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Query: UNIPROT:P06889 (Mol)
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Six R sequences have been described as members of a new family of dispersed repetitive DNA in the mouse genome (Gebhard et al., 1982). Several sequenced regions were extended in the 5' direction (R1, R2 and R6) and two new sequences were determined (R7 and R8). On the basis of our sequence and blot hybridization data it is concluded that the R sequence are adjacent to the so-called small Bam family (Fanning, 1982), which in turn runs into the MIF sequence part (Brown & Piechaczyk, 1983) of the large Bam sequences (Meunier-Rotival et al., 1982). In one of our clones a sequence of 1290 base-pairs comprises MIF, Bam and R sequences in a contiguous arrangement which seems to be characteristic of the long repeat unit of the mouse genome. Several repeat units were found to be truncated within their Bam or R sequence parts. Evidence is also reported for transposition events involving R sequences; for instance of one R sequence (R1) into another (R7). Two R sequences (R1 and R4) have apparently been transposed together with part of the adjacent Bam sequences. Truncation and transposition events may also explain the imbalance of copy numbers within the large repeat unit (25,000 to 50,000 for the small Bam sequences and 100,000 for the R sequences). The spreading of R sequences and other interspersed DNA sequences within the mouse genome may have occurred by transposition events on the DNA level and/or by transcription, retrotranscription and insertion processes.
J Mol Biol 1983 Oct 25
PMID:Organization of the R family and other interspersed repetitive DNA sequences in the mouse genome. 631 40

The free energy of the binding reaction between EcoRI restriction endonuclease and a specific cognate dodecadeoxynucleotide (d(CGCGAATTCGCG)) has contributions from both electrostatic and nonelectrostatic components. These contributions were dissected by measuring the effects of varying salt concentration on the equilibrium binding constant and applying the thermodynamic analyses of Record et al. (Record, M. T., Jr., Lohman, T. M., and deHaseth, P. L. (1976) J. Mol. Biol. 107, 145-158). Endonuclease mutation S187 (Arg 187 to Ser) (Greene, P. J., Gupta, M., Boyer, H. W., Brown, W. E., and Rosenberg, J. M. (1981) J. Biol. Chem. 256, 2143-2153) did not significantly affect the nonelectrostatic component but did perturb the electrostatic contribution to the binding energy (we are numbering the amino acid residues according to the DNA sequence). The former was determined by extrapolating the linear portion of the salt dependence curve (0.125 to 0.25 M KCl) to 1 M ionic strength, with the same result for both wild type and S187 endonucleases at both pH 6.0 and 7.4 (-8.5 +/- 1.5 kcal/mol or greater than 50% of the total binding free energy). The slopes of these same curves yield estimates of eight ionic interactions between wild type endonuclease and the DNA at both pH values. By contrast, binding of EcoRI-S187 to dodecanucleotide involves six charge-charge interactions at pH 6.0. Only two ionic interactions are observed at pH 7.4. This was unexpected since gel permeation chromatography demonstrated that the recognition complex for both wild type and S187 proteins contains an enzyme dimer and a DNA duplex. EcoRI-S187 endonuclease retains wild type DNA sequence specificity, and the rate of the phosphodiester hydrolysis step is also unchanged. Thus, electrostatic interactions are functionally separable from sequence recognition and strand cleavage. Our results also establish that arginine 187 plays a key role in the electrostatic function and suggest that it might be located at the DNA-protein interface. The disproportionate loss of ion pairs at pH 7.4 can be rationalized by a model which suggests that six conformationally mobile ionic groups on the protein act in a coordinated manner during the interaction with DNA.
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PMID:Coordinate ion pair formation between EcoRI endonuclease and DNA. 631 32

Sixteen single point mutations near the beginning of the lacZ gene have been isolated and their effect on lacZ expression has been measured. Five mutations were obtained that alter a potential stem-and-loop structure in the messenger RNA that masks the initiation codons. Formation of this stem-and-loop is a result of transcription of DNA sequences introduced during the cloning of the lac regulatory region. The mutations isolated were then moved into a background that deleted this structure. Analysis of these mutations indicated that the secondary structure inhibited lacZ expression 5.8-fold and that either single point mutations or a 9 base-pair deletion could relieve this inhibition completely. In addition, it was found that an A to C transversion in the first base following the initiation codon (in the absence of the inhibitory secondary structure) decreases lacZ expression almost twofold, whereas C to U transitions in the next two positions have negligible effects. Mutations were also obtained that either increase or decrease the length of the Shine-Dalgarno sequence. The effects of these mutations were studied in the presence or absence of the secondary structure that involves the two initiation codons. It was found that when translation initiation was inhibited by the secondary structure, increasing the length of the Shine-Dalgarno sequence increased lacZ expression 2.8-fold and decreasing the length of this sequence reduced lacZ expression 12-fold. When translation initiation was not inhibited by the secondary structure, increasing the length of the Shine-Dalgarno sequence had no effect and decreasing the length of this sequence only reduced lacZ expression sixfold. The mechanistic implications of these results are discussed. Two initiation codons are located in the beginning of the lacZ gene, 7 and 13 bases from the Shine-Dalgarno sequence. NH2-terminal sequence analysis indicated that the majority of the protein synthesized initiate at the first initiation codon in the wild-type lacZ gene (in agreement with results reported previously by J. L. Brown and his colleagues). Upon introduction of sequences that result in a change in the mRNA secondary structure, both initiation codons are used in almost equal amounts. Three mutations and two pseudorevertants were obtained, which are located in the first initiation codon. It was found that when the first initiation codon is changed from AUG to GUG, translation initiation is decreased tenfold at that codon.(ABSTRACT TRUNCATED AT 400 WORDS)
J Mol Biol 1984 Aug 25
PMID:lacZ translation initiation mutations. 643 47

In this paper I lay a quantitative theoretical groundwork for understanding the proportions of the possible types of base substitutions observed between 12 genes sharing a common ancestor and isolated from extant species. The experimentally observed types of base substitution between two sequenced genes do not give a direct measure of the types of base substitutions that occur during evolutionary descent. However, by use of a statistical assemblage of these observations, we can recover, without the assumption of parsimony, the conditional base substitution probabilities that determine this descent. Three methods - direct count, regression, and informational entropy maximization - are described by which these probabilities can be estimated from experimental data. The methods are complementary in that each is most useful for somewhat different types of experimental data. These methods are used to study the ratio of transversions to transitions during gene divergence. Though this ratio is not constant during divergence, it does approach a stable limiting value that in principle can vary from zero, corresponding to 100% transition differences, to infinity, corresponding to 0% transition differences. In practice the limiting ratio tends to hover around a value of two, which is expected on a random basis. However, base substitution pathways that are very nonrandom also may lead to a limiting ratio of exactly two, so that such a value is not diagnostic for random pathways. The limiting ratio can be directly calculated from a knowledge of the twelve conditional probabilities for each type of base substitution, or from a knowledge of the equilibrium base composition of the DNAs compared. An expression is given for this calculation. Fifteen years ago Jean Derancourt, Andrew Lebor and Emile Zuckerkandl (1967), analyzing the amino acid sequence of globin chains coded by nuclear genes, made the original observation that the proportion of transition differences decreases with increasing evolutionary time. Recently Brown et al. (1982) and Brown and Simpson (1982) have reported a decrease in the observed proportion of transition differences in mitochondrial DNA with increasing evolutionary divergence. The conditions that must be satisfied for this type of behavior to occur at stable base composition and with stable base substitution probabilities are defined. Multiple substitutions per se do not lead to a decrease in transition differences with increasing evolutionary divergence.
J Mol Evol 1983
PMID:Transitions and transversions in evolutionary descent: an approach to understanding. 657 Dec 18

The dynamics of the substitution process for mammalian mitochondrial DNA have been modeled. The temporal behavior of several quantities has been studied and the model's predictions have been compared with estimates obtained from recent mtDNA sequence data for an increasingly divergent series of primates, the mouse and the cow (Anderson et al. 1981, 1982; Bibb et al. 1981; Brown et al. 1982). The results are consistent with the hypothesis that the decrease in the proportion of transitions observed as divergence increases is a consequence of the highly biased substitution process. In addition, the results support the hypothesis that, although a portion of the mtDNA molecule evolves at an extremely rapid rate, a significant portion of the molecule is under strong selective constraints.
Mol Biol Evol 1984 Sep
PMID:An analysis of the dynamics of mammalian mitochondrial DNA sequence evolution. 659 74

A method that relates molecular structure to the forces that maintain it and to its X-ray diffraction pattern is described and applied to muscle. In a computer model, the potential energy of the movable components (here the myosin heads) is minimized by letting them move down the steepest gradient in three dimensions from a variety of starting positions. Initial values are assumed for the parameters that determine the forces, and for those that define the structure and arrangement of the fixed components. The X-ray pattern expected from the resulting structures can be calculated in a straightforward manner and compared with relevant observed data. Discrepancies can then be minimized by varying the values initially assumed for the parameters, as in the conventional "trial and error" method. This first application of the present method is concerned with the effects of the hexagonal lattice on the myosin head configuration in thick filaments of the type found in vertebrate skeletal muscle. For that purpose, a very simple model was used with the following main features: smooth cylinders for the thin filaments and for the thick filament backbones, two spherical heads attached by Hookean springs to each point of a 9/3 helix on the surface of the backbone, and repulsive forces of the electrostatic double-layer type acting between each head and all other surfaces. The myosin head configuration was calculated for an isolated thick filament and a study was made of the effects of packing such filaments into a hexagonal lattice of various side spacings in the presence or absence of thin filaments. For the isolated filament, it was found that the 9/3 helical symmetry is maintained in the myosin head configuration and that the two heads of each molecule are splayed azimuthally. When such filaments are packed into the hexagonal lattice with thin filaments present, the 9/3 helical symmetry of the myosin head configuration is lost. As the lattice side spacing is reduced, the myosin heads become increasingly displaced not only in the radial and azimuthal directions but also in the axial direction, although they interact primarily with smooth cylinders. The axial separation of the two heads in each molecule becomes different in one level from that in the other two in the 43 nm axial repeat, thus increasing the repeat in projection onto the axis from 14.3 to 43 nm. This effect may contribute to the "forbidden meridionals" described by Huxley & Brown (1967).(ABSTRACT TRUNCATED AT 400 WORDS)
J Mol Biol 1984 Mar 25
PMID:Application of potential energy calculations to the determination of muscle structure from X-ray data with special reference to the configuration of myosin heads. 671 80

Six recessive second chromosomal mutants of Drosophila melanogaster exhibiting larval hypersensitivity to methyl methanesulfonate have been identified and assigned to six complementation groups. The strains have been analyzed for their sensitivities to UV, X-ray, nitrogen mustard and formaldehyde. Two classes of mutants not previously observed in Drosophila have been identified. The mus 204A1 and mus 205A1 mutants exhibit sensitivity to MMS and UV but not X-ray or nitrogen mustard, while the mus 206A1 and mus 207A1 mutants display sensitivity to MMS, UV, and nitrogen mustard. Four of the seven strains exhibit poor female fertility and two of these are shown to have a weak meiotic disjunctional defect. Biochemical studies of the mus 205A1 mutant suggest a defect in DNA synthetic ability associated with excision and postreplication repair performed on UV and alkylation-damaged templates (Boyd and Harris 1981; Brown and Boyd 1981 b; R.L. Dusenbery, manuscript in preparation).
Mol Gen Genet 1982
PMID:Mutagen sensitivity of Drosophila melanogaster. V. Identification of second chromosomal mutagen sensitive strains. 681 27

Allergen challenge of sensitized Brown-Norway (BN) rats results in increased excretion of cysteinyl-leukotrienes (cLTs) in bile. It is unclear whether this reflects an increased capacity of lung cells to synthesize 5-lipoxygenase products, and, if so, which cells are of primary importance. We have examined the effects of allergen challenge on the capacity of a mixture of isolated lung cells from ovalbumin (OA)-sensitized BN rats to synthesize LTs and other eicosanoids. Cells were isolated by enzymatic digestion of lung tissue before and either 6 or 24 h after challenge of sensitized rats with either OA or saline. A23187-induced synthesis of eicosanoids by these cells was measured using high-pressure liquid chromatography. OA challenge resulted in a significant influx of neutrophils into the lungs and a significant increase in the synthesis of 5-lipoxygenase products, in particular LTB4, by lung cells after 6 h. There was a positive correlation between the percentage of neutrophils in unfractionated lung cells and the amounts of LTB4 produced by these cells. OA challenge had little or no effect on the production of cLTs and the cyclooxygenase product 12-hydroxy-5,8,10-heptadecatrienoic acid. There was a significant increase in the infiltration of eosinophils into the lungs 24 h after OA challenge but no increase in the production of cLTs by lung cells at this time, suggesting that eosinophils from BN rats are unlikely to be the major site for the production of these substances. This was confirmed in experiments with partially purified eosinophils obtained from Sephadex-treated rats. In contrast, cLTs were major products of arachidonic acid metabolism by alveolar macrophages from BN rats. We conclude that allergen challenge results in an increased capacity of lung cells to synthesize 5-lipoxygenase products, in particular LTB4. Macrophages, rather than eosinophils, may be an important site for the synthesis of cLTs in BN rat lungs.
Am J Respir Cell Mol Biol 1995 Oct
PMID:Cellular infiltration and eicosanoid synthesis in brown Norway rat lungs after allergen challenge. 754 78

Brown adipose tissue is a mammalian thermogenic tissue. Its ability to dissipate energy as heat is due to a unique mitochondrial protein, uncoupling protein (UCP). Activation and expression of UCP is under control of the sympathetic nervous system acting through beta -adrenergic receptors (AR). In this study we used Siberian hamster brown adipocytes differentiated in vitro to investigate the expression of the fat specific beta 3-AR. Binding studies using the new labelled beta 3 adrenergic ligand [3H]SB 206606 showed a density of beta 3-AR in brown adipocyte plasma membranes comparable to that measured in vivo. beta 3-AR mRNA expression was very high in mature brown adipocytes and was started to be expressed during differentiation before UCP mRNA. Its half-life was approximately 50 min. Treatment of cells with non-specific beta adrenergic agonists, specific beta 3-adrenergic agonists, and dibutyryl cyclic AMP resulted in a marked down regulation of beta 3-AR mRNA level within several hours.
Mol Cell Endocrinol 1995 Apr 01
PMID:Control of beta 3-adrenergic receptor gene expression in brown adipocytes in culture. 766 82

We have cloned and characterized the 5'-flanking region of the gene encoding human squalene synthase. We report here the promoter activity of successively 5'-truncated sections of a 1 kilobase of this region by fusing it to the coding region of a luciferase reporter gene. DNA segments of 200 base pairs (bp) 5' to the transcription start site, as determined by primer extension analysis, show a strong promoter effect on the expression of the luciferase chimeric gene and a high response to the presence of sterols when transiently transfected into the human hepatoma cell line HepG2 or to the hamster-derived CHO-K1 cells. An approximately 50-fold induction of luciferase activity, in the absence of sterols, was observed in transiently transfected HepG2 cells for fusion constructs containing sections of 200, 459, and 934 bp of the putative human squalene synthase promoter. Loss of promoter activity and response to sterols was localized to a 69-bp section located 131 nucleotides 5' to the transcription start site. Sequence analysis of this region showed that it contained a sterol regulatory element 1 (SRE-1) previously identified in other sterol regulated genes (Smith, J. R., Osborne, T. F., Brown, M. S., Goldstein, J. L., and Gil, G. (1988). J. Biol. Chem. 263, 18480-18487) and two potential NF-1 binding sites. Additional CCAAT box, SRE-1 element, and two Sp1 sites were identified 3' to this section. Sequences within this 69-bp DNA, including the SRE-1 cis-acting element, show strong binding to the purified nuclear transcription factor ADD1 (Tonzonoz, P., Kim, J. B., Graves, R. A., and Spiegelman B. M. (1993) Mol. Cell Biol. 13, 4753-4759) by mobility shift assay and footprinting analyses.
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PMID:Molecular cloning and functional analysis of the promoter of the human squalene synthase gene. 766 18


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