Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED; OMIM *240300, also called APS 1,) is a rare autosomal recessive disorder that is more frequent in certain isolated populations. It is generally characterized by two of the three major clinical symptoms that may be present, Addison's disease and/or hypoparathyroidism and/or chronic mucocutaneous candidiasis. Patients may also have a number of other clinical symptoms including chronic gastritis, gonadal failure, and rarely, autoimmune thyroid disease and insulin-dependent diabetes mellitus. We and others have recently identified the gene for APECED, which we termed AIRE (for autoimmune regulator). AIRE is expressed in thymus, lymph nodes, and fetal liver and encodes a protein containing motifs suggestive of a transcriptional regulator, including two zinc finger motifs (PHD finger), a proline-rich region, and three LXXLL motifs. Six mutations, in cluding R257X, the predominant Finnish APECED allele, have been defined. R257X was also observed in non-Finnish APECED patients occurring on different chromosomal haplotypes suggesting different mutational origins. Here we present mutation analyses in an extended series of patients, mainly of Northern Italian origin. We have detected 12 polymorphisms, including one amino acid substitution, and two additional mutations, R203X and X546C, in addition to the previously described mutations, R257X, 1096-1097insCCTG, and a 13-bp deletion (1094-1106del). R257X was also the common mutation in the Northern Italian patients (10 of 18 alleles), and 1094-1106del accounted for 5 of 18 Northern Italian alleles. Both R257X and 1094-1106del were both observed in patients of four different geo-ethnic origins, and both were associated with multiple different haplotypes using closely flanking polymorphic markers showing likely multiple mutation events (six and four, respectively). The identification of common AIRE mutations in different APECED patient groups will facilitate its genetic diagnosis. In addition, the polymorphisms presented provide the tools for investigation of the involvement of AIRE in other autoimmune diseases, particularly those affecting the endocrine system.
Mol Endocrinol 1998 Aug
PMID:Common mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients of different origins. 971 37

We isolated a full-length cDNA that encodes ATP-dependent phosphoenolpyruvate carboxykinase (EC 4.1.1.49, PCK) from leaves of maize, an NADP-malic enzyme type C4 plant. The mRNA was specifically and rather abundantly expressed in bundle sheath cells in accordance with the recent finding of cell-type-specific localization of PCK protein in maize, which has been detected with antibodies against cucumber PCK protein. The predicted protein had an N-terminal extension, which is characteristic of plant PCKs. The transcript level was much higher in the daytime than at night in 14-day old seedlings. However, in 42-day old plants the extent of diurnal change decreased. The maize PCK was expressed in Escherichia coli with the pET32 plasmid and purified to homogeneity. Through digestion with enterokinase, two types of enzyme were prepared; one with an intact N-terminus and the other lacking its N-terminal 77 amino acid residues due to over-digestion. The truncated protein had about 2-fold higher specific activity than the intact one, and was inhibited by 3-phosphoglycerate (3-PGA) with an I0.5 of 17.5 mM. In contrast, the intact protein was almost insensitive to 3-PGA. These results strongly suggest that the intact N-terminal extension may be involved in the regulation of PCK activity in vivo through some modification such as reversible phosphorylation.
Plant Mol Biol 1999 Oct
PMID:cDNA cloning and characterization of maize phosphoenolpyruvate carboxykinase, a bundle sheath cell-specific enzyme. 1059 98

In Bacillus subtilis, the ComQXPA quorum-sensing system controls cell density-dependent phenotypes such as the production of degradative enzymes and antibiotics and the development of genetic competence. Bacillus subtilis (natto) NAF12, a mutant defective in poly-gamma-glutamate (gamma-PGA) production, was derived from B. subtilis (natto) NAF4 by Tn917-LTV1 insertional mutagenesis. Determination of the mutant DNA sequences flanking the Tn917-LTV1 insert revealed that the insertion had inactivated comP in this mutant, indicating that gamma-PGA synthesis in B. subtilis (natto) is under the control of the ComP-ComA signal transduction system. A comparison of the amino acid sequences revealed striking variation in the primary structures of ComQ (44% identity), ComX (26%) and the sensor domain of ComP (36%) between B. subtilis (natto) NAF4 and B. subtilis 168. In contrast, the amino acid and nucleotide sequences of the kinase domains of ComP and of the ComA response regulator share 95% and 100% identity respectively. The comP genes of NAF4 and 168 restored the impaired competence of B. subtilis BD1658 (comP:cat) and gamma-PGA production of B. subtilis (natto) NAF12 (comP:Tn917-LTV1) to only 15% of the level achieved by the respective parent comP genes. However, when introduced together with the cognate comQ and comX genes, the comP genes restored the relevant defect of the heterologous comP mutants nearly to wild-type levels. Analogous to the comCDE system of Streptococcus strains and the agrBCDE system of Staphylococcus aureus, the concerted variation in the comQXP genes appears to establish specific intercellular communication between B. subtilis strains sharing the same pheromone system.
Mol Microbiol 2000 Sep
PMID:Divergent structure of the ComQXPA quorum-sensing components: molecular basis of strain-specific communication mechanism in Bacillus subtilis. 1097 33

Prostaglandin A1 (PGA1) increases heat shock element (HSE)-mediated transcription, thereby enhancing expression of HSE-bearing genes, including heat shock proteins. Because we recently found functional HSEs in the human and rodent c-fos promoters, we hypothesized that PGA1 might increase c-fos expression through the HSE. In this study, we revealed that PGA1 induces c-fos expression at least partly by increasing the binding between heat shock factor-1 and the HSE, and that PGA1 enhances activity of activating protein-1 (AP-1). Interestingly, so far as PGA, is present in the medium, AP-1-mediated transcription enhanced by PGA1 cannot be detected by the standard luciferase reporter gene assay. Instead, it can be detected by either checking luciferase mRNA levels in the presence of PGA1 or measuring luciferase activities just after removal of PGA1. These results showed that protein products of some stress-responsive genes can increase, not during the stressful condition, but immediately after recovery from stress.
Mol Cell Endocrinol 2000 Jun
PMID:Prostaglandin A1 enhances c-fos expression and activating protein-1 activity. 1102 60

Prostaglandin A(2) (PGA(2)), an experimental chemotherapeutic agent, causes growth arrest associated with decreased cyclin D1 expression in several cancer cell lines. Here, using human non-small-cell lung carcinoma H1299 cells, we investigated the mechanisms whereby PGA(2) down-regulates cyclin D1 expression. Transcription rates of the cyclin D1 gene, studied using a cyclin D1 promoter-luciferase construct and nuclear run-on assays, were not affected by PGA(2) treatment. Instead, the cyclin D1 mRNA was rendered unstable after exposure to PGA(2). Since the stability of labile mRNA is modulated through binding of proteins to specific mRNA sequences, we sought to identify protein(s) recognizing the cyclin D1 mRNA. In electrophoretic mobility-shift assays using radiolabeled RNA probes derived from different regions of cyclin D1 mRNA, we observed that (i) lysates prepared from PGA(2)-treated cells exhibited enhanced protein-cyclin D1 RNA complex formation; (ii) the kinetics of complex formation correlated closely with that of cyclin D1 mRNA loss; and (iii) binding occurred within a 390-base cyclin D1 3' untranslated region (UTR) (K12). This binding activity could be cross-linked, revealing proteins ranging from 30 to 47 kDa. The RNA-binding protein AUF1, previously associated with the degradation of target mRNAs, bound cyclin D1 mRNA, because anti-AUF1 antibodies were capable of supershifting or immunoprecipitating cyclin D1 mRNA-protein complexes. Finally, insertion of K12 in the 3'UTR of reporter genes markedly reduced the expression and half-life of the resulting chimeric mRNAs in transfected, PGA(2)-treated cells. Our data demonstrate that PGA(2) down-regulates cyclin D1 expression by decreasing cyclin D1 mRNA stability and implicates a 390-base element in the 3'UTR in this regulation.
Mol Cell Biol 2000 Nov
PMID:Down-regulation of cyclin D1 expression by prostaglandin A(2) is mediated by enhanced cyclin D1 mRNA turnover. 1102 61

We describe prostaglandin (PG) biosynthesis by microsomal-enriched fractions of fat body prepared from true armyworms, Pseudaletia unipuncta. PG biosynthesis was sensitive to experimental conditions, including incubation time, temperature, pH, substrate and protein concentration. Optimal PG biosynthesis conditions included 1 mg of microsomal-enriched protein, incubated at 28 degrees C for 7.5 min at pH 8. These preparations yielded four major PGs: PGA(2), PGE(2), PGD(2) and PGF(2alpha). PGA(2) and PGE(2) were the predominant eicosanoids produced under these conditions. Two non-steroidal anti-inflammatory drugs, indomethacin and naproxen, effectively inhibited PG biosynthesis. Unlike other invertebrate PG biosynthetic systems studied so far, the true armyworm system appeared to be independent of the usual exogenous co-factors required by mammalian and other invertebrate systems. These findings are discussed with respect to PG biosynthesis in other invertebrate and vertebrate systems.
Insect Biochem Mol Biol 2001 Mar 15
PMID:Prostaglandin biosynthesis by fat body from true armyworms, Pseudaletia unipuncta. 1122 53

Neurotrophins influence growth and survival of sympathetic and sensory neurons through activation of their receptors, Trk receptor tyrosine kinases. Previously, we identified Src homology 2-B (SH2-B) and APS, which are structurally similar adapter proteins, as substrates of Trk kinases. In the present study, we demonstrate that both SH2-B and APS exist in cells as homopentamers and/or heteropentamers, independent of Trk receptor activation. Structure-function analyses revealed that the SH2-B multimerization domain resides within its amino terminus, which is necessary for SH2-B-mediated nerve growth factor (NGF) signaling. Overexpression of SH2-B enhances both the magnitude and duration of TrkA autophosphorylation following exposure of PC12 cells to NGF, and this effect requires the amino-terminal multimerization motif. Moreover, the amino terminus of SH2-B is necessary for TrkA/SH2-B-mediated morphological differentiation of PC12 cells. Together, these results indicate that the multimeric adapters SH2-B and APS influence neurotrophin signaling through direct modulation of Trk receptor autophosphorylation.
Mol Cell Biol 2001 Mar
PMID:SH2-B and APS are multimeric adapters that augment TrkA signaling. 1123 98

Prostaglandins of the A-type (PGAs) induce heat shock protein (HSP) synthesis in a wide variety of mammalian cells resulting in protection against cellular stresses. The effect of PGAs on HSP-induction in cardiac myocytes is unknown. Therefore, we investigated the effect of PGA1 on HSP synthesis in adult rat cardiac myocytes. After 24 h of treatment, HSP72 was significantly increased 2.9-, 5.6- and 5.0-fold by PGA1 used at concentrations of 10, 20 or 40 microg/ml, respectively (P<0.05). However, the PGA1-concentration of 40 microg/ml, was found to be cytotoxic as evidenced by the release of LDH. In addition to HSP72, HSP32 was significantly increased by PGA1. The HSP32 induction was more vigorous with a marked increase with only 4 microg/ml of PGA1. No differences in the levels of HSP27, HSP60 or HSP90 were detected. When isolated cardiac myocytes were treated with PGA1, clear activation of heat shock factor (HSF) 1, one of the transcription factors for HSPs, was observed. In addition, another stress-induced transcription factor NFkappaB was also activated by PGA exposure. Despite the significant upregulation of both HSP72 and HSP32 cytoprotective properties against hypoxia and reoxygenation were absent. In conclusion, these experiments show for the first time that PGA1 induces differential expression of heat shock proteins in cardiac myocytes probably mediated through the activation of both HSF1 and NFkappaB.
J Mol Cell Cardiol 2001 Aug
PMID:Regulation of prostaglandin A1-induced heat shock protein expression in isolated cardiomyocytes. 1144 33

Computational comparative techniques were applied to analysis of the aromatic amino acid regulons in gamma-proteobacteria. This resulted in characterization of the TrpR and TyrR regulons in the genomes of Yersinia pestis, Haemophilus influenzae, Vibrio cholerae and other bacteria and identification of new members of the PhhR regulon in the genome of Pseudomonas aeruginosa. Candidate attenuators were constructed for all studied genomes, including the trpBA operon of the very distantly related bacterium Chlamidia trachomatis. The pheA attenuator of Y. pestis is an integration site for the insertion element IS-200. It was shown that the triplication of the DAHP-synthase genes occurred prior to the divergence of families Enterobacteriaceae, Vibrionaceae and Alteromonadaceae. The candidate allosteric control site of the DAHP-syntheases was identified. This site is deteriorated in AroH of Buchnera sp. APS. The known DAHP-synthase of Bordetella pertussis is likely to be feedback-inhibited by phenylalanine, and the DAHP-synthase of Corynebacterium glutamicum could be inhibited by tyrosine. Overall, the most extensive regulation was observed in Escherichia coli, whereas the regulation in other genomes seems to be less developed. At the extreme, the tryptophan production in the aphid endosymbiont Buchnera sp. APS is free from transcriptional, attenuation, and allosteric control.
J Mol Microbiol Biotechnol 2001 Oct
PMID:Regulation of aromatic amino acid biosynthesis in gamma-proteobacteria. 1154 72

In the gram-negative model organism Escherichia coli, the effector molecule of the stringent response, (p)ppGpp, is synthesized by two different enzymes, RelA and SpoT, whereas in the gram-positive model organism Bacillus subtilis only one enzyme named Rel is responsible for this activity. Rel and SpoT also possess (p)ppGpp hydrolase activity. BLAST searches were used to identify orthologous genes in databases. The construction and bootstrapping of phylogenetic trees allowed classification of these orthologs. Four groups could be distinguished: With the exception of Neisseria and Bordetella (beta subdivision), the RelA and SpoT groups are exclusively found in the gamma subdivision of proteobacteria. Two Rel groups representing the actinobacterial and the Bacillus/Clostridium group were also identified. The SpoT proteins are related to the gram positive Rel proteins. RelA proteins carry substitutions in the HD domain (Aravind and Koonin, 1998, TIBS 23: 469-472) responsible for ppGpp degradation. A theory for the evolution of the specialized, paralogous relA and spoT genes is presented: After gene duplication of an ancestral rellike gene, the spoT and relA genes evolved from the duplicated genes. The distribution pattern of the paralogous RelA and SpoT proteins supports a new model of linear bacterial evolution (Gupta, 2000, FEMS Microbiol. Rev. 24: 367-402). This model postulates that the gamma subdivision of proteobacteria represents the most recently evolved bacterial lineage. However, two paralogous, closely related genes of Porphyromonas gingivalis (Cytophaga-Flavobacterium-Bacteroides phylum) encoding proteins with functions probably identical to the RelA and SpoT proteins do not fit in this model. Completely sequenced genomes of several obligately parasitic organisms (Treponema pallidum, Chlamydia species, Rickettsia prowazekii) and the obligate aphid symbiont Buchnera sp. APS as well as archaea do not contain rel-like genes but they are present in the Arabidopsis genome. In crosslinking experiments using different analogs of ppGpp as crosslinking reagents and RNA polymerase preparations of Escherichia coli, binding of ppGpp to distinct regions at the C-terminus of the beta subunit (the RpoB gene product) and/or at the N-terminus of the beta subunit (the RpoC gene product) was observed previously. RpoB and RpoC sequences of the species which do not possess a rel like gene do not exhibit specific insertions or deletions in the ppGpp binding regions.
J Mol Microbiol Biotechnol 2001 Oct
PMID:Comparative genomics and evolution of genes encoding bacterial (p)ppGpp synthetases/hydrolases (the Rel, RelA and SpoT proteins). 1154 76


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