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PubMed1999

Solution structure of the DNA-binding domain of NtrC with three alanine substitutions.

The structure of the 20 kDa C-terminal DNA-binding domain of NtrC from Salmonella typhimurium (residues Asp380-Glu469) with alanine replacing Arg456, Asn457, and Arg461, was determined by NMR spectroscopy. NtrC is a homodimeric enhancer-binding protein that activates the transcription of genes whose products are required for nitrogen metabolism. The 91-residue C-terminal domain contains the determinants necessary for dimerization and DNA-binding of the full length protein. The mutant protein does not bind to DNA but retains many characteristics of the wild-type protein, and the mutant domain expresses at high yield (20 mg/l) in minimal medium. Three-dimensional (1)H/(13)C/(15)N triple-resonance, (1)H-(13)C-(13)C-(1)H correlation and (15)N-separated nuclear Overhauser effect (NOE) spectroscopy experiments were used to make backbone and side-chain (1)H,(15)N, and (13)C assignments. The structures were calculated using a total of 1580 intra and inter-monomer distance and hydrogen bond restraints (88 hydrogen bonds; 44 hydrogen bond restraints), and 88 phi dihedral restraints for residues Asp400 through Glu469 in both monomers. A total of 54 ambiguous restraints (intra or inter-monomer) involving residues close to the 2-fold symmetry axis were also included. Each monomer consists of four helical segments. Helices A (Trp402-Leu414) and B (Leu421-His440) join with those of another monomer to form an antiparallel four-helix bundle. Helices C (Gln446-Leu451) and D (Ala456-Met468) of each monomer adopt a classic helix-turn-helix DNA-binding fold at either end of the protein. The backbone rms deviation for the 28 best of 40 starting structures is 0.6 (+/-0.2) A. Structural differences between the C-terminal domain of NtrC and the homologous Factor for Inversion Stimulation are discussed.

Alanine↗
PubMed2000

Interleukin-6 release by cultured peripheral blood mononuclear cells inversely correlates with height velocity, bone age, insulin-like growth factor-I, and insulin-like growth factor binding protein-3 serum levels in children with perinatal HIV-1 infection.

Spontaneous and phytohemagglutinin (PHA)-stimulated interleukin (IL)-6 release by cultured peripheral blood mononuclear cells was related to height velocity, bone age, insulin-like growth factor-I (IGF-I), and IGF binding protein-3 (IGFBP-3) serum level standard deviation scores (SDS) of 32 children [aged 91 (median; range 13-151) months] with human immunodeficiency virus-type 1 (HIV-1) perinatal infection and severe disease. Spontaneous and PHA-stimulated IL-6 release inversely correlated with height velocity, bone age, IGF-I, and IGFBP-3 SDS. Ten children with height velocity SDS </= -2, compared to 22 children with height velocity SDS > -2, showed higher spontaneous and PHA-stimulated IL-6 release and lower IGF-I and IGFBP-3 SDS (irrespective of CD4-positive T-lymphocyte counts, viral load, liver disease, or nutrition status). IL-6 overproduction may be a mechanism of IGF-I and IGFBP-3 down-regulation and impaired linear growth in children with perinatal HIV-1 infection. Growth-promoting strategies, including targeted anticytokine treatments, could be devised for such children.

Age Determination by Skeleton↗
PubMed2004

Activation of signaling lymphocytic activation molecule triggers a signaling cascade that enhances Th1 responses in human intracellular infection.

T cell production of IFN-gamma contributes to host defense against infection by intracellular pathogens, including mycobacteria. Lepromatous leprosy, the disseminated form of infection caused by Mycobacterium leprae, is characterized by loss of cellular response against the pathogen and diminished Th1 cytokine production. Relieving bacterial burden in Ag-unresponsive patients might be achieved through alternative receptors that stimulate IFN-gamma production. We have previously shown that ligation of signaling lymphocytic activation molecule (SLAM) enhances IFN-gamma in mycobacterial infection; therefore, we investigated molecular pathways leading from SLAM activation to IFN-gamma production in human leprosy. The expression of the SLAM-associated protein (an inhibitory factor for IFN-gamma induction) on M. leprae-stimulated cells from leprosy patients was inversely correlated to IFN-gamma production. However, SLAM ligation or exposure of cells from lepromatous patients to a proinflammatory microenvironment down-regulated SLAM-associated protein expression. Moreover, SLAM activation induced a sequence of signaling proteins, including activation of the NF-kappaB complex, phosphorylation of Stat1, and induction of T-bet expression, resulting in the promotion of IFN-gamma production, a pathway that remains quiescent in response to Ag in lepromatous patients. Therefore, our findings reveal a cascade of molecular events during signaling through SLAM in leprosy that cooperate to induce IFN-gamma production and strongly suggest that SLAM might be a focal point for therapeutic modulation of T cell cytokine responses in diseases characterized by dysfunctional Th2 responses.

Adjuvants, Immunologic↗
PubMed1995

DNA looping by Saccharomyces cerevisiae high mobility group proteins NHP6A/B. Consequences for nucleoprotein complex assembly and chromatin condensation.

The formation of higher order protein.DNA structures often requires bending of DNA strands between specific sites, a process that can be facilitated by the action of nonspecific DNA-binding proteins which serve as assembly factors. A model for this activity is the formation of the invertasome, an intermediate structure created in the Hin-mediated site-specific DNA inversion reaction, which is stimulated by the prokaryotic nucleoid-associated protein HU. Previously, we have shown that the mammalian HMG1/2 proteins substitute for HU in this system and display efficient DNA wrapping activity in vitro. In the present work, we isolate the primary sources of assembly factor activity in Saccharomyces cerevisiae, as measured by the ability to stimulate invertasome formation, and show that these are the previously identified NHP6A/B proteins. NHP6A/B have comparable or greater activity in DNA binding, bending, and supercoiling with respect to HU and HMG1 and appear to form more stable protein.DNA complexes. In addition, expression of NHP6A in mutant Escherichia coli cells lacking HU and Fis restores normal morphological appearance to these cells, specifically in nucleoid condensation and segregation. From these data we predict diverse architectural roles for NHP6A/B in manipulating chromosome structure and promoting the assembly of multicomponent protein.DNA complexes.

Base Sequence↗
PubMed2000

Potency of ligands correlates with affinity measured against agonist and inverse agonists but not against neutral ligand in constitutively active chemokine receptor.

ORF-74, a 7TM receptor oncogene encoded by human herpes virus 8, shows 50% constitutive activity in stimulating phosphatidylinositol turnover and binds a large variety of CXC chemokines. These endogenous ligands cover a full spectrum of pharmacological properties with growth-related oncogene (GRO)-alpha and -gamma functioning as full agonists; GRObeta as a partial agonist; interleukin (IL)-8, neutrophil-activating peptide (NAP)-2, and epithelial cell-derived activating peptide (ENA)-78 as neutral ligands; granulocyte colony-stimulating factor (GCP)-2 as a partial inverse agonist; and interferon-gamma inducible protein (IP)-10 and stromal cell-derived factor (SDF)-1alpha as full inverse agonists. The affinity for the agonists was independent of whether it was determined in competition binding against the agonist (125)I-GROalpha, against the inverse agonist (125)I-IP-10, or against the neutral ligand (125)I-IL-8. Similarly, the affinities of the inverse agonists were within 1 order of magnitude independent of the choice of radioligand. In contrast, the neutral ligands IL-8, NAP-2, and ENA-78, which all displaced (125)I-IL-8 with single-digit nanomolar affinity showed up to 1000-fold lower affinity against both the radioactive agonist and against the radioactive inverse agonist. A close correlation was observed between the EC(50) values for the ligands and their IC(50) values measured against either radioactive agonist or radioactive inverse agonist, but a poor correlation was found to the IC(50) value measured against the neutral ligand. It is concluded that in ORF-74, ligands compete for binding more according to pharmacological property than to structural homology and that both agonists and inverse agonists, in contrast to neutral ligands, apparently bind with high affinity either to a common conformation of the receptor or to readily interconvertible states, not available for the neutral ligands.

Amino Acid Sequence↗
PubMed2000

Characterization of bacteriophage lambda excisionase mutants defective in DNA binding.

The bacteriophage lambda excisionase (Xis) is a sequence-specific DNA binding protein required for excisive recombination. Xis binds cooperatively to two DNA sites arranged as direct repeats on the phage DNA. Efficient excision is achieved through a cooperative interaction between Xis and the host-encoded factor for inversion stimulation as well as a cooperative interaction between Xis and integrase. The secondary structure of the Xis protein was predicted to contain a typical amphipathic helix that spans residues 18 to 28. Several mutants, defective in promoting excision in vivo, were isolated with mutations at positions encoding polar amino acids in the putative helix (T. E. Numrych, R. I. Gumport, and J. F. Gardner, EMBO J. 11:3797-3806, 1992). We substituted alanines for the polar amino acids in this region. Mutant proteins with substitutions for polar amino acids in the amino-terminal region of the putative helix exhibited decreased excision in vivo and were defective in DNA binding. In addition, an alanine substitution at glutamic acid 40 also resulted in altered DNA binding. This indicates that the hydrophilic face of the alpha-helix and the region containing glutamic acid 40 may form the DNA binding surfaces of the Xis protein.

Amino Acid Sequence↗
PubMed1999

Growth stimulation of murine fibroblasts by TGF-beta1 depends on the expression of a functional p53 protein.

Transforming Growth Factor-beta1 (TGF-beta1) inhibits the proliferation of most cells, but stimulates some mesenchymal cell types, including murine NIH3T3 fibroblasts. We show here that TGF-beta1 growth stimulation of NIH3T3 fibroblasts is reversed when these cells are transformed by SV40 or are transfected with a plasmid encoding the SV40 Large T antigen. Inversion of the TGF-beta1 growth stimulation of NIH3T3 cells is not observed when these cells are transfected with plasmids expressing either a mutant Large T, unable to bind P53, or the E1A adenovirus oncoprotein which binds the retinoblastoma protein pRB but not P53. But when the TGF-beta1-growth stimulated cells are transfected with a plasmid expressing a mutant form of Large T capable of binding to P53, but not to pRB, or with one expressing the E1B-55 kD adenovirus oncoprotein, which also binds to P53 but not to pRB, the cells are growth-inhibited by TGF-beta1. The cdk inhibitor p21Waf is decreased in TGF-beta1-stimulated NIH3T3 fibroblasts and increased in TGF-beta1-inhibited SV40-transformed cells. Finally, we show that T12 fibroblasts, from a P53 knockout mouse, are growth inhibited by TGF-beta1 and that they remain so upon transfection with a P53 which is mutant at restrictive temperature, but become growth-stimulated by this factor at permissive temperature when P53 is functional. These data strongly suggest that growth-stimulation of fibroblasts by TGF-beta1 depends on the presence of a functional P53 protein and that inversion of this response occurs if P53 is absent or inactivated.

3T3 Cells↗
PubMed1977

Effect of medium composition on protein degradation and DNA synthesis in rat embryo fibroblasts.

Fibroblasts in medium deficient in serum, amino acids, phosphate, or glucose stop synthesizing DNA and increase the rate of degradation of their long-lived cellular proteins approximately 2-fold. There is no difference in the rate of degradation of short-lived proteins under these conditions. Insulin, dexamethasone, and fibroblast growth factor act synergistically to inhibit protein degradation and to stimulate thymidine incorporation to about the same extent as serum. When the medium content in serum or fibroblast growth factor is varied over a wide range, there is a close, inverse correlation between the rate of protein degradation and the extent of thymidine incorporation. When serum is added to cells that have been deprived of serum, the inhibition of protein degradation is immediate whereas the enhanced rate of protein degradation in serum-free medium is attained within 1 hr after serum removal. A 30-min exposure to serum followed by incubation in serum-free medium was as effective as continuous exposure to serum in stimulating thymidine incorporation after 8-24 hr.

Animals↗
PubMed1992

Sodium vanadate, a tyrosine phosphatase inhibitor, affects expression of hematopoietic growth factors and extracellular matrix RNAs in SV40-transformed human marrow stromal cells.

Protein tyrosine kinases represent a subset of proteins that mediate signal transduction between the extracellular environment and the nucleus. We have previously described a coordinated upregulation between RNA transcripts of a tyrosine kinase, c-abl, and those of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 6 (IL-6) in human marrow stromal cells (SVMSC). Moreover, an inverse relationship exists between expression of c-abl transcripts and those of extracellular matrix proteins such as type collagen I transcripts. In the present study, these inverse relationships were again seen in SVMSC when tyrosine kinase effects were enhanced by treatment of the cells with the tyrosine phosphatase inhibitor sodium orthovanadate. This suggests that tyrosine kinases are involved in the coordinate regulation of these genes.

Bone Marrow Cells↗
PubMed1989

Modification of tissue-factor mRNA and protein response to thrombin and interleukin 1 by high glucose in cultured human endothelial cells.

Because diabetic vascular disease is accompanied by a state of hypercoagulability, manifested by increased thrombin activity and foci of intravascular coagulation, we investigated whether a specific procoagulant property of the endothelium--production and surface expression of tissue factor--is modified by elevated glucose concentrations. In unperturbed human vascular endothelial cells, tissue factor mRNA and expression of the functional protein were undetectable and were not induced by 10-12 days of exposure to 30 mM glucose. In thrombin-stimulated cultures, tissue-factor expression was related inversely to cellular density, with confluent cultures producing (per 10(5) cells) half the amount of tissue factor measured in sparse cultures. Cells exposed to high glucose and studied when cell number and thymidine incorporation were identical to control cells manifested increased tissue-factor mRNA level and functional protein production in response to thrombin (P = .002). This effect was not attributable to hypertonicity and was not observed after short exposure to high glucose. In contrast, the tissue-factor response to interleukin 1, a modulator of endothelial function in the context of host defense, was decreased in cells cultured in high glucose (P = .04). These findings indicate that exposure to high glucose can alter tissue-factor gene expression in perturbed vascular endothelium. The reciprocal effects of high glucose on the tissue-factor response to thrombin and interleukin 1 points to different pathways of tissue-factor stimulation by the two agents and suggests functional consequences pertinent to the increased thrombin activity and compromised host-defense mechanisms observed in diabetes.

Cells, Cultured↗
PubMed1987

Cellular factors couple recombination with growth phase: characterization of a new component in the lambda site-specific recombination pathway.

Here we characterize FIS (factor for inversion stimulation), a new cellular component of the lambda site-specific recombination pathway. This host protein binds to a specific region in the lambda attP overlapping the Xis binding sites and can bind cooperatively with Xis to these sites. FIS stimulates lambda excision up to 20-fold in vitro in the presence of suboptimal Xis concentrations, but has no effect in the presence of saturating Xis; FIS has no effect on integrative recombination. FIS can replace one Xis molecule in a series of cooperative and competitive interactions but cannot carry out excision in the absence of Xis. FIS's role in the regulation of recombination has been inferred from in vivo modification of DNA. In exponentially growing cells the lambda FIS site is fully occupied, whereas in stationary-phase cells this binding site is vacant.

Bacteriophage lambda↗
PubMed1987

Genetic functions promoting homologous recombination in Escherichia coli: a study of inversions in phage lambda.

We have studied homologous recombination in a derivative of phage lambda containing two 1.4-kb repeats in inverted orientation. Inversion of the intervening 2.5-kb segment occurred efficiently by the Escherichia coli RecBC pathway but markedly less efficiently by the lambda Red pathway or the E. coli RecE or RecF pathways. Inversion by the RecBCD pathway was stimulated by Chi sites located to the right of the invertible segment; this stimulation decreased exponentially by a factor of about 2 for each 2.2 kb between the invertible segment and the Chi site. In addition to RecA protein and RecBCD enzyme, inversion by the RecBC pathway required single-stranded DNA binding protein, DNA gyrase, DNA polymerase I and DNA ligase. Inversion appeared to occur either intra- or intermolecularly. These results are discussed in the framework of a current molecular model for the RecBC pathway of homologous recombination.

Bacteriophage lambda↗
PubMed2000

The regulation of the Escherichia coli mazEF promoter involves an unusual alternating palindrome.

The Escherichia coli mazEF system is a chromosomal "addiction module" that, under starvation conditions in which guanosine-3',5'-bispyrophosphate (ppGpp) is produced, is responsible for programmed cell death. This module specifies for the toxic stable protein MazF and the labile antitoxic protein MazE. Upstream from the mazEF module are two promoters, P(2) and P(3) that are strongly negatively autoregulated by MazE and MazF. We show that the expression of this module is positively regulated by the factor for inversion stimulation. What seems to be responsible for the negative autoregulation of mazEF is an unusual DNA structure, which we have called an "alternating palindrome." The middle part, "a," of this structure may complement either the downstream fragment, "b," or the upstream fragment, "c". When the MazE.MazF complex binds either of these arms of the alternating palindrome, strong negative autoregulation results. We suggest that the combined presence of the two promoters, the alternating palindrome structure and the factor for inversion stimulation-binding site, all permit the expression of the mazEF module to be sensitively regulated under various growth conditions.

Antitoxins↗
PubMedDate not supplied

Diet, blood pressure, and multicollinearity.

Recent reports of an inverse association between dietary calcium intake and hypertension stimulated this analysis of the relationship of blood pressure to more than 20 dietary factors among a group of 8000 Japanese men in Hawaii. Reported intakes of potassium, calcium, protein, and milk were all inversely associated with blood pressure levels when examined one at a time while controlling for other risk factors. Alcohol intake was directly associated with blood pressure, and was treated as a confounding variable in the analysis. The association of potassium intake with blood pressure was relatively stronger than the associations for other nutrients, but the intake of potassium was so highly correlated with intakes of calcium, milk, and protein that it was not statistically possible to identify the independent association of potassium and blood pressure. Calcium intake was strongly correlated with milk and potassium intakes, and only calcium from dairy sources was associated with blood pressure. These data thus indicate that several dietary factors are inversely related to blood pressure levels independently of other risk factors such as age, body mass, and alcohol intake. The high degree of intercorrelation (multicollinearity) among these dietary factors, however, indicates that the independent role of any specific nutrient cannot be conclusively separated from the possible effects of other nutrients in this type of study.

Adult↗
PubMed1998

Requirement of GM2 ganglioside activator for phospholipase D activation.

Sequence analysis of a heat-stable protein necessary for the activation of ADP ribosylation factor-dependent phospholipase D (PLD) reveals that this protein has a structure highly homologous to the previously known GM2 ganglioside activator whose deficiency results in the AB-variant of GM2 gangliosidosis. The heat-stable activator protein indeed has the capacity to enhance enzymatic conversion of GM2 to GM3 ganglioside that is catalyzed by beta-hexosaminidase A. Inversely, GM2 ganglioside activator purified separately from tissues as described earlier [Conzelmann, E. & Sandhoff, K. (1987) Methods Enzymol. 138, 792-815] stimulates ADP ribosylation factor-dependent PLD in a dose-dependent manner. At higher concentrations of ammonium sulfate, the PLD activator protein apparently substitutes for protein kinase C and phosphatidylinositol 4,5-bisphosphate, both of which are known as effective stimulators of the PLD reaction. The mechanism of action of the heat-stable PLD activator protein remains unknown.

Amino Acid Sequence↗
PubMed1995

The role of the epidermal growth factor receptor in human gliomas: II. The control of glial process extension and the expression of glial fibrillary acidic protein.

Our earlier investigations of the biology of the epidermal growth factor receptor (EGFR) in human gliomas demonstrated that the level of EGFR expression did not directly predict the glioma growth response to EGF, suggesting that the function of the EGFR in glioblastomas might not be limited to mediating the growth effects of EGF. We conducted the current studies to investigate the function(s) of the EGFR not related to growth control in human gliomas. These investigations show that the EGFR mediates the stimulative effects of EGF on glial process extension and glial fibrillary acidic protein (GFAP) expression. In addition, the level of EGFR expression correlates inversely with glioma cell responsiveness to differentiation promoting agents (for example, nerve growth factor and transforming growth factor-beta) that act through transmembrane tyrosine kinase receptors. Thus, glioma lines with a high level of EGFR expression (for example, T-98G cells) responded to fewer differentiation promoting factors than lines with a low level of EGFR expression (such as U-373MG cells). Our results suggest that the EGFR in gliomas may participate in mediating the process extension and GFAP stimulative effects of both EGF and other differentiation promoting agents. These properties represent components of the differentiated state in glia because their expression is stimulated by dibutyryl cyclic adenosine monophosphate in normal astrocytes. The involvement of the EGFR in the expression of these glial specific properties suggests that the EGFR may play an important role in glial differentiation.

Animals↗
PubMed1996

Effects of a factor derived from polymorphonuclear leukocytes on the growth and collagen metabolism in normal and scleroderma skin fibroblast cultures.

Effects of a factor (15 kDa) derived from polymorphonuclear leukocytes (PMNs) on the growth and collagen metabolism of normal and scleroderma skin fibroblasts in culture were investigated. Skin fibroblasts from papillary, reticular or whole dermis of 5 patients with scleroderma and 7 normal controls were cultured in the presence or absence of PMN factor. The factor affected skin fibroblasts, (i) to stimulate cell proliferation, (ii) to stimulate collagenase production as observed by its functional activity, but (iii) to suppress collagen production with little effect on collagen types at a stage before the translational level. Scleroderma fibroblasts were less susceptible to the factor than normal fibroblasts in terms of cell proliferation and protein synthesis including collagen. Stimulation of cell proliferation by the factor was higher with reticular cells than papillary cells, while stimulation of collagenase production was inversely high in papillary cells and little stimulation was noted with reticular cells. Suppression of collagen production was also eminent in papillary cells, compared with that in reticular cells. These results suggest that PMNs function at the inflammatory stage in shifting tissue metabolism to a catabolic phase by releasing a factor which stimulates connective tissue cells, and that decreased susceptibility of scleroderma cells and reticular cells to PMN factor may provide for a positive factor in the accumulation of collagen in the reticular dermis of scleroderma skin.

Cell Division↗
PubMed2002

Blood-brain barrier breakdown in septic encephalopathy and brain tumours.

Septic encephalopathy is associated with breakdown of the blood-brain barrier and cerebral oedema. These features are also common properties of brain tumours. Perimicrovessel oedema, disruption of associated astrocyte end feet and neuronal injury occur in a porcine model of acute septic encephalopathy. The adrenergic system has been implicated in the inflammatory response to sepsis and may play a role in controlling blood-brain barrier permeability, since the beta2-adrenoceptor agonist dopexamine inhibits perimicrovessel oedema formation whereas the alpha1-adrenoceptor agonist methoxamine provokes it. Electron microscopy revealed tight junction opening in high-grade astrocytoma microvessels. Expression of the tight junction protein occludin is reduced in these microvessels and this reduction is inversely correlated with the degree of cerebral oedema. Normal astrocytes secrete factors that induce barrier properties in endothelial cells, whereas high-grade astrocytomas secrete vascular endothelial growth factor, which stimulates angiogenesis, down regulates occludin and increases endothelial cell permeability. The water channel protein aquaporin-4 is normally expressed in astrocyte foot processes around cerebral microvessels. Its expression is massively up-regulated in high-grade astrocytoma and around metastatic adenocarcinoma. There is a significant correlation between aquaporin-4 expression and the degree of cerebral oedema, but it is not clear whether increased aquaporin-4 expression enhances oedema formation or clearance. These results suggest that the pathophysiology of brain oedema is multifactorial, but that there may be common processes operating regardless of the aetiology.

Aquaporin 4↗