Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The stress response promoter element (STRE) confers increased transcription to a set of genes following environmental or metabolic stress in Saccharomyces cerevisiae. A lambda gt11 library was screened to isolate clones encoding STRE-binding proteins, and one such gene was identified as MSN2, which encoded a zinc-finger transcriptional activator. Disruption of the MSN2 gene abolished an STRE-binding activity in crude extracts as judged by both gel mobility-shift and Southwestern blot experiments, and overexpression of MSN2 intensified this binding activity. Northern blot analysis demonstrated that for the known or suspected STRE-regulated genes DDR2, CTT1, HSP12, and TPS2, transcript induction was impaired following heat shock or DNA damage treatment in the msn2-disrupted strain and was constitutively activated in a strain overexpressing MSN2. Furthermore, heat shock induction of a STRE-driven reporter gene was reduced more than 6-fold in the msn2 strain relative to wild-type cells. Taken together, these data indicate that Msn2p is the transcription factor that activates STRE-regulated genes in response to stress. Whereas nearly 85% of STRE-mediated heat shock induction was MSN2 dependent, there was significant MSN2-independent expression. We present evidence that the MSN2 homolog, MSN4, can partially replace MSN2 for transcriptional activation following stress. Moreover, our data provides evidence for the involvement of additional transcription factors in the yeast multistress response.
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PMID:Msn2p, a zinc finger DNA-binding protein, is the transcriptional activator of the multistress response in Saccharomyces cerevisiae. 865 Jan 68

Dual inhibitors of the two zinc metallopeptidases, neutral endopeptidase (NEP, EC 3.4.24.11) and angiotensin-I-converting enzyme (ACE, EC 2.4.15.1), have been the focus of much clinical interest for the treatment of hypertension and congestive heart failure. We have previously reported that compound 2 (N-[[1-[(2(S)-mercapto-3-methyl-1-oxobutyl) amino]-1-cyclopentyl]-carbonyl]-L-tyrosine) was a potent dual inhibitor in vitro (IC50 (ACE) = 7.0 nM, IC50 (NEP) = 1.5 nM) (Fink et al. J. Med. Chem. 1995, 38, 5023-5030). This compound was found to have oral activity; however, its duration of effect was short. A series of thioacetate carboxylic acid ester analogs of compound 2 was prepared. Modifications were also made to the tyrosine phenol. These compounds were evaluated for their ability to inhibit plasma ACE activity when administered orally to conscious normotensive rats. Most of the compounds prepared were found to be orally active with longer durations of effect than compound 2. Compound 38 (N-[[1-[(2(S)-(acetylthio)-3-methyl-1-oxobutyl) amino]-1-cyclopentyl]carbonyl]-O-methyl-L-tyrosine ethyl ester), administered at 11.7 mg/kg po, was found to be more efficacious than captopril at 10 mg/kg po. This compound was also found to inhibit plasma NEP activity following oral administration to conscious rats and was more efficacious than acetorphan. Compound 38 was found to lower blood pressure in the aorta-ligated rat and the spontaneously hypertensive rat when administered orally. The synthesis and biological activity of these dual inhibitors are discussed.
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PMID:Mercaptoacyl dipeptides as orally active dual inhibitors of angiotensin-converting enzyme and neutral endopeptidase. 875 37

Segmentation of the hindbrain has been conserved throughout the vertebrate species and results in the transient formation of rhombomeres, which are lineage-restricted compartments. Studies on the molecular mechanisms underlying the segmentation process have revealed that rhombomeric boundaries coincide with the expression limits of several evolutionary conserved genes such as the zinc-finger transcription factor Krox-20 and homeobox genes which are expressed in a specific spatial and temporal order and have been shown to be important regulators of segmental identity. In addition to Krox-20 and Hox genes, several members of the Eph subfamily of receptor protein tyrosine kinase (RTK) genes are also expressed in a segment-restricted manner in the hindbrain, suggesting that these receptors may act in concert with Hox genes to establish regional identity. In the cascade of regulatory interactions leading to segmental identity, Krox-20 appears to act "upstream" of Hox genes, but the identity of the "downstream" effectors has not yet been identified. We report here the isolation of the zebrafish orthologue of the mouse RTK gene MDK1 which belongs to the Eph receptor subfamily and show that the major expression domains of the mouse and the zebrafish genes have been conserved through evolution. Since the coincident spatial and temporal expression of Hoxa-2 and MDK1 in the mouse hindbrain suggested a possible regulatory link between them, we analyzed the expression of the MDK1 in Hoxa-2 null mutant embryos. A selective lack of MDK1 expression in rhombomere 3 of Hoxa-2 mutant hindbrains together with an overall altered expression pattern in the other rhombomeres was observed, thus demonstrating that MDK1 lies downstream of Hoxa-2 in the morphogenetic signaling cascade.
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PMID:The expression pattern of the mouse receptor tyrosine kinase gene MDK1 is conserved through evolution and requires Hoxa-2 for rhombomere-specific expression in mouse embryos. 880 19

Selective and mixed inhibitors of the three zinc metallopeptidases that degrade neurotensin (NT), e.g. endopeptidase 24-16 (EC 3.4.24.16), endopeptidase 24-11 (EC 3.4.24.11 or neutral endopeptidase, NEP) and endopeptidase 24-15 (EC 3.4.24.15), and leucine-aminopeptidase (type IV-S), that degrades the NT-related peptides, Neuromedin N (NN), are of great interest. On the structural basis of compound JMV 390-1 (N-[3-[(hydroxyamino)carbonyl]-1-oxo-2(R)-benzylpropyl]-L- isoleucyl-L-leucine), which was a full inhibitor of the major NT degrading enzymes, several hydroxamate inhibitors corresponding to the general formula HONHCO-CH2-CH(CH2-C6H5)CO-X-Y-OH (with X-Y = dipeptide) have been synthesized. Compound 7a (X-Y = Ile-Ala) was nearly 40-times more potent in inhibiting EC 24-16 than NEP and more than 800-times more potent than EC 24-15, with an IC50 (12 nM) almost equivalent to that of compound JMV 390-1. Therefore, this compound is an interesting selective inhibitor of EC 24-16, and should be an interesting probe to explore the physiological involvement of EC 24-16 in the metabolism of neurotensin.
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PMID:New hydroxamate inhibitors of neurotensin-degrading enzymes. Synthesis and enzyme active-site recognition. 887 32

The ash2 gene is a member of the trithorax group of genes whose products function to maintain active transcription of homeotic selector genes. Mutations in ash2 cause the homeotic transformations expected for a gene in this group but, in addition, cause a variety of pattern formation defects that are not necessarily expected. The ash2 gene is located in cytogenetic region 96A17-19 flanked by slowpoke and tolloid and is included in a cosmid that contains part of slowpoke. The ash2 transcript is 2.0 kb and is present throughout development. The ASH2 protein predicted from the nucleotide sequence of the open reading frame has a putative double zinc-finger domain, called a PHD finger, that is present not only in the products of other trithorax group genes such as TRX and ASH1, but also in the product of a Polycomb group gene, PCL. Polyclonal antibodies directed against ASH2 detect the protein in imaginal discs and in the nuclei of salivary gland and fat body cells. On immunoblots these affinity-purified antibodies detect a 70-kDa protein in larvae and a 53-kDa protein in pupae.
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PMID:Molecular genetic analysis of Drosophila ash2, a member of the trithorax group required for imaginal disc pattern formation. 888 25

A bioresorbable aliphatic polyester was synthesized by bulk copolymerization of a 1/1 M/M L,L-lactide/epsilon-caprolactone mixture using zinc metal as initiator. The actual composition of the copolymer was found to be 1.5/1 as deduced from 1H NMR spectra obtained in DMSO-d6 solutions where higher resolution was obtained as compared with chlorinated solvents. Resonances due to L-lactyl units (L) exhibited triads stereosensitivity, epsilon-oxycaproyl units (C) being sensitive to dyads. Average lengths of both poly(lactic acid) and polycaprolactone sequences were evaluated and showed the presence of rather long PLA blocks. Furthermore, no CLC triad signal was found, suggesting the absence of transesterification rearrangements. 10 x 10 x 2 mm specimens made of the copolymer were allowed to age in isoosmolar pH = 7.4 phosphate buffer at 37 degrees C. Degradation was monitored by various analytical techniques such as SEC, X-ray diffractometry, DSC, and 1H NMR. Data were compared with the behaviour of PCL and PLA homopolymers allowed to age under similar conditions. Crystallinity and composition changes are discussed in terms of preferential degradation in L- and C-containing amorphous domains, crystallized long PLA blocks being much more resistant.
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PMID:Structural characterization and hydrolytic degradation of a Zn metal initiated copolymer of L-lactide and epsilon-caprolactone. 899 92

The staphylococcal enterotoxins, SEA and SEE, bind one zinc atom per molecule of protein. The presence of this metal atom enhances the binding of the toxins to MHC class II molecules, presumably through an interaction with histidine 81 of the beta chain. L cell transfectants expressing HLA-DR1 and HLA-DR7 molecules, with mutations in either the alpha1 or beta1 domains, were tested for their ability to bind SEA and present it to T cells. Cells expressing DR1 molecules with alanine at positions 77, 78, 80, 83, 84 and 85, or serine at position 79 could all bind SEA and present it to either polyclonal or monoclonal T cells. Most point mutations within the alpha-helical portion of the DR7 beta chain had no effect on binding and presentation. However, substitution of histidine 81 with alanine, glutamate, or aspartate, abrogated SEA binding as well as T cell stimulation by the superantigen. This effect was also observed when the non-polymorphic aspartate, at position 76 was changed to alanine. Mutation of the asparagine at position 82 had an intermediate effect. Point mutations of the DR alpha chain had little effect on binding of SEA as determined by a flow cytometric assay. However, mutation of lysine at position 39 of the alpha chain and, to a lesser extent methionine at position 36, markedly decreased the ability of SEA to stimulate toxin-responsive mouse T cell hybridomas. Finally, the monoclonal antibody, L243 binds to the alpha chain of HLA-DR, and was able to block T cell activation by SEA without blocking SEA binding. These data support the model whereby HLA-DR has two binding sites for SEA. A low affinity site, present on the alpha chain, is required for T cell stimulation by the superantigen, but is insufficient to mediate toxin binding. High affinity binding of HLA-DR to SEA occurs solely through residues on the beta chain, including both histidine 81 and aspartate 76.
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PMID:Functional activity of staphylococcal enterotoxin A requires interactions with both the alpha and beta chains of HLA-DR. 912 63

The cell surface zinc metalloproteinase CD10/neutral endopeptidase 24.11 ([NEP] neprilysin) functions as part of a regulatory loop to control local concentrations of peptide substrates and associated peptide-mediated signal transduction. The physiologic role of the enzyme depends on available substrates in specific organs and cell types. Although CD10/NEP is expressed on a restricted subset of normal and malignant lymphoid progenitors, the enzyme is also expressed by a variety of epithelial cells. To explore the mechanism of tissue-specific expression of this regulatory enzyme, we characterized the major (type 2) CD10/NEP promoter and identified three functionally active transcription factor binding sites (regions I to III). CBF/NF-Y binds to the inverted CCAAT box in region I, whereas a second positive and a third negative factor bind to regions II and III, respectively. Although region I is required for maximal CD10/NEP-driven luciferase activity in the examined epithelial cell lines, this region is not required for maximal activity in the evaluated lymphoid cell lines. The apparent tissue-specific differences in requirements for region I (and CBF/NF-Y) are of particular interest because lymphoid and epithelial cells express alternatively spliced versions of CBF/NF-Y that differ in biologic activity.
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PMID:The type 2 CD10/neutral endopeptidase 24.11 promoter: functional characterization and tissue-specific regulation by CBF/NF-Y isoforms. 916 56

In patients with Denys-Drash syndrome, mutations of the Wilms' tumor suppressor gene are associated with nephroblastomas and developmental abnormalities of the genital tract and renal glomerulus. Normally, the Wilms' tumor gene product (WT1) is expressed at high levels in visceral glomerular epithelial cells (VGEC) of the emerging fetal glomerulus. We demonstrate that WT1 could normally serve to suppress EGF receptor expression in VGEC, since immunoreactive EGF receptor is strikingly absent compared to epithelial cells of the emerging proximal and distal tubule, which lack WT1. When HEK293 cells were co-transfected with plasmids containing EGFR enhancer/promoter elements linked to a CAT reporter and plasmids containing WT1 cDNA, EGFR enhancer/promoter activity was suppressed by all wild-type WT1 isoforms, but not by deletion mutants of WT1 lacking normal zinc-finger or N-terminal domains. Surprisingly, plasmids expressing a Denys-Drash WT1 mutant (R394W) retained the ability to suppress EGFR promoter activity in this system. Furthermore, we found that immunoreactive EGFR was appropriately undetectable in glomeruli from a three-year-old girl with Denys-Drash syndrome and in sections of her Wilm's tumor. These data suggest that faulty suppression of EGFR cannot account for the abnormalities of glomerulogenesis seen in Denys-Drash patients.
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PMID:Regulation of renal EGF receptor expression is normal in Denys-Drash syndrome. 929 Nov 79

The DDR2 gene of Saccharomyces cerevisiae is a multistress response gene whose transcription is rapidly and strongly induced by a diverse array of xenobiotic agents, and environmental and physiological conditions. The multistress response of this gene requires the pentanucleotide, 5' CCCCT, (C4T;STRE (STress Response Element)) and the zinc-finger transcription factors, Msn2p and Msn4p. A 51bp oligonucleotide (oligo 31/32) containing two STREs from the DDR2 promoter region was previously shown to direct heat shock activation of a lacZ reporter gene. In this work we demonstrate that the same element conferred a complete multistress response to an E. coli galK reporter gene introduced into yeast cells. A variant oligonucleotide in which both the STRE spacing and neighboring sequences were altered responded to the same spectrum of stresses, while substitution of nucleotides within the pentanucleotide completely abolished the multistress response. These results directly demonstrate that STREs are not only necessary but are sufficient for mediating a transcriptional response to a surprisingly diverse set of environmental and physiological conditions.
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PMID:Functional analysis of the stress response element and its role in the multistress response of Saccharomyces cerevisiae. 947 71


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