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PubMed1998

Expression of mutant dynamin inhibits toxicity and transport of endocytosed ricin to the Golgi apparatus.

Endocytosis and intracellular transport of ricin were studied in stable transfected HeLa cells where overexpression of wild-type (WT) or mutant dynamin is regulated by tetracycline. Overexpression of the temperature-sensitive mutant dynG273D at the nonpermissive temperature or the dynK44A mutant inhibits clathrin-dependent endocytosis (Damke, H., T. Baba, A.M. van der Blieck, and S.L. Schmid. 1995. J. Cell Biol. 131: 69-80; Damke, H., T. Baba, D.E. Warnock, and S.L. Schmid. 1994. J. Cell Biol. 127:915-934). Under these conditions, ricin was endocytosed at a normal level. Surprisingly, overexpression of both mutants made the cells less sensitive to ricin. Butyric acid and trichostatin A treatment enhanced dynamin overexpression and increased the difference in toxin sensitivity between cells with normal and mutant dynamin. Intoxication with ricin seems to require toxin transport to the Golgi apparatus (Sandirg, K., and B. van Deurs. 1996. Physiol. Rev. 76:949-966), and this process was monitored by measuring the incorporation of radioactive sulfate into a modified ricin molecule containing a tyrosine sulfation site. The sulfation of ricin was much greater in cells expressing dynWT than in cells expressing dynK44A. Ultrastructural analysis using a ricin-HRP conjugate confirmed that transport to the Golgi apparatus was severely inhibited in cells expressing dynK44A. In contrast, ricin transport to lysosomes as measured by degradation of 125I-ricin was essentially unchanged in cells expressing dynK44A. These data demonstrate that although ricin is internalized by clathrin-independent endocytosis in cells expressing mutant dynamin, there is a strong and apparently selective inhibition of ricin transport to the Golgi apparatus. Also, in cells with mutant dynamin, there is a redistribution of the mannose-6-phosphate receptor.

Biological Transport↗
PubMed1998

Distinct requirements for chromatin assembly in transcriptional repression by thyroid hormone receptor and histone deacetylase.

Histone deacetylase and chromatin assembly contribute to the control of transcription of the Xenopus TRbetaA gene promoter by the heterodimer of Xenopus thyroid hormone receptor and 9-cis retinoic acid receptor (TR-RXR). Addition of the histone deacetylase inhibitor Trichostatin A (TSA) relieves repression of transcription due to chromatin assembly following microinjection of templates into Xenopus oocyte nuclei, and eliminates regulation of transcription by TR-RXR. Expression of Xenopus RPD3p, the catalytic subunit of histone deacetylase, represses the TRbetaA promoter, but only after efficient assembly of the template into nucleosomes. In contrast, the unliganded TR-RXR represses templates only partially assembled into nucleosomes; addition of TSA also relieves this transcriptional repression. This result indicates the distinct requirements for chromatin assembly in mediating transcriptional repression by the deacetylase alone, compared with those needed in the presence of unliganded TR-RXR. In addition, whereas hormone-bound TR-RXR targets chromatin disruption as assayed through changes in minichromosome topology and loss of a regular nucleosomal ladder on micrococcal nuclease digestion, addition of TSA relieves transcriptional repression but does not disrupt chromatin. Thus, TR-RXR can facilitate transcriptional repression in the absence of hormone through mechanisms in addition to recruitment of deacetylase, and disrupts chromatin structure through mechanisms in addition to the inhibition or release of deacetylase.

Amino Acid Sequence↗
PubMed1999

5-Oxo-6,8,11,14-eicosatetraenoic acid induces important eosinophil transmigration through basement membrane components: comparison of normal and asthmatic eosinophils.

Basement membrane transmigration is an important step in tissue recruitment of eosinophils into inflamed tissue. Recent reports showed that this phenomenon is modulated by platelet-activating factor (PAF) in combination with cytokines and proteinases. We investigated the in vitro efficacy of 5-oxo-6,8,11, 14-eicosatetraenoic acid (5-oxo-ETE), a metabolite of arachidonic acid and known as a potent eosinophil chemotactic factor, in promoting the transmigration of blood eosinophils from normal and asthmatic subjects through a Matrigel basement membrane. 5-Oxo-ETE proved to be a more potent (> 10-fold) inducer of eosinophil transmigration than PAF, and this effect was similar in cells from normal and asthmatic subjects (82.0 +/- 3.7% and 88.1 +/- 3.7%, respectively). Moreover, 5-oxo-ETE was active in the absence of interleukin (IL)-5, although this cytokine amplified the effect of 5-oxo-ETE from 61.3 +/- 3.3% to 92.8 +/- 1.8% (p = 0.003). The membrane receptor for urokinase plasminogen activator (CD87), a serine protease, was observed on eosinophils, and its expression was increased by IL-5. The inhibition of both metalloproteinases (MMP) and plasmin/plasminogen complex with inhibitor or monoclonal antibodies decreased cell transmigration by about 50%. Combination of an MMP inhibitor with anti-CD87 antibodies had no additive effect. These data show that 5-oxo-ETE is an efficient promoter of eosinophil transmigration in vitro, and is much more potent in this respect than PAF. The data suggest that 5-oxo-ETE could play an important role in eosinophil recruitment in vivo. Moreover, they demonstrate that in addition to MMP, the plasmin/plasminogen system could be involved in eosinophil transmigration.

Adult↗
PubMed2004

Human mitochondrial peptide deformylase, a new anticancer target of actinonin-based antibiotics.

Peptide deformylase activity was thought to be limited to ribosomal protein synthesis in prokaryotes, where new peptides are initiated with an N-formylated methionine. We describe here a new human peptide deformylase (Homo sapiens PDF, or HsPDF) that is localized to the mitochondria. HsPDF is capable of removing formyl groups from N-terminal methionines of newly synthesized mitochondrial proteins, an activity previously not thought to be necessary in mammalian cells. We show that actinonin, a peptidomimetic antibiotic that inhibits HsPDF, also inhibits the proliferation of 16 human cancer cell lines. We designed and synthesized 33 chemical analogs of actinonin; all of the molecules with potent activity against HsPDF also inhibited tumor cell growth, and vice versa, confirming target specificity. Small interfering RNA inhibition of HsPDF protein expression was also antiproliferative. Actinonin treatment of cells led to a tumor-specific mitochondrial membrane depolarization and ATP depletion in a time- and dose-dependent manner; removal of actinonin led to a recovery of the membrane potential consistent with indirect effects on the electron transport chain. In animal models, oral or parenteral actinonin was well tolerated and inhibited human prostate cancer and lung cancer growth. We conclude that HsPDF is a new human mitochondrial enzyme that may provide a novel selective target for anticancer therapy by use of actinonin-based antibiotics.

Amidohydrolases↗
PubMed2000

Quantitative PCR analysis of HbF inducers in primary human adult erythroid cells.

The development and evaluation of drugs to elevate fetal hemoglobin in the treatment of the genetic diseases of hemoglobin would be facilitated by the availability of reliable cell assays. We have used real-time, quantitative polymerase chain reaction (PCR) analyses of globin messenger RNA (mRNA) levels in a biphasic, erythropoietin-dependent primary culture system for human adult erythroid cells in order to assay compounds for their ability to modulate levels of adult (beta) and fetal (gamma) globin mRNA. Complementary DNA synthesized from total RNA extracted at timed intervals from aliquots of cells were assayed throughout the period that the culture was studied. gamma-globin mRNA levels were found to be much lower (less than 1%) than beta-globin mRNA levels. At concentrations of agents chosen for minimal effect on cell division, we find that the 3 drugs studied, 5-azacytidine (5 micromol/L), hydroxyurea (40 micromol/L), and butyric acid (0.5 mmol/L), significantly increase gamma-globin mRNA levels. Interestingly, hydroxyurea also had a small stimulatory effect on beta-globin mRNA levels, while butyric acid caused a twofold inhibition of beta-globin mRNA levels, and 5-azacytidine had little effect on beta-globin mRNA levels. The net result of all 3 drugs was to increase the gamma/(gamma + beta) mRNA ratios by threefold to fivefold. These data suggest that the mechanism is distinct for each drug. The profile of butyric-acid-induced changes on globin gene expression is also quite distinct from changes produced by trichostatin A, a known histone deacetylase inhibitor. Quantitative PCR analyses of human erythroid cells should prove useful for studying the mechanism(s) of action of known inducers of gamma-globin and identifying new drug candidates.

Adult↗
PubMedDate not supplied

Suppression of ovarian oxytocin secretion after intra-luteal administration of the arachidonate 5-lipoxygenase inhibitor BWA4C in the ewe.

The effect of an intra-luteal injection of the 5-lipoxygenase (5-LO) inhibitor BWA4C (2 mg in 50 microl DMSO) on the secretion of oxytocin (OT) from the corpus luteum in response to a close-arterial infusion of prostaglandin (PG)-F2alpha (5 ng min(-1)) was examined in anaesthetised sheep. Within 30 minutes of administration both basal (pre-infusion) and PGF2alpha-stimulated OT release into the posterior vena cava were significantly (P<0.01) reduced. These results are consistent with the proposition that 5-LO products of arachidonic acid may modulate OT secretion from the ovine corpus luteum.

Animals↗
PubMed1970

Repression of phenolic acid-synthesizing enzymes and its relation to iron uptake in Bacillus subtilis.

Excretion of the metal-chelating phenolic acid, 2,3-dihydroxybenzoate, by a tryptophan-requiring strain (M-13) of Bacillus subtilis was inversely proportional to the iron added to the medium. Addition of iron as the ferric chelates of two secondary hydroxamates (ferri-schizokinen and Desferal) markedly reduced excretion. Synthesis of 2,3-dihydroxybenzoate from chorismate by extracts of B. subtilis M-13, grown in low-iron medium, was unaltered by additions of FeSO(4), FeCl(3), ferrischizokinen, 2,3-dihydroxybenzoate, the 2,3-dihydroxybenzoate-iron complex, or by extracts of cells grown in high-iron medium (which contained no demonstrable 2,3-dihydroxybenzoate-synthesizing activity) to the extracts of "low-iron cells." Iron control seemed to involve repression of synthesis of the enzymes in the 2,3-dihydroxybenzoate pathway. Both ferri-schizokinen and 2,3-dihydroxybenzoate plus iron enhanced considerably the otherwise minimal repressive effects of iron at low concentrations. Ferri-schizokinen delayed derepression of the pathway in B. subtilis M-13, and reduced its rate of synthesis after derepression. Addition of FeSO(4) to derepressed cells of B. subtilis M-13 halted synthesis of the enzymes after a lag period. The effect of the ferric hydroxamates was related to the capacity of B. subtilis M-13 to incorporate (59)Fe(3+) from Desferal-(59)Fe(3+). Cellular accumulation of (59)Fe(3+) from Desferal-(59)Fe(3+) after 20 min was nearly double that incorporated from (59)FeCl(3).

Bacillus subtilis↗
PubMed1978

The alternate respiratory pathway of Candida albicans.

Candida albicans contains a cryptic cyanide and antimycin A insensitive respiratory system. This alternate oxidase was found (i) at all growth rates from mu = 0.05 to 0.26 in a chemostat culture and (ii) in both mycelial and yeast forms of the organism. Neither chloramphenicol nor cycloheximide prevented the expression of the alternate oxidase. Salicylhydroxamic acid was a potent inhibitor of the cyanide insensitive respiration. The respiration of mitochondria grown in the presence of antimycin A was not inhibited by cyanide or antimycin A but was inhibited by salicylhydroxamic acid.

Antifungal Agents↗
PubMed2006

Substrate and inhibitor specificity of class 1 and class 2 histone deacetylases.

Histone deacetylases (HDACs) are key enzymes in the transcriptional regulation of gene expression in eukaryotic cells. In recent years HDACs have attracted considerable attention as promising new targets in anticancer therapy. Currently, different histone deacetylase subtypes are divided into four groups denoted as classes 1-4. Here, we compare in more detail representatives of class 1 HDACs and FB188 HDAH as a close bacterial homologue of class 2 HDAC6, in regard of substrate and inhibitor specificity. Structure comparison is used to identify candidate regions responsible for observed specificity differences. Knowledge of these structural elements expedite studies on the biochemical role of different HDAC subtypes as well as the development of highly selective HDAC inhibitors as antitumor agents.

Amino Acid Sequence↗
PubMed2006

Synthesis, characterization, reactivity, and catalytic potential of model vanadium(IV, V) complexes with benzimidazole-derived ONN donor ligands.

Reaction between [VO(acac)(2)] and the ONN donor Schiff base Hsal-ambmz (I) (Hsal-ambmz = Schiff base obtained by the condensation of salicylaldehyde and 2-aminomethylbenzimidazole) resulted in the formation of the complexes [V(IV)O(acac)(sal-ambmz)] (1), [V(V)O(2)(acac-ambmz)] (2) (Hacac-ambmz = Schiff base derived from acetylacetone and 2-aminomethylbenzimidazole), and the known complex [V(IV)O(sal-phen)] (3) (H(2)sal-phen = Schiff base derived from salicylaldehyde and o-phenylenediamine). Similarly, [V(IV)O(acac)(sal-aebmz)] (7) has been isolated from the reaction with Hsal-aebmz (II) (Hsal-aebmz derived from salicylaldehyde and 2-aminoethylbenzimidazole). Aerial oxidation of the methanolic solutions/suspensions of 1 and 7 yielded the dioxovanadium(V) complexes [V(V)O(2)(sal-ambmz)] (4) and [V(V)O(2)(sal-aebmz)] (8), respectively. Reaction of VOSO(4) with II gave [{V(IV)O(sal-aebmz)}(2)SO(4)] (9) and [V(IV)O(sal-aebmz)(2)] (10), along with 3 and 8. Under similar reaction conditions, I gave only [{V(IV)O(sal-ambmz)}(2)SO(4)] (5) and 3 as major products. Treatment of 1 and 7 with benzohydroxamic acid (Hbha) yielded the mixed-chelate complexes [V(V)O(bha)(sal-ambmz)] (6) and [V(V)O(bha)(sal-aebmz)] (11). The crystal and molecular structures of 2, 3.1/2DMF, 7.1/4H(2)O, 8, 9.2H(2)O, 10, and 11 have been determined, confirming the ONN binding mode of the ligands. In complex 10, one of the ligands is coordinated through the azomethine nitrogen and phenolate oxygen only, leaving the benzimidazole group free. In the dinuclear complex 9, bridging functions are the phenolate oxygens from both of the ligands and two oxygens of the sulfato group. The unstable oxoperoxovanadium(V) complex [V(V)O(O(2))(sal-aebmz)] (12) has been prepared by treatment of 7 with aqueous H(2)O(2). Acidification of methanolic solutions of 7 and 10 lead to (reversible) protonation of the bemzimidazole, while 8 was converted to an oxo-hydroxo species. Complexes 2, 4, and 8 catalyze the oxidation of methyl phenyl sulfide to methyl phenyl sulfoxide and methyl phenyl sulfone, a reaction mimicking the sulfideperoxidase activity of vanadate-dependent haloperoxidases. These complexes are also catalytically active in the oxidation of styrene to styrene oxide, benzaldehyde, benzoic acid, and 1-phenylethane-1,2-diol.

Benzimidazoles↗
PubMed2005

BCL11B functionally associates with the NuRD complex in T lymphocytes to repress targeted promoter.

BCL11 genes play crucial roles in lymphopoiesis and have been associated with hematopoietic malignancies. Specifically, disruption of the BCL11B (B-cell chronic lymphocytic leukemia/lymphoma 11B) locus is linked to T-cell acute lymphoblastic leukemia, and the loss of heterozygosity in mice results in T-cell lymphoma. BCL11 proteins are related C2H2 zinc-finger transcription factors that act as transcriptional repressors. Here, we demonstrate the association of the endogenous BCL11B with the nucleosome remodeling and histone deacetylase (NuRD) complex, one of the major transcriptional corepressor complexes in mammalian cells. BCL11B complexes from T lymphocytes possess trichostatin A-sensitive histone deacetylase activity, confirming the functionality of the complexes. Analysis of the BCL11B-NuRD association demonstrated that BCL11B directly interacted with the metastasis-associated proteins MTA1 and MTA2 through the amino-terminal region. We provide evidence for the functional requirement of MTA1 in transcriptional repression mediated by BCL11B through the following: (1) overexpression of MTA1 enhanced the transcriptional repression mediated by BCL11B, (2) knockdown of MTA1 expression by small interfering RNA inhibited BCL11B transcriptional repression activity and (3) MTA1 was specifically recruited to a BCL11B targeted promoter. Taken together, these data support the hypothesis that the NuRD complex mediates transcriptional repression function of BCL11B.

Amino Acid Sequence↗
PubMed2001

YkrB is the main peptide deformylase in Bacillus subtilis, a eubacterium containing two functional peptide deformylases.

Peptide deformylation is an essential process in eubacteria. The peptide deformylase Def has been suggested to be an attractive target for antibacterial drug discovery. Some eubacteria including medically important pathogens possess two def-like genes. Until now, the functionality of both genes has been tested only in Staphylococcus aureus with the result that one gene copy was functional. Here, expression of two functional def-like gene products in Bacillus subtilis is demonstrated. Besides the def gene, which is chromosomally located close to the formyltransferase gene fmt and which was overexpressed and biochemically tested previously, B. subtilis possesses a second def-like gene, called ykrB. The encoded protein is 32% identical to the def gene product. It was shown that either def or ykrB had to be present for growth of B. subtilis in rich medium (each was individually dispensable). Studies with a def/ykrB double deletion strain with xylose-inducible ykrB copy demonstrated that, besides def, the gene ykrB is a second cellular target of deformylase inhibitors such as the antibiotic actinonin. The gene products exhibited similar enzymic properties, exemplified by similar inhibition efficacy of actinonin in biochemical assays. Antibiotic susceptibility tests with different deletion strains and Northern analyses indicated that YkrB is probably the predominant deformylase in B. subtilis. It was shown that duplication of the deformylase function does not lead to an increased actinonin-resistance frequency in comparison to B. subtilis mutants carrying only one deformylase gene.

Amidohydrolases↗

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