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Results for “regulatory module”

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PubMed1986

Steroidal modulation of the regulatory neuropeptides: luteinizing hormone releasing hormone, neuropeptide Y and endogenous opioid peptides.

Recent studies show that a large number of neuropeptides may play important roles in the hypothalamic control of reproduction and related sexual, feeding and locomotor behaviours. Based on the evidence summarized here we propose that gonadal steroids may exert a "trophic" influence on the regulatory peptides namely LHRH, NPY and EOP locally in the hypothalamus.

Animals↗

PubMed1990

Nucleosome positioning modulates accessibility of regulatory proteins to the mouse mammary tumor virus promoter.

Minichromosomes containing the MMTV hormone responsive element (HRE) exhibit precisely positioned nucleosomes. Chromatin reconstitution of short HRE DNA fragments also results in precise positioning of nucleosomes as revealed by footprinting, which suggests that information for nucleosome phasing is contained within this short sequence. While hormone receptors bind naked DNA and reconstituted nucleosomes with similar affinities (3- to 5-fold difference), NFI, a transcription factor essential for efficient utilization of the MMTV promoter, binds naked DNA very tightly but does not bind the nucleosomally organized promoter. Hormone receptor binding to the MMTV nucleosome does not dissociate the nucleosome but leads to greater accessibility of the promoter-proximal end to exonuclease III. Precise positioning of one nucleosome over the MMTV promoter could repress transcription by preventing NFI binding in the absence of hormone, while still allowing interaction of activated hormone receptor with HRE.

Animals↗

PubMed2002

Modulation of apoptotic regulatory proteins and early activation of cytochrome C following systemic 3-nitropropionic acid administration.

The present study utilized the administration of the mitochondrial toxin, 3-nitropropionic acid (3-NP), to mimic the pathology associated with Huntington's disease (HD). 3-NP causes striatal cell degeneration via the inhibition of succinate dehydrogenase. There is growing evidence suggesting the role of apoptosis in 3-NP cell death. TUNEL staining, DNA fragmentation, and changes in bcl-2 mRNA levels have been associated with this metabolic impairment. We wish to further elucidate the apoptotic cascade in this model of HD pathogenesis. 3-NP was administered to rats intraperitoneally at 20mg/kg/day for up to 3 days. At 3 days, characteristic behavioral and morphological effects became evident. While cell death did not become apparent within the first 3 days, there were changes in the levels of apoptotic regulatory proteins and translocation of cytochrome c. Within 24 h after 3-NP administration there were elevations in both bcl-xl and bax. However, bcl-xl protein levels quickly returned to control levels while bax levels continued to increase, resulting in a detrimental bax/bcl-xl ratio. Bax has been demonstrated to facilitate cytochrome c release by forming mitochondrial pores. We saw cytochrome c translocate from the mitochondria to the cytosol approximately 24 h after initial 3-NP administration when compared to saline-injected controls. This evidence generated using the 3-NP degeneration model may help elucidate the apoptotic cascade associated with HD neurodegeneration.

Animals↗

PubMed1999

Dynamic modulation of the regulatory domain of myosin heads by pH, ionic strength, and RLC phosphorylation in synthetic myosin filaments.

The position of the myosin head with respect to the filament backbone is thought to be a function of pH, ionic strength (micro) and the extent of regulatory light chain (RLC) phosphorylation [Harrington (1979) Proc. Natl. Acad. Sci. U.S.A. 76, 5066-5070]. The object of this study is to examine the dynamics of the proximal part of the myosin head (regulatory domain) which accompany the changes in head disposition. The essential light chain was labeled at Cys177 with the indanedione spin-label followed by the exchange of the labeled proteins into myosin. The mobility of the labeled domain was investigated with saturation transfer electron paramagnetic resonance in reconstituted, synthetic myosin filaments. We have found that the release of the heads from the myosin filament surface by reduction of electrostatic charge is accompanied by a 2-fold increase in the mobility of the regulatory domain. Phosphorylation of the RLC by myosin light chain kinase resulted in a smaller 1. 5-fold increase of motion, establishing that the head disordering observed by electron microscopy [Levine et al. (1996) Biophys. J. 71, 898-907] is due to increased mobility of the heads. This result indirectly supports the hypothesis that the RLC phosphorylation effect on potentiation of force arises from a release of heads from the filament surface and a shift of the heads toward actin.

Animals↗

PubMed2000

Distinct structural forms of type I collagen modulate cell cycle regulatory proteins in mesangial cells.

BACKGROUND: Extracellular matrix molecules profoundly regulate cell behavior, including proliferation. In glomerulonephritis, type I collagen accumulates in the mesangium and is constantly structurally modified and degraded during the course of the disease. METHODS: We studied how two structurally distinct forms of type I collagen, monomer versus polymerized fibrils, affect cell proliferation, mitogen-activated protein kinase (MAPK) activation, and expression of G1-phase regulatory proteins in cultured rat mesangial cells (MCs). To analyze the possible involvement of collagen-binding integrins in type I collagen-derived growth signals further, distribution patterns of integrin chains were examined by immunocytochemistry. RESULTS: Polymerized type I collagen completely prevented the increase of DNA synthesis and cell replication induced by 5% fetal calf serum (FCS) or 25 ng/mL platelet-derived growth factor (PDGF) in MCs on monomer type I collagen. Protein expression of cyclins D1 and E was markedly down-regulated in MCs plated on polymerized type I collagen for eight hours in 5% FCS, as compared with MCs on monomer type I collagen. Incubation with 5% FCS reduced expression of the cdk-inhibitor protein p27Kip1 on monomer but not on polymerized type I collagen. Moreover, polymerized type I collagen markedly reduced cyclin E-associated kinase activity in the presence of 5% FCS. Polymerized type I collagen diminished the PDGF-induced phosphorylation and nuclear translocation of p42/p44 MAPK, but did not affect phosphorylation of PDGF beta-receptors. In MCs plated on monomer type I collagen, alpha1, alpha2, and beta1 integrin chains were recruited into focal contacts. However, on polymerized type I collagen, alpha2 and beta1, but not alpha1, integrin chains were condensed into focal contacts. CONCLUSIONS: The growth-inhibitory effect of polymerized type I collagen is characterized by rapid changes of expression and/or activation of MAPK and G1-phase regulators and could result from the lack of alpha1beta1 integrin signaling in MCs on polymerized type I collagen. Conceivably, deposition of polymerized type I collagen might reflect a reparative response to control MC replication in glomerular inflammation.

Animals↗

PubMed2000

Regulatory mechanisms for modulation of signaling through the cell integrity Slt2-mediated pathway in Saccharomyces cerevisiae.

Signal transduction mediated by the mitogen-activated protein kinase (MAPK) Slt2 pathway is essential to maintain the cell wall integrity in Saccharomyces cerevisiae. Stimulation of MAPK pathways results in activation by phosphorylation of conserved threonine and tyrosine residues of MAPKs. We have used an antibody that specifically recognizes dually phosphorylated Slt2 to gain insight into the activation and modulation of signaling through the cell integrity pathway. We show that caffeine and vanadate activate this pathway in the absence of osmotic stabilization. The lack of the putative cell surface sensor Mid2 prevents vanadate- but not caffeine-induced Slt2 phosphorylation. Disruption of the Rho1-GTPase-activating protein genes SAC7 and BEM2 leads to constitutive Slt2 activation, indicating their involvement as negative regulators of the pathway. MAPK kinases also seem to participate in signaling regulation, Mkk1 playing a greater role than Mkk2 in signal transmission to Slt2. Additionally, one of the phosphatases involved in Slt2 dephosphorylation is likely to be the dual specificity phosphatase Msg5, since overexpression of MSG5 in a sac7Delta mutant eliminates the high Slt2 phosphorylation, and disruption of MSG5 in wild type cells results in increased phospho-Slt2 levels. These data present the first evidence for a negative regulation of the cell integrity pathway.

DNA-Binding Proteins↗

PubMed2006

Modulation of biological regulatory networks during nephrogenesis.

Mesenchymal-to-epithelial transition is an important biological event during the course of renal cell differentiation as condensing mesenchyme gives rise to tubuloepithelial structures. Wilms' tumor suppressor gene (Wt1) has been identified as a master regulator of the complex genetic events that mediate mesenchymal transdifferentiation. Evidence is summarized here showing that the tightly regulated series of genetic and biochemical events during nephrogenesis is disrupted by superactivation of aryl hydrocarbon receptor (Ahr) by benzo(a)pyrene (BaP), a ubiquitous polycyclic aromatic hydrocarbon and renal carcinogen (Falahatpisheh and Ramos, 2003). Nephron formation is inhibited by BaP, a response that involves inhibition of metanephric cell differentiation and shifts in the relative abundance of Wt1 splice variants. A systems biology paradigm that combined approaches from genomics, transcriptomics, and bioinformatics revealed that the global response of murine metanephric cultures to BaP involves downregulation of Ahr and disruption of downstream targets of Wt1. Discrete networks of genetic regulation were resolved using Boolean idealizations and included genes involved in renal cell differentiation and metabolic control. This work has established a role for Ahr in renal cell differentiation and kidney development and resolved putative molecular interactions between Ahr and Wt1.

Animals↗

PubMed1996

Interferon-gamma and interleukin-10 have cross-regulatory roles in modulating the class I and class II MHC-mediated presentation of epitopes of Listeria monocytogenes by infected macrophages.

IFN-gamma is an important cytokine in resistance to infection with Listeria monocytogenes, and interleukin 10 is known to exacerbate infection with Listeria and other intracellular pathogens. We examined the effects of these cytokines on antigen presentation by macrophages infected with live Listeria. Listeriolysin O, a hemolysin secreted by Listeria, is an immunodominant antigen presented by both class I and class II MHC on infected cells. Thioglycollate-elicited macrophages were pretreated with exogenous IFN-gamma, IL-10, or both cytokines overnight, infected with bacteria, and then fixed. Epitope-specific, MHC-restricted, T cell hybridomas were then added to detect the presentation of the class I or class II ligand. We found that IFN-gamma enhanced the presentation of both the class I and class II epitopes and IL-10 strongly inhibited the presentation of both ligands. The degree of inhibition of presentation caused by IL-10 was dose dependent. IL-10 was also able to inhibit the presentation of exogenously added class II-binding peptide but had a less dramatic effect on the presentation of the added class I-binding polypeptide epitope. Flow cytometric analysis of expression of class I and class II on treated macrophages demonstrated that the inhibitory effect of IL-10 on antigen presentation was not due to significant downregulation of MHC expression. This loss of antigen presentation was also not due to downregulation of the costimulatory molecule, B7-2. We have found that IFN-gamma and IL-10 have opposing immunoregulatory effects on the presentation of antigens derived from an intracellular pathogen and that the class I vs. class II-mediated presentation of antigens is differentially regulated by IL-10.

Animals↗

PubMed1999

Hepatitis C virus NS5A protein modulates cell cycle regulatory genes and promotes cell growth.

The phosphoprotein NS5A of hepatitis C virus has recently been suggested to control PKR protein kinase for resistance to interferon. To investigate other functions of NS5A, studies were initiated on the regulation of transcription of important cellular genes and of cell growth by this protein. The results suggested that NS5A protein represses transcription of the cell cycle regulatory gene p21WAF1, while it activates the human proliferating cell nuclear antigen gene in murine fibroblasts and human hepatoma cells. Furthermore, introduction of NS5A into murine fibroblasts (NIH3T3) promoted anchorage-independent growth and tumour formation in nude mice. Thus, NS5A appears to exhibit a role in cell growth regulation.

Animals↗

PubMed1995

The global regulatory protein FruR modulates the direction of carbon flow in Escherichia coli.

The Escherichia coli fructose repressor, FruR, is known to regulate expression of several genes concerned with carbon utilization. Using a previously derived consensus sequence for FruR binding, additional potential operators were identified and tested for FruR binding in DNA band migration retardation assays. Operators in the control regions of operons concerned with carbon metabolism bound FruR, while those in operons not concerned with carbon metabolism did not. In vivo assays with transcriptional lacZ fusions showed that FruR controls the expression of FruR operator-containing genes encoding key enzymes of virtually every major pathway of carbon metabolism. Moreover, a fruR null mutation altered the rates of utilization of at least 36 carbon sources. In general, oxidation rates for glycolytic substances were enhanced while those for gluconeogenic substances were depressed. Alignment of FruR operators revealed that the consensus sequence for FruR binding is the same for operons that are activated and repressed by FruR and permitted formulation of a revised FruR-binding consensus sequence. The reported observations indicate that FruR modulates the direction of carbon flow by transcriptional activation of genes encoding enzymes concerned with oxidative and gluconeogenic carbon flow and by repression of those concerned with fermentative carbon flow.

Bacterial Proteins↗

PubMed2005

Divergent modulation of iron regulatory proteins and ferritin biosynthesis by hypoxia/reoxygenation in neurones and glial cells.

Ferritin, the main iron storage protein, exerts a cytoprotective effect against the iron-catalyzed production of reactive oxygen species, but its role in brain injury caused by hypoxia/reoxygenation is unclear. Ferritin expression is regulated mainly at post-transcriptional level by iron regulatory proteins (IRP1 and IRP2) that bind specific RNA sequences (IREs) in the 5'untranslated region of ferritin mRNA. Here, we show that hypoxia decreases IRP1 binding activity in glial cells and enhances it in cortical neurons. These effects were reversed by reoxygenation in both cell types. In glial cells there was an early increase of ferritin synthesis during hypoxia and reoxygenation. Conversely, in cortical neurons, ferritin synthesis increased during the late phase of reoxygenation. Steady-state analysis of ferritin mRNA levels suggested that ferritin synthesis is regulated mainly post-transcriptionally by IRPs in glioma cells, both transcriptionally and post-transcriptionally in type-1 astrocytes, and mainly at transcriptional level in an IRP-independent way in neurons. The different regulation of ferritin expression may account for the different vulnerability of neurons and glial cells to the injury elicited by oxygen and glucose deprivation (OGD)/reoxygenation. The greater vulnerability of cortical neurons to hypoxia-reoxygenation was strongly attenuated by the exogenous administration of ferritin during OGD/reoxygenation, suggesting the possible cytoprotective role exerted by this iron-segregating protein.

Animals↗

PubMed2002

Modulating modulation: crosstalk between regulatory pathways of presynaptic calcium channels.

The activity of some voltage-gated calcium channels (VGCCs) can be inhibited by specific G protein beta subunits. Conversely, in the case of N-type VGCCs, protein kinase C can relieve Gbeta-dependent inhibition by phosphorylating at least one specific site on the calcium channel. A recent publication describes a newly identified method of intracellular regulation of specific VGCCs. Wu et al. have uncovered that VGCC activity can be regulated by phosphatidylinositol-4',5'-bisphosphate (PIP2). Whereas PIP2 is important for maintaining the activity (open state) of Cav2.1 (N-type) and Cav2.2 (P/Q-type) channels, the enzymatic breakdown of PIP2 leads to the inactivation of these channels. Additionally, PIP2 can cause changes in voltage-dependent activation of Cav2.2 (P/Q-type) channels that make it more difficult for these channels to open (from the closed state). Furthermore, protein kinase A activity can circumvent PIP2-mediated inhibition. Thus, the PIP2-mediated regulation of VGCCs is tightly controlled by the functions of kinases (and phosphatases), as well as phospholipases. Wu et al. stress that because PIP2 can be found at synapses, PIP2-dependent control of VGCCs "could have profound consequences on synaptic transmission and plasticity."

Animals↗

PubMed2004

Inhibition of prostate cancer cell colony formation by the flavonoid quercetin correlates with modulation of specific regulatory genes.

The natural product quercetin is a flavonoid found in many fruits and vegetables. Previous research has shown that quercetin has antitumor, anti-inflammatory, antiallergic, and antiviral activities. In the present investigation we studied the effect of quercetin on the ability of prostate cancer cell lines with various degrees of aggressive potential to form colonies in vitro. Specifically, we examined the molecular mechanisms underlying this effect, including the expression of cell cycle and tumor suppressor genes as well as oncogenes. We observed that quercetin at concentrations of 25 and 50 micro M significantly inhibited the growth of the highly aggressive PC-3 prostate cancer cell line and the moderately aggressive DU-145 prostate cancer cell line, whereas it did not affect colony formation by the poorly aggressive LNCaP prostate cancer cell line or the normal fibroblast cell line BG-9. Using the gene array methodology, we found that quercetin significantly inhibited the expression of specific oncogenes and genes controlling G(1), S, G(2), and M phases of the cell cycle. Moreover, quercetin reciprocally up-regulated the expression of several tumor suppressor genes. In conclusion, our results demonstrate that the antitumor effects of quercetin directly correlate with the aggressive potential of prostate cancer cells and that the mechanism(s) of quercetin-mediated antitumor effects may involve up-regulation of tumor suppressor genes and reciprocal down-regulation of oncogenes and cell cycle genes. The results of these studies provide a scientific basis for the potential use of flavonoids as nutraceuticals in the chemoprevention of cancer.

Antineoplastic Agents, Phytogenic↗

PubMed1999

rsmC of the soft-rotting bacterium Erwinia carotovora subsp. carotovora negatively controls extracellular enzyme and harpin(Ecc) production and virulence by modulating levels of regulatory RNA (rsmB) and RNA-binding protein (RsmA).

Previous studies have shown that the production of extracellular enzymes (pectate lyase [Pel], polygalacturonase [Peh], cellulase [Cel], and protease [Prt]) and harpin(Ecc) (the elicitor of hypersensitive reaction) in Erwinia carotovora subsp. carotovora is regulated by RsmA, an RNA-binding protein, and rsmB, a regulatory RNA (Rsm stands for regulator of secondary metabolites) (Y. Liu et al., Mol. Microbiol. 29:219-234, 1998). We have cloned and characterized a novel regulatory gene, rsmC, that activates RsmA production and represses extracellular enzyme and harpin(Ecc) production, rsmB transcription, and virulence in E. carotovora subsp. carotovora. In an rsmC knockout mutant of E. carotovora subsp. carotovora Ecc71 carrying the chromosomal copy of the wild-type rsmA(+) allele, the basal levels of Pel, Peh, Cel, Prt, and harpin(Ecc) as well as the amounts of rsmB, pel-1, peh-1, celV, and hrpN(Ecc) transcripts are high, whereas the levels of rsmA transcripts and RsmA protein are low. Furthermore, the expression of an rsmA-lacZ gene fusion is lower in the RsmC(-) mutant than in the RsmC(+) parent. Conversely, the expression of an rsmB-lacZ operon fusion is higher in the RsmC(-) mutant than in the RsmC(+) parent. These observations establish that RsmC negatively regulates rsmB transcription but positively affects RsmA production. Indeed, comparative studies with an RsmC(-) mutant, an RsmA(-) mutant, and an RsmA(-) RsmC(-) double mutant have revealed that the negative effects on exoprotein production and virulence are due to the cumulative regulatory effects of RsmC on rsmA and rsmB. Exoprotein production by the RsmC(-) mutant is partially dependent on the quorum sensing signal, N-(3-oxohexanoyl)-L-homoserine lactone. Southern blot data and analysis of PCR products disclosed the presence of rsmC sequences in E. carotovora subsp. atroseptica, E. carotovora subsp. betavasculorum, and E. carotovora subsp. carotovora. These findings collectively support the idea that rsmA and rsmB expression in these plant pathogenic Erwinia species is controlled by RsmC or a functional homolog of RsmC.

Amino Acid Sequence↗

PubMed2006

Using local gene expression similarities to discover regulatory binding site modules.

BACKGROUND: We present an approach designed to identify gene regulation patterns using sequence and expression data collected for Saccharomyces cerevisae. Our main goal is to relate the combinations of transcription factor binding sites (also referred to as binding site modules) identified in gene promoters to the expression of these genes. The novel aspects include local expression similarity clustering and an exact IF-THEN rule inference algorithm. We also provide a method of rule generalization to include genes with unknown expression profiles. RESULTS: We have implemented the proposed framework and tested it on publicly available datasets from yeast S. cerevisae. The testing procedure consists of thorough statistical analyses of the groups of genes matching the rules we infer from expression data against known sets of co-regulated genes. For this purpose we have used published ChIP-Chip data and Gene Ontology annotations. In order to make these tests more objective we compare our results with recently published similar studies. CONCLUSION: Results we obtain show that local expression similarity clustering greatly enhances overall quality of the derived rules, both in terms of enrichment of Gene Ontology functional annotation and coherence with ChIP-Chip binding data. Our approach thus provides reliable hypotheses on co-regulation that can be experimentally verified. An important feature of the method is its reliance only on widely accessible sequence and expression data. The same procedure can be easily applied to other microbial organisms.

Binding Sites↗

PubMed2001

Pseudo-phosphatase Sbf1 contains an N-terminal GEF homology domain that modulates its growth regulatory properties.

Sbf1 (SET binding factor 1) is a pseudo-phosphatase related to the myotubularin family of dual specificity phosphatases, some of which have been implicated in cellular growth and differentiation by virtue of their mutation in human genetic disorders. Sbf1 contains germline-encoded alterations of its myotubularin homology domain that render it non-functional as a phosphatase. We report here the complete structure of Sbfl and further characterization of its growth regulatory properties. In addition to its similarity to myotubularin, the predicted full-length Sbf1 protein contains pleckstrin (PH) and GEF homology domains that are conserved in several proteins implicated in signaling and growth control. Forced expression of wild-type Sbfl in NIH 3T3 cells inhibited their proliferation and altered their morphology. These effects required intact PH, GEF and myotubularin homology domains, implying that growth inhibition may be an intrinsic property of wild-type Sbf1. Conversely, deletion of its conserved N-terminal 44 amino acids alone was sufficient to convert Sbf1 from an inhibitor of cellular growth to a transforming protein in NIH 3T3 cells. Oncogenic forms of Sbf1 partially localized to the nucleus, in contrast to the exclusively cytoplasmic subcellular localization of endogenous Sbf1 in all cell lines and mammalian tissues tested. These data show that the N-terminal GEF homology domain serves to inhibit the transforming effects of Sbf1, possibly sequestering the protein to the cytoplasm, and suggest that this region may be a modulatory domain that relays growth control signals.

3T3 Cells↗

PubMed2005

Platelet factor 4 differentially modulates CD4+CD25+ (regulatory) versus CD4+CD25- (nonregulatory) T cells.

Active suppression mediated by CD4(+)CD25(+) T regulatory (Tr) cells plays an important role in the down-regulation of T cell responses to both foreign and self-Ags. Platelet factor 4 (PF4), a platelet-derived CXC chemokine, has been shown to strongly inhibit T cell proliferation as well as IFN-gamma and IL-2 release by isolated T cells. In this report we show that human PF4 stimulates proliferation of the naturally anergic human CD4(+)CD25(+) Tr cells while inhibiting proliferation of CD4(+)CD25(-) T cells. In coculture experiments we found that CD4(+)CD25(+) Tr cells exposed to PF4 lose the ability to inhibit the proliferative response of CD4(+)CD25(-) T cells. Our findings suggest that human PF4, by inducing Tr cell proliferation while impairing Tr cell function, may play a previously unrecognized role in the regulation of human immune responses. Because platelets are the sole source of PF4 in the circulation, these findings may be relevant to the pathogenesis of certain immune-mediated disorders associated with platelet activation, such as heparin-induced thrombocytopenia and autoimmune thrombocytopenic purpura.

Antibodies, Monoclonal↗

PubMed2000

GluR3 autoantibodies destroy neural cells in a complement-dependent manner modulated by complement regulatory proteins.

GluR3 autoantibodies have been implicated in the development of Rasmussen's encephalitis, a rare neurodegenerative disease of humans characterized by epilepsy and degeneration of a single cerebral hemisphere. GluR3 autoantibodies are found in some Rasmussen's encephalitis patients, and GluR3 antibodies raised in rabbits destroy cultured cortical cells in a complement-dependent manner. In this study, the cellular targets of anti-GluR3 antisera-mediated cytotoxicity were examined in mixed primary neuronal-glial cultures of rat cortex. Unexpectedly, astrocytes were the principal target of the cytotoxic effects as assessed by immunohistochemistry and lactate dehydrogenase activity; neurons were destroyed to a lesser extent. Astrocyte vulnerability was rescued by transfection with complement regulatory proteins, and neuronal resistance was defeated by impairing complement regulatory protein function. Astrocyte death may occur in Rasmussen's encephalitis, and destruction of this cell type may play a critical role in the progression of this disorder. The present findings suggest complement regulatory protein expression may in part determine the nature and severity of Rasmussen's encephalitis and other complement-dependent nervous system diseases and thus underscore the need for a systematic investigation of the expression of all known complement regulatory proteins in healthy and diseased nervous system tissues.

Animals↗