systems, the high frequency of stable transformation in Toxoplasma allows this parasite to be used for molecular genetic analysis. The ability to control homologous vs. non-homologous recombination in T. gondii permits gene knockouts/allelic replacements at previously cloned loci, and saturation insertional mutagenesis of the entire parasite genome (and cloning of the tagged loci). T. gondii also exhibits unusual ultrastructural clarity, facilitating cell biological analysis. The accessibility of Toxoplasma as an experimental system allows this parasite to be used as a surrogate for asking many questions that cannot easily be addressed in Plasmodium itself. T. gondii also serves as a model system for genetic exploration of parasite biology and host-parasite interactions. Success stories include: biochemical analysis of antifolate resistance mechanisms; pharmacological studies on the mechanisms of macrolide activity; genetic identification of nucleobase/nucleoside transporters and metabolic pathways; and cell biological characterization of the apicomplexan plastid. As with any model system, not all questions of interest to malariologists can be addressed in Toxoplasma; differentiating between sensible and foolish questions requires familiarity with the biological similarities and differences of these systems.

Animals↗
PubMed2006

Notch signaling suppresses p38 MAPK activity via induction of MKP-1 in myogenesis.

Cross-talks among intracellular signaling pathways are important for the regulation of cell fate decisions and cellular responses to extracellular signals. Both the Notch pathway and the MAPK pathways play important roles in many biological processes, and the Notch pathway has been shown to interact with the ERK-type MAPK pathway. However, its interaction with the other MAPK pathways is unknown. Here we show that Notch signaling activation in C2C12 cells suppresses the activity of p38 MAPK to inhibit myogenesis. Our results show that Notch specifically induces expression of MKP-1, a member of the dual-specificity MAPK phosphatase, which directly inactivates p38 to negatively regulate C2C12 myogenesis. The Notch-induced expression of MKP-1 is shown to depend on RBP-J. Moreover, inhibition of MKP-1 expression by short interfering RNA suppresses p38 inactivation and partially rescues the negative regulation of myogenesis. These results reveal a novel cross-talk between the Notch pathway and the p38 MAPK pathway that is mediated by Notch induction of MKP-1.

Animals↗
PubMed1999

Redox reactions related to indoleamine 2,3-dioxygenase and tryptophan metabolism along the kynurenine pathway.

The heme enzyme indoleamine 2,3-dioxygenase (IDO) oxidizes the pyrrole moiety of L-tryptophan (Trp) and other indoleamines and represents the initial and rate-limiting enzyme of the kynurenine (Kyn) pathway. IDO is a unique enzyme in that it can utilize superoxide anion radical (O2*- ) as both a substrate and a co-factor. The latter role is due to the ability of O2*- to reduce inactive ferric-IDO to the active ferrous form. Nitrogen monoxide (*NO) and H2O2 inhibit the dioxygenase and various inter-relationships between the nitric oxide synthase- and IDO-initiated amino acid degradative pathways exist. Induction of IDO and metabolism of Trp along the Kyn pathway is implicated in a variety of physiological and pathophysiological processes, including anti-microbial and anti-tumor defense, neuropathology, immunoregulation and antioxidant activity. Antioxidant activity may arise from O2*- scavenging by IDO and formation of the potent radical scavengers and Kyn pathway metabolites, 3-hydroxyanthranilic acid and 3-hydroxykynurenine. Under certain conditions, these aminophenols and other Kyn pathway metabolites may exhibit pro-oxidant activities. This article reviews findings indicating that redox reactions are involved in the regulation of IDO and Trp metabolism along the Kyn pathway and also participate in the biological activities exhibited by Kyn pathway metabolites.

Animals↗
PubMed2000

A lipopolysaccharide-deficient mutant of Neisseria meningitidis elicits attenuated cytokine release by human macrophages and signals via toll-like receptor (TLR) 2 but not via TLR4/MD2.

Meningococcal disease severity correlates with circulating concentrations of lipopolysaccharide (LPS) and proinflammatory cytokines. Disruption of the lpxA gene of Neisseria meningitidis generated a viable strain that was deficient of detectable LPS. The potency of wild-type N. meningitidis to elicit tumor necrosis factor (TNF)-alpha production by human monocyte-derived macrophages was approximately 10-fold greater than that of the lpxA mutant. Killed wild-type N. meningitidis and its soluble products induced interleukin (IL)-8 and TNF-alpha secretion by transfected HeLa cells expressing Toll-like receptor (TLR) 4/MD2, but the lpxA mutant was inactive via this pathway. In contrast, both strains induced IL-8 promoter activity in TLR2-transfected HeLa cells. These data provide evidence that N. meningitidis contains components other than LPS that can elicit biological responses via pathways that are independent of the TLR4/MD2 receptor system, and TLR2 is one of these alternate pathways. These findings have implications for future therapeutic strategies against meningococcal disease on the basis of the blockade of TLRs and the modulation of LPS activity.

Acyltransferases↗
PubMed2004

ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions.

Conserved signaling pathways that activate the mitogen-activated protein kinases (MAPKs) are involved in relaying extracellular stimulations to intracellular responses. The MAPKs coordinately regulate cell proliferation, differentiation, motility, and survival, which are functions also known to be mediated by members of a growing family of MAPK-activated protein kinases (MKs; formerly known as MAPKAP kinases). The MKs are related serine/threonine kinases that respond to mitogenic and stress stimuli through proline-directed phosphorylation and activation of the kinase domain by extracellular signal-regulated kinases 1 and 2 and p38 MAPKs. There are currently 11 vertebrate MKs in five subfamilies based on primary sequence homology: the ribosomal S6 kinases, the mitogen- and stress-activated kinases, the MAPK-interacting kinases, MAPK-activated protein kinases 2 and 3, and MK5. In the last 5 years, several MK substrates have been identified, which has helped tremendously to identify the biological role of the members of this family. Together with data from the study of MK-knockout mice, the identities of the MK substrates indicate that they play important roles in diverse biological processes, including mRNA translation, cell proliferation and survival, and the nuclear genomic response to mitogens and cellular stresses. In this article, we review the existing data on the MKs and discuss their physiological functions based on recent discoveries.

Amino Acid Sequence↗
PubMed2004

Adenylate cyclase regulation via proteasome-mediated modulation of Galphas levels.

The adenylate cyclase (AC)/cyclic AMP (cAMP)/cAMP-dependent protein kinase pathway controls many biological phenomena. The ubiquitin/proteasome system, controlling the levels of many proteins, modulates important cellular processes such as cell cycle and cell growth. Here we describe a novel mechanism for AC regulation by proteasome pathway. Pharmacological inhibition of proteasome function in human osteosarcoma U2OS cells results in up-regulation of AC activity, increase of levels of alpha subunit of heterotrimeric stimulatory GTP-binding proteins (alphas) and, remarkably, also in preventing of beta-adrenergic receptor-mediated down-regulation of alphas protein levels. Accumulation of alphas protein is also accompanied by the appearance of polyubiquitinated alphas species. Our results: (1) identify alphas protein as a novel proteasome substrate in mammalian cells; (2) indicate that proteasome might play a physiological role in controlling AC/cAMP mediated pathways by modulating the levels of Galphas protein; (3) suggest a role for the proteasome also in controlling alphas-mediated signaling pathways other than those affecting AC complex.

Adenylyl Cyclases↗
PubMed2004

Targeting MAPK signalling: Prometheus' fire or Pandora's box?

MAPK (Mitogen Activated Protein Kinase) pathways mediate fundamental biological processes and have moved into the limelight of drug discovery during the past decade. Here we review the biochemistry and biology of MAPK signalling with a focus on ERK, JNK and p38. We summarise current drug discovery efforts and clinical trials. Further, we critically discuss the rationale behind current strategies of using MAPK pathways as drug targets and suggest new approaches that take the complexity of MAPK signalling networks into account.

Animals↗
PubMed2006

UVB radiation induces expression of HIF-1alpha and VEGF through the EGFR/PI3K/DEC1 pathway.

EGFR is involved in the UV signal transduction pathway leading to skin cancer. UV radiation, mediated by EGFR, induces activation of PI3 kinase and AKT with a result of activation of a number of transcription factors. Transcription factor HIF-1alpha correlates with tumorigenicity and angiogenesis. Transcription factors DEC1 and DEC2 also play pivotal roles in multiple signaling pathways impacting various biological processes including development, cell differentiation, cell death, and oncogenesis. We investigated whether UV radiation and associated hypoxia induce expression of HIF-1alpha and its target genes such as VEGF and the signaling pathway mediating such responses. We found that UV radiation induced HIF-1alpha and VEGF protein expression in a dose- and time-dependent manner in cultured human keratinocytes. UV radiation also induced VEGF mRNA expression in a dose-dependent manner with maximum effect at 4 h post treatment, but did not affect HIF-1alpha mRNA expression. We also observed that UV radiation induced activation of EGFR in a time- and dose-dependent manner which was inhibited by EGFR inhibitor PD153035. In egfr (-/-) MEF cells, UV radiation did not induce HIF-1alpha and VEGF expression, in contrast, in egfr (+/+) MEF cells, UV radiation strongly induced HIF-1alpha and VEGF expression. EGFR kinase inhibitor, PD153035, inhibited UV-induced HIF-1alpha and VEGF protein expression in a dose-dependent manner. Further, we found that PI3K inhibitors, LY294002 and Wortmannin, inhibited HIF-1alpha and VEGF expression induced by UV radiation. In DEC1 (-/-) HaCat cells, UV radiation did not induce HIF-1alpha and VEGF expression, in contrast, in DEC1 (+/+) HaCat cells, UV radiation strongly enhanced HIF-1alpha and VEGF protein expression. We conclude that UV radiation induces HIF-1alpha and VEGF expression via the EGFR/PI3K/DEC1 signaling pathway.

Androstadienes↗
PubMed2000

Recruitment and activation of Raf-1 kinase by nitric oxide-activated Ras.

Nitric oxide (NO) and related species serve as cellular messengers in various physiological and pathological processes. The monomeric G protein, Ras, transduces multiple signaling pathways with varying biological responses. We have previously reported that NO triggers Ras activation and recruitment of an effector, phosphatidylinositol 3'-kinase (PI3K) and Ras-dependent activation of mitogen-activated protein (MAP) kinases which include extracellular signal regulated kinases (ERKs), c-Jun NH(2)-terminal kinase (JNK), and p38 MAP kinase. In this study, we further defined NO-activated Ras signaling pathways. We have identified Raf-1 as another effector recruited by NO-activated Ras in T lymphocytes. NO activation results in association of Ras and Raf-1 and is biologically significant, as we observe an NO-induced increase in Raf-1 kinase activity. Downstream to Raf-1 kinase lie MAP kinases and their subsequent downstream targets, transcription factors. We found that treatment of T lymphocytes with NO yielded phosphorylation of the transcription factor, Elk-1. This phoshorylation is dependent on NO binding to the cysteine 118 residue of Ras. By further delineating the pathway with pharmacological inhibitors, Elk-1 phosphorylation was also found to be dependent on PI3K and ERK. Moreover, NO triggered an increase in mRNA levels of the proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), which was ERK dependent. Thus, we have defined an NO-induced signaling pathway in T lymphocytes arising at the membrane where NO-activated Ras recruits Raf-1 and culminating in the nucleus where Elk-1 is phosphorylated and TNF-alpha messenger RNA is induced. This NO-activated Ras-mediated signaling pathway may play a critical role in Elk-1-induced transcriptional activation of T lymphocytes, host defense and inflammation.

Androstadienes↗
PubMed2006

Drought effects on carbon and nitrogen metabolism of pea nodules can be mimicked by paraquat: evidence for the occurrence of two regulation pathways under oxidative stresses.

Biological nitrogen fixation (BNF) is dramatically affected by environmental constraints such as water stress or heavy metals. It has been reported that these stresses induce the over-production of reactive oxygen species (ROS) and, in turn, oxidative stress that may be responsible for the above-mentioned BNF decline at the molecular level. Oxidative stress, occurring under different environmental stresses, has been widely related to physiological damage. However, a direct relationship between oxidative stress and the decline of BNF, independently from any other cellular damage resulting from adverse environmental situations, has yet to be demonstrated. In order to study the likely in vivo relationship between ROS and BNF inhibition in the legume-Rhizobium symbiosis, two paraquat (PQ) doses, 1 (LPQ) and 10 (HPQ) mmol m(-3), were applied to pea roots for 96 h in order to exacerbate ROS production. Whole-plant physiology and nodule metabolism parameters were determined every 24 h to monitor the evolution of plant responses to ROS. LPQ provoked BNF decline, which was preceded by a prior decrease in sucrose synthase (SS) activity. However, HPQ gave rise to a faster and more pronounced BNF inhibition, which coincided with a decline in SS and also with a reduction in leghaemoglobin (Lb) content. These results indicate a likely involvement of ROS in the effects of environmental stresses on BNF. Furthermore, these results support the occurrence of two regulation pathways for BNF under oxidative stress, one of these involving carbon shortage and the other involving Lb/oxygen flux.

Carbon↗
PubMed2006

A stochastic model of Escherichia coli AI-2 quorum signal circuit reveals alternative synthesis pathways.

Quorum sensing (QS) is an important determinant of bacterial phenotype. Many cell functions are regulated by intricate and multimodal QS signal transduction processes. The LuxS/AI-2 QS system is highly conserved among Eubacteria and AI-2 is reported as a 'universal' signal molecule. To understand the hierarchical organization of AI-2 circuitry, a comprehensive approach incorporating stochastic simulations was developed. We investigated the synthesis, uptake, and regulation of AI-2, developed testable hypotheses, and made several discoveries: (1) the mRNA transcript and protein levels of AI-2 synthases, Pfs and LuxS, do not contribute to the dramatically increased level of AI-2 found when cells are grown in the presence of glucose; (2) a concomitant increase in metabolic flux through this synthesis pathway in the presence of glucose only partially accounts for this difference. We predict that 'high-flux' alternative pathways or additional biological steps are involved in AI-2 synthesis; and (3) experimental results validate this hypothesis. This work demonstrates the utility of linking cell physiology with systems-based stochastic models that can be assembled de novo with partial knowledge of biochemical pathways.

Bacterial Physiological Phenomena↗
PubMed2026

Zhiling Jiangya decoction treats hypertension in rats: An integrative study of network pharmacology, immune infiltration, molecular simulation, and 16S rDNA sequencing.

OBJECTIVE: This study integrated network pharmacology, immune infiltration analysis, molecular docking, molecular dynamics simulation, ADMET prediction, 16S rDNA sequencing, and rat experiments to elucidate the potential mechanisms underlying the antihypertensive effects of Zhiling Jiangya Decoction (ZLJYD). METHODS: Active compounds and their potential targets were screened from the PubChem, TCMSP, NovoPro, and SwissTargetPrediction databases. Hypertension-related targets were retrieved from the OMIM and GeneCards databases, and overlapping targets were identified. The STRING database and Cytoscape 3.10.1 software were used to construct a protein-protein interaction network and a herb-component-target-disease network. Gene Ontology functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed to identify the key biological processes and signaling pathways involved. Using the CIBERSORT algorithm combined with correlation analysis, we investigated the association between key targets and immune cell infiltration. Molecular docking, molecular dynamics simulations, and ADMET predictions were performed to assess the binding stability and pharmacokinetic properties of the main compounds with their corresponding targets. Finally, the antihypertensive efficacy of ZLJYD was validated using a spontaneously hypertensive rat model, and alterations in gut microbiota were analyzed using 16S rDNA sequencing. RESULTS: A total of 123 active compounds and 267 hypertension-related targets of ZLJYD were identified. Enrichment analysis revealed that these targets were primarily associated with the PI3K-Akt signaling pathway and lipid and atherosclerosis pathways. Immune infiltration analysis suggested that the therapeutic effects of ZLJYD may involve the regulation of follicular helper T cells, naïve B cells, and naïve CD4⁺ T cells. Molecular docking and dynamics simulations supported the stable binding of key compounds to their target proteins, while ADMET predictions indicated favorable pharmacokinetic properties and safety profiles. Rat experiments demonstrated that ZLJYD significantly reduced blood pressure in spontaneously hypertensive rats, partially alleviated gut microbiota dysbiosis, and altered microbial community structure and phylogenetic diversity. CONCLUSION: This study systematically elucidates the potential mechanisms underlying the antihypertensive effects of ZLJYD through multiple components, targets, and pathways, particularly immune regulation and gut microbiota remodeling. These findings provide mechanistic insights into its potential therapeutic application.

16S rDNA sequencing↗
PubMed2000

Ubiquitin-like proteins: new wines in new bottles.

Ubiquitin is a small polypeptide that covalently modifies other cellular proteins and targets them to the proteasome for degradation. In recent years, ubiquitin-dependent proteolysis has been demonstrated to play a critical role in the regulation of many cellular processes, such as cell cycle progression, cell signaling, and immune recognition. The recent discovery of three new ubiquitin-like proteins, NEDD8, Sentrin/SUMO, and Apg12, has further broadened the horizon of this type of post-translational protein modification. This review will focus on the biology and biochemistry of the Sentrin/SUMO and NEDD8 modification pathways, which are clearly distinct from the ubiquitination pathway and have unique biological functions.

Amino Acid Sequence↗
PubMed2004

Interleukin-12 enhances the sensitivity of human osteosarcoma cells to 4-hydroperoxycyclophosphamide by a mechanism involving the Fas/Fas-ligand pathway.

Cyclophosphamide (CY) and its derivative ifosfamide are alkylating agents used to treat osteosarcoma (OS). The purpose of these studies was to determine whether alkylating agents affect the expression of Fas ligand (FasL) and whether interleukin 12 enhances the sensitivity of human OS cells to alkylating agents. 4-Hydroperoxycyclophosphamide (4-HC), the preactivated CY compound, and 4-hydroperoxydidechlorocloclophosphamide (4-HDC), its nonalkylating analogue, human OS LM6 cells, and a clone of cells derived by transfection with the interleukin 12 gene (LM6-#6) were used for these studies. Incubation of LM6 and LM6-#6 with 10 micro M 4-HC increased the expression of FasL mRNA (2.5- and 3.0-fold, respectively). By contrast, 4-HDC, Adriamycin (ADR), cisplatin (CDP), and methotrexate (MTX) had no effect on FasL mRNA expression. Increased FasL expression after treatment with 4-HC was also demonstrated by immunohistochemistry and flow cytometry. Drug-induced FasL was functional and mediated cell death. We examined the effect of FasL up-regulation by 4-HC on LM6 and LM6-#6 cells. Flow cytometry showed that LM6-#6 cells expressed 2.2-fold more Fas than LM6 cells. Cytotoxicity of 4-HC, 4-HDC, ADR, CDP, and MTX on LM6, LM6-neo, and LM6-#6 were quantified. Colony-forming assay revealed an IC(50) of 2.10 micro M for 4-HC in LM6-neo cells compared with 0.41 micro M in LM6-#6 cells. The IC(50) for 4-HDC, ADR, CDP, and MTX were not significantly different between the two cell lines. We concluded that the increased expression of Fas enhanced LM6-#6 sensitivity to 4-HC. These data indicate that Fas/FasL may be involved in the cytotoxic pathway of CY. Combining biological agents with chemotherapeutic agents that have complementary Fas/FasL pathway actions may offer new therapeutic alternatives.

Antineoplastic Agents↗
PubMed2006

Integration and mining of malaria molecular, functional and pharmacological data: how far are we from a chemogenomic knowledge space?

The organization and mining of malaria genomic and post-genomic data is important to significantly increase the knowledge of the biology of its causative agents, and is motivated, on a longer term, by the necessity to predict and characterize new biological targets and new drugs. Biological targets are sought in a biological space designed from the genomic data from Plasmodium falciparum, but using also the millions of genomic data from other species. Drug candidates are sought in a chemical space containing the millions of small molecules stored in public and private chemolibraries. Data management should, therefore, be as reliable and versatile as possible. In this context, five aspects of the organization and mining of malaria genomic and post-genomic data were examined: 1) the comparison of protein sequences including compositionally atypical malaria sequences, 2) the high throughput reconstruction of molecular phylogenies, 3) the representation of biological processes, particularly metabolic pathways, 4) the versatile methods to integrate genomic data, biological representations and functional profiling obtained from X-omic experiments after drug treatments and 5) the determination and prediction of protein structures and their molecular docking with drug candidate structures. Recent progress towards a grid-enabled chemogenomic knowledge space is discussed.

Animals↗
PubMed2006

VEGFR-1 and VEGFR-2: two non-identical twins with a unique physiognomy.

Angiogenesis involves endothelial cell differentiation, proliferation, migration and cord formation, which lead to tubulogenesis to form vessels. One group of growth factor receptors implicated in angiogenesis is the VEGFR family of receptor tyrosine kinases. VEGFR-1 and VEGFR-2 are closely related receptor tyrosine kinases and have both common and specific ligands. VEGFR-1 is a kinase-impaired RTK whereas VEGFR-2 is a highly active kinase. Despite their differential kinase activation potentials, both VEGFR-1 and VEGFR-2 are required for normal development and angiogenesis. VEGFR-1 regulates angiogenesis by mechanisms that involve ligand-trapping, receptor homo- and heterodimerization. VEGFR-2 stimulates variety of signaling pathways and broad biological responses in vitro. The mechanisms that govern VEGFR-2 activation, its ability to recruit signaling proteins and to undergo downregulation are highly regulated by its carboxyl terminus. This review highlights recent insights into the mechanism of activation of VEGFR-1 and VEGFR-2, and focuses on the signaling pathways employed by VEGFR-1 and VEGFR-2 that regulate angiogenesis.

Animals↗
PubMed2001

The ras signaling pathway in mammary tumorigenesis and metastasis.

The Ras superfamily of GTPases act as important regulatory switches to co-ordinate extracellular stimuli with activation of intracellular signaling pathways and appropriate biological responses. The Ras branch of this superfamily includes H-, K- and N-Ras, which are commonly mutated in particular human cancers, but notably not in those of the breast. Instead, in breast cancer the signaling pathways involving these GTPases may be upregulated due to increased coupling to growth factor receptors or other tyrosine kinases commonly overexpressed in this disease, or increased expression of regulators, the Ras protein itself, or downstream effectors. Functional studies utilizing both in vitro and in vivo models demonstrate that Ras signaling can regulate a variety of endpoints relevant to breast cancer progression, including anchorage dependent and independent growth, tumorigenesis, steroid sensitivity and invasion. Finally, analysis of the processing and signaling mechanisms of the Ras superfamily has identified potential targets for therapeutic intervention.

Animals↗