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Query: UNIPROT:P06889 (Mol)
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Knowledge of the pattern of nucleotide substitution is important both to our understanding of molecular sequence evolution and to reliable estimation of phylogenetic relationships. The method of parsimony analysis, which has been used to estimate substitution patterns in real sequences, has serious drawbacks and leads to results difficult to interpret. In this paper a model-based maximum likelihood approach is proposed for estimating substitution patterns in real sequences. Nucleotide substitution is assumed to follow a homogeneous Markov process, and the general reversible process model (REV) and the unrestricted model without the reversibility assumption are used. These models are also applied to examine the adequacy of the model of Hasegawa et al. (J. Mol. Evol. 1985;22:160-174) (HKY85). Two data sets are analyzed. For the psi eta-globin pseudogenes of six primate species, the REV models fits the data much better than HKY85, while, for a segment of mtDNA sequences from nine primates, REV cannot provide a significantly better fit than HKY85 when rate variation over sites is taken into account in the models. It is concluded that the use of the REV model in phylogenetic analysis can be recommended, especially for large data sets or for sequences with extreme substitution patterns, while HKY85 may be expected to provide a good approximation. The use of the unrestricted model does not appear to be worthwhile.
J Mol Evol 1994 Jul
PMID:Estimating the pattern of nucleotide substitution. 806 67

The immediate-early gene c-fos (a nuclear transcription factor) has been viewed as a nuclear "third messenger" or cellular "master switch." Both in vitro and in vivo studies have suggested that the proenkephalin (Penk) and tyrosine hydroxylase (TH) genes are potential targets of this immediate-early gene. We investigated the relationships between the activation of the c-fos gene and the activation of the Penk and TH genes in both rat hippocampus and adrenal using a commonly used model, metrazole (MTZ)-induced convulsions. The administration of MTZ produced a sequential elevation in c-fos, preproenkephalin (PPenk), and TH mRNAs. One hour after MTZ administration, c-fos mRNA was increased about 10-fold in rat hippocampus and about 5-fold in rat adrenal, without a significant change in spinal cord levels. Immunocytochemistry revealed that Fos-like immunoreactivity was greatly increased in both hippocampus and adrenal medulla at 3 hr after MTZ administration. The levels of PPenk and TH mRNAs were significantly increased (5-fold and 3-fold, respectively) in the adrenal 6 hr after MTZ treatment. The effects of MTZ on c-fos, PPenk, and TH mRNAs were dose dependent in both adrenal and hippocampus. In the adrenal, both the basal levels and the MTZ induction of PPenk mRNA were significantly attenuated by hypophysectomy (hypox) and were partially reinstated by adrenocorticotropic hormone (ACTH) replacement. In contrast, the basal levels of c-fos and TH mRNAs were not altered in hypox rat adrenal. ACTH treatment completely blocked the MTZ induction of adrenal c-fos mRNA and the subsequent induction of Fos-like immunoreactivity, whereas MTZ increased PPenk and TH mRNAs nearly 3-fold. Thus, in hypox rats MTZ can increase adrenal c-fos and TH mRNA levels without a corresponding increase in PPenk mRNA, whereas in ACTH-treated rats PPenk and TH mRNA levels in adrenal can be increased by MTZ without a preceding increase in c-fos mRNA. The MTZ induction of c-fos appears neither sufficient nor always necessary for the subsequent MTZ induction of Penk and TH gene expression. We conclude that c-fos, Penk, and TH genes can be differentially regulated in the adrenal of hypox rats or animals treated with ACTH, although they are co-localized in the same medullary cells.
Mol Pharmacol 1993 Aug
PMID:Metrazole induces the sequential activation of c-fos, proenkephalin, and tyrosine hydroxylase gene expression in the rat adrenal gland: modulation by glucocorticoid and adrenocorticotropic hormone. 810 82

More than an order of magnitude difference in substitution rate exists among sites within hypervariable region 1 of the control region of human mitochondrial DNA. A two-rate Poisson mixture and a negative binomial distribution are used to describe the distribution of the inferred number of changes per nucleotide site in this region. When three data sets are pooled, however, the two-rate model cannot explain the data. The negative binomial distribution always fits, suggesting that substitution rates are approximately gamma distributed among sites. Simulations presented here provide support for the use of a biased, yet commonly employed, method of examining rate variation. The use of parsimony in the method to infer the number of changes at each site introduces systematic errors into the analysis. These errors preclude an unbiased quantification of variation in substitution rate but make the method conservative overall. The method can be used to distinguish sites with highly elevated rates, and 29 such sites are identified in hypervariable region 1. Variation does not appear to be clustered within this region. Simulations show that biases in rates of substitution among nucleotides and non-uniform base composition can mimic the effects of variation in rate among sites. However, these factors contribute little to the levels of rate variation observed in hypervariable region 1.
J Mol Evol 1993 Dec
PMID:Substitution rate variation among sites in hypervariable region 1 of human mitochondrial DNA. 811 14

In this study we investigate the 57 kD heat shock protein of Chlamydia trachomatis for potential HLA-B27 restricted T cell epitopes. This protein is known to elicit T cell immunity, as judged by delayed type hypersensitivity. We synthesized 24 peptides containing the B27 anchor amino acid arginine at position 2, according to the rules previously described for peptide binding to MHC class I molecules. The nonamer peptides were tested in an in vitro assembly assay; six out of the 24 peptides bind to HLA-B27 although their sequences only partially match the HLA-B27 binding motif. Two of these six peptides carry negatively charged amino acids which apparently fit into the P1 pocket and in three out of the six a positively charged amino acid fits into the P3 pocket. In addition, two octamer peptides stabilized the HLA-B27 molecule without containing an appropriate amino or carboxy terminus. Therefore our data suggest that current binding rules will need to be refined before they can be used to accurately predict potential T cell epitopes. Furthermore our HLA-B27-binding peptides should prove useful probes for the study of the processing and presentation of this bacterial antigen, and of changes in the T cell repertoire induced by this form of infection.
Mol Immunol 1994 Apr
PMID:HLA-B27 binding peptides derived from the 57 kD heat shock protein of Chlamydia trachomatis: novel insights into the peptide binding rules. 815 35

Apomyoglobin adopts a partly folded intermediate conformation (I), sometimes referred to as a molten globule intermediate, near pH 4. To determine which histidine residues trigger this partial unfolding reaction, we made mutants in which nine of the twelve histidine residues in the protein are substituted individually. We then measured acid and urea-induced unfolding curves for these substituted proteins. Two acid unfolding transitions are observed: native (N) to intermediate (I), and I to unfolded (U). These data were fitted using a simple three-state model which has been shown to give an adequate description of acid and urea-induced unfolding of wild-type apomyoglobin. The aim is to quantify changes in the apparent standard Gibbs energy differences between N, I and U, as well as the unfolding mechanism, that result from these substitutions, and to test how well the model fits data for substituted proteins. In most cases, the model fits the data reasonably well, and significant changes in fitted unfolding parameters of various mutants are also clearly visible in the primary data. The following conclusions are drawn. (1) Histidines 24 and 119 synergistically stabilize native apomyoglobin (N) at pH 8, but together destabilize N as pH is decreased below seven. (2) Histidine 36 stabilizes N when it is protonated. (3) Histidine substitutions in the heme-binding pocket (residues 64, 93 and 97) have little effect on the stability of N, suggesting that the heme-binding pocket is open. (4) Histidine substitutions affect the N to I transition but have little effect on the I to U transition. (5) The simple model we use to describe the unfolding of apomyoglobin cannot account for all the data, particularly the effects of the H36Q mutation. The effect of protonated histidine 36 on stabilizing N is not included in the model. We suggest that breaking the hydrogen bond between histidines 24 and 119 by protonation when the pH is decreased from 6 to 4 is an important part of triggering the partial unfolding of N to I, and likewise that formation of the hydrogen bond between histidines 24 and 119 may be a rate-determining step in the kinetic process of forming N from I during refolding.
J Mol Biol 1994 Apr 15
PMID:Molecular mechanisms of acid denaturation. The role of histidine residues in the partial unfolding of apomyoglobin. 815 39

The ICL1 gene encoding isocitrate lyase was cloned from the dimorphic fungus Yarrowia lipolytica by complementation of a mutation (acuA3) in the structural gene of isocitrate lyase of Escherichia coli. The open reading frame of ICL1 is 1668 bp long and contains no introns in contrast to currently sequenced genes from other filamentous fungi. The ICL1 gene encodes a deduced protein of 555 amino acids with a molecular weight of 62 kDa, which fits the observed size of the purified monomer of isocitrate lyase from Y. lipolytica. Comparison of the protein sequence with those of known pro- and eukaryotic isocitrate lyases revealed a high degree of homology among these enzymes. The isocitrate lyase of Y. lipolytica is more similar to those from Candida tropicalis and filamentous fungi than to Saccharomyces cerevisiae. This enzyme of Y. lipolytica has the putative glyoxysomal targeting signal S-K-L at the carboxy-terminus. It contains a partial repeat which is typical for eukaryotic isocitrate lyases but which is absent from the E. coli enzyme. Surprisingly, deletion of the ICL1 gene from the genome not only inhibits the utilization of acetate, ethanol, and fatty acids, but also reduces the growth rate on glucose.
Mol Gen Genet 1993 Nov
PMID:Cloning of the isocitrate lyase gene (ICL1) from Yarrowia lipolytica and characterization of the deduced protein. 824 96

We have previously reported that the administration of metrazole (MTZ) produces a sequential, dose-dependent induction of c-fos and proenkephalin (Penk) gene expression in the rat hippocampus and adrenal. The adrenal is more sensitive to induction of these genes by MTZ. In the present study, we have compared the induction of c-fos and Penk in the hippocampus and adrenal, and examined the consequences of selected pharmacological manipulations. Treatment with LY274614, a competitive NMDA-receptor antagonist, blocked MTZ-induced convulsions and the MTZ-induction of c-fos and PPenk mRNAs in the hippocampus, and PPenk mRNA in the adrenal. However, in the adrenal the MTZ-induction of c-fos was only partially inhibited by LY274614. A combination of peripheral acting cholinergic antagonists (chlorisondamine plus methylatropine) prevented the MTZ-induction of adrenal c-fos and PPenk mRNA without significant alterations in the MTZ-induction of hippocampal c-fos mRNA or convulsions. Trifluoperazine, a calcium/calmodulin inhibitor, attenuated the MTZ-induction of c-fos mRNA while potentiating the MTZ-induction of PPenk mRNA in both the hippocampus and the adrenal. These results demonstrate that the MTZ induction of c-fos and Penk gene expression in the rat adrenal can be modulated by drugs acting in the CNS at NMDA receptors, in the periphery at postsynaptic cholinergic receptors and intracellularly at the calcium/calmodulin signal transduction pathway. Furthermore, we provide additional evidence that MTZ-induction of c-fos and Penk mRNAs can be dissociated by drugs acting at these sites.
Brain Res Mol Brain Res 1993 Oct
PMID:Metrazole induction of c-fos and proenkephalin gene expression in the rat adrenal and hippocampus: pharmacological characterization. 825 73

A transcriptional initiator (Inr) for mammalian RNA polymerase II can be defined as a DNA sequence element that overlaps a transcription start site and is sufficient for (i) determining the start site location in a promoter that lacks a TATA box and (ii) enhancing the strength of a promoter that contains a TATA box. We have prepared synthetic promoters containing random nucleotides downstream of Sp1 binding sites to determine the range of DNA sequences that convey Inr activity. Numerous sequences behaved as functional Inrs in an in vitro transcription assay, but the Inr activities varied dramatically. An examination of the functional elements revealed loose but consistent sequence requirements, with the approximate consensus sequence Py Py A+1 N T/A Py Py. Most importantly, almost every functional Inr that has been described fits into the consensus sequence that we have defined. Although several proteins have been reported to bind to specific Inrs, manipulation of those elements failed to correlate protein binding with Inr activity. The simplest model to explain these results is that all or most Inrs are recognized by a universal binding protein, similar to the functional recognition of all TATA sequences by the same TATA-binding protein. The previously reported proteins that bind near specific Inr elements may augment the strength of an Inr or may impart transcriptional regulation through an Inr.
Mol Cell Biol 1994 Jan
PMID:DNA sequence requirements for transcriptional initiator activity in mammalian cells. 826 80

Felsenstein's maximum-likelihood approach for inferring phylogeny from DNA sequences assumes that the rate of nucleotide substitution is constant over different nucleotide sites. This assumption is sometimes unrealistic, as has been revealed by analysis of real sequence data. In the present paper Felsenstein's method is extended to the case where substitution rates over sites are described by the gamma distribution. A numerical example is presented to show that the method fits the data better than do previous models.
Mol Biol Evol 1993 Nov
PMID:Maximum-likelihood estimation of phylogeny from DNA sequences when substitution rates differ over sites. 827 61

The effect of a previous exposure to hyperbaric oxygen (HBO) on the synthesis capacity of prostaglandin (PG) and thromboxane (TX) was investigated in the brain of male rats. Three groups of rats were used: 1. Neurotoxic HBO (n = 11): The rats were exposed to sixfold the atmospheric pressure (101.3 kPa), i.e., 6 absolute atmospheres (ATA), of pure O2 up to the first convulsion (6 ATA O2); 2. Mild hyperoxia (n = 10): The rats were exposed to compressed air at the same absolute pressure and for a similar time than that of the neurotoxic HBO group (here PO2 is 1.26 ATA); 3. Normoxia at atmospheric pressure (PO2 is 0.21 ATA) for control. There was no convulsion in groups 2 and 3. Decompression of the high pressure groups lasted 15 min. After decapitation, samples of the frontal cortex and the striatum were taken, weighed, washed, and then incubated in Krebs-Ringer bicarbonate for 1 h. The release of eicosanoids in the medium was determined by enzyme immunoassay. Mild hyperoxia only significantly reduced in the striatum the release of 6-keto-PGF1 alpha (1.3 +/- 2.4 vs 10.9 +/- 6.6 pg/mg wet tissue, p < 0.001; mean +/- SD) and PGE2 (3.2 +/- 2.7 vs 7.8 +/- 6.5 pg/mg wet tissue, p < 0.05), whereas TXB2 did not change.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Chem Neuropathol 1993 Oct
PMID:Effect of hyperbaric oxygen on prostaglandin and thromboxane synthesis in the cortex and the striatum of rat brain. 829 21


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