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Neurite growth and guidance depends on the transduction of extracellular guidance cues into motile responses by the sensory apparatus at the tip of the neurite, the growth cone. Contact of the growth cone with extracellular ligands leads to the cytoskeletal reorganisation required for changes in rate of motility and direction of outgrowth. Differential adhesion mediated by cell adhesion molecules and signal transduction pathways mediated by growth cone receptors were once seen as separate but cooperative events in controlling growth cone motility. However, recent findings suggest that cell adhesion molecules can activate novel signalling pathways in the growth cone by the recruitment of fibroblast growth factor receptors leading to neurite outgrowth. This Review focuses on work by various laboratories centering on the intracellular consequences of the cell adhesion molecule-mediated activation of the fibroblast growth factor receptor. These include activation of a lipase cascade including phospholipase C and diacylglycerol lipase and culminating in the release of arachidonic acid. This release of arachidonic acid is proposed to activate the transient opening of voltage dependent ion-channels leading to localised rises in growth Ca(2+). Recent findings demonstrating this previously undetectable rise in Ca(2+) in the growth cone are discussed in light of the proposed roles and mechanisms of Ca(2+) in controlling neurite outgrowth. The Ca(2+) rises are thought to induce the activation of GAP43 and Ca(2+)/calmodulin-dependent kinase II, molecules implicated in the modulation of cytoskeletal remodelling. The evidence that this pathway may be involved in the guidance of retinal ganglion cells is evaluated.
Mol Cell Biol Res Commun 2000 May
PMID:The generation of localized calcium rises mediated by cell adhesion molecules and their role in neuronal growth cone motility. 1096 48

Thermophilic fungi are a small assemblage in mycota that have a minimum temperature of growth at or above 20 degrees C and a maximum temperature of growth extending up to 60 to 62 degrees C. As the only representatives of eukaryotic organisms that can grow at temperatures above 45 degrees C, the thermophilic fungi are valuable experimental systems for investigations of mechanisms that allow growth at moderately high temperature yet limit their growth beyond 60 to 62 degrees C. Although widespread in terrestrial habitats, they have remained underexplored compared to thermophilic species of eubacteria and archaea. However, thermophilic fungi are potential sources of enzymes with scientific and commercial interests. This review, for the first time, compiles information on the physiology and enzymes of thermophilic fungi. Thermophilic fungi can be grown in minimal media with metabolic rates and growth yields comparable to those of mesophilic fungi. Studies of their growth kinetics, respiration, mixed-substrate utilization, nutrient uptake, and protein breakdown rate have provided some basic information not only on thermophilic fungi but also on filamentous fungi in general. Some species have the ability to grow at ambient temperatures if cultures are initiated with germinated spores or mycelial inoculum or if a nutritionally rich medium is used. Thermophilic fungi have a powerful ability to degrade polysaccharide constituents of biomass. The properties of their enzymes show differences not only among species but also among strains of the same species. Their extracellular enzymes display temperature optima for activity that are close to or above the optimum temperature for the growth of organism and, in general, are more heat stable than those of the mesophilic fungi. Some extracellular enzymes from thermophilic fungi are being produced commercially, and a few others have commercial prospects. Genes of thermophilic fungi encoding lipase, protease, xylanase, and cellulase have been cloned and overexpressed in heterologous fungi, and pure crystalline proteins have been obtained for elucidation of the mechanisms of their intrinsic thermostability and catalysis. By contrast, the thermal stability of the few intracellular enzymes that have been purified is comparable to or, in some cases, lower than that of enzymes from the mesophilic fungi. Although rigorous data are lacking, it appears that eukaryotic thermophily involves several mechanisms of stabilization of enzymes or optimization of their activity, with different mechanisms operating for different enzymes.
Microbiol Mol Biol Rev 2000 Sep
PMID:Thermophilic fungi: their physiology and enzymes. 1097 22

Canaries appear to be primarily seed-eaters, although there are no reports of their feeding ecology in the wild. In captivity, they are offered seed-based diets, preferring to consume seeds such as canary, rapeseed and millet. The mean daily dry-matter intake ranges from 3 to 4 g, which corresponds to a mean gross energy intake of approximately 70 kJ per bird per day. The efficiency of dietary metabolism is high (0.85), which equates to individual metabolizable energy intakes of 45-75 kJ per bird per day. For a canary of average body weight (22 g) the data can be fitted to a regression equation to predict a requirement of 62 kJ ME per day. This corresponds to published information on the energy requirements of other passerine species, but deviates from the predictive equation for poultry. The digestibility values for protein, fat and carbohydrate are similar to those obtained for the budgerigar, although it is likely that the digestibility coefficient is dependent upon the seed type and alimentary tract lipase and amylase activities. Nutrient requirements of canary chicks have not yet been determined, although recent studies have provided data on the nutrient intakes of developing chicks. The newly-hatched canary chick has a rapid growth rate, achieving 90% of its asymptotic body mass by 11 days of age. Gross energy intake is approximately 3 kJ per day following hatching and by day 10 is equivalent to that of an adult canary. It appears that the protein intake should lie between 16.5 and 21.9% of the diet (as is), with peak intake occurring between 8 and 10 days of age.
Comp Biochem Physiol B Biochem Mol Biol 2000 Jul
PMID:Nutrition and energetics of the canary (Serinus canarius). 1100 69

The identity of the neutral cholesteryl ester hydrolase (CEH) in human monocyte/macrophages is uncertain. Prior studies indicate that hormone sensitive lipase (HSL) is a major CEH in mouse macrophages, and that HSL mRNA is present in human THP-1 monocytes. In the present study, HSL mRNA expression was examined in THP-1 cells as a function of differentiation status and cholesterol enrichment. By RT-PCR with primer pairs that span exon boundaries, HSL mRNA was demonstrated in THP-1 monocytes and phorbol-ester differentiated THP-1 macrophages. cDNA identities were confirmed by sequencing. By Northern blotting, with HSL cDNA as probe, THP-1 monocytes were found to contain HSL mRNA of approximately 3 and 3.9 kb. In THP-1 macrophages, the 3 kb mRNA was greatly diminished, while the level of the 3.9 kb mRNA was maintained. mRNA of approximately 3 and 3.9 kb are those expected of the 86-kDa (adipocyte) and 117-kDa (testicular) HSL isoforms, respectively. The presence of the testicular isoform mRNA was confirmed in THP-1 cells by amplification and sequencing of an isoform-specific cDNA. Additionally, Northern-blot comparisons showed that the 3 and 3.9 kb mRNA in THP-1 comigrated with the HSL mRNA in 3T3-L1 adipocytes and rat testis, respectively. The level of the 3.9 kb mRNA did not vary greatly with cholesterol enrichment. Thus, the HSL gene is transcribed in THP-1 cells both before and after differentiation into macrophages; after differentiation, the predominant mRNA is that for the 117-kDa isoform. This isoform is a CEH, and may mediate some CE turnover in THP-1 cells.
Comp Biochem Physiol B Biochem Mol Biol 2000 Aug
PMID:Hormone sensitive lipase mRNA in both monocyte and macrophage forms of the human THP-1 cell line. 1102 66

EST2 is a novel thermophilic carboxylesterase, isolated and cloned from Alicyclobacillus (formerly Bacillus) acidocaldarius, which optimally hydrolyses esters with acyl chain lengths of six to eight carbon atoms at 70 degrees C. On the basis of the amino acid sequence homology, it has been classified as a member of the mammalian hormone-sensitive lipase (HSL) subfamily. The crystal structure of EST2, complexed with a sulphonyl derivative, has been determined at 2.6 A resolution by a multiple wavelength anomalous diffraction experiment on a seleno-methionine derivative. EST2 presents a canonical alpha/beta hydrolase core, shielded at the C-terminal side by a cap region built up of five helices. It contains the lipase-like catalytic triad, Ser155, His282 and Asp252, whereby the nucleophile is covalently modified. This allows an unambiguous view of the putative active site of EST2, detecting the oxyanion hole, in whose formation the amino acid sequence motif His81-Gly82-Gly83-Gly84 is involved, and the hydrophobic binding pocket for the acyl chain. The structural model here reported provides the first example of a transition state analogue of an esterase/lipase belonging to the HSL group, thus affording useful information for the design of medical inhibitors. Moreover, as the first X-ray structure of a thermophilic carboxylesterase, the comparison with its mesophilic homologue, the Brefeldin A esterase (BFAE) from Bacillus subtilis, allows the identification of putative determinants of thermal stability.
J Mol Biol 2000 Nov 10
PMID:A snapshot of a transition state analogue of a novel thermophilic esterase belonging to the subfamily of mammalian hormone-sensitive lipase. 1106 74

Various proteins/enzymes obtained commercially were tested for the presence of endogenously nitrated tyrosine by Western blot analysis omitting reducing agent in the step of SDS-PAGE. Histones II-S and VIII-S, IgG, cAMP-dependent protein kinase (PKA), phosphorylase b, and phosphorylase kinase exhibited strong immunoreactive bands. Histone VI-S, glycogen synthase, lactate dehydrogenase, actin, thyroglobulin, and macroglobulin exhibited moderate immunoreactivity. Histone III-S, casein, acetyl cholinesterase, DNase I, and lipase had only traceable immunoreactivity. Whereas histone VII-S, pyruvate kinase, trypsin, pepsin, chymotrypsin, protease IV, and protease XIII, and glutathione S-transferase lacked immunoreactivity. A variation of immunoreactivity between hypertensive and normaltensive rat hearts was found in the histone-agarose fractions of crude extracts. Additionally, nitrotyrosine immunoreactivity was observed in non-mammalian organisms including Eschericia coli, Saccharomyces cerevisiae and Triticum vulgaris. Upon the treatment of 15 microM peroxynitrite (PN), strong oxidant derived from nitric oxide (NO), the apparent Km of PKA for cAMP increased from approximately 10(-8) to 10(-6) M. The results imply that the varied nitration of tyrosine residues in proteins/enzymes may occur as a post-translational modification in vivo, and such discriminative nitration may be vital in PN/NO-regulated signal transduction cascade.
Mol Cell Biochem 2000 Nov
PMID:Protein nitration. 1119 83

Genistein is a phytoestrogen found in several plants eaten by humans and food-producing animals and exerting a wide spectrum of biological activity. In this experiment, the impact of genistein on lipogenesis and lipolysis was studied in isolated rat adipocytes. Incubation of the cells (10(6) cells/ml in plastic tubes at 37 degrees C with Krebs-Ringer buffer, 90 min) with genistein (0.01, 0.3, 0.6 and 1 mM) clearly restricted (1 nM) [U-14C]glucose conversion to total lipids in the absence and presence of insulin. When [14C]acetate was used as the substrate for lipogenesis, genistein (0.01, 0.1 and 1 mM) exerted a similar effect. Thus, the anti-lipogenetic action of genistein may be an effect not only of alteration in glucose transport and metabolism, but this phytoestrogen can also restrict the fatty acids synthesis and/or their esterification. Incubation of adipocytes with estradiol at the same concentrations also resulted in restriction of lipogenesis, but the effect was less marked. Genistein (0.1 and 1 mM) augmented basal lipolysis in adipocytes. This process was strongly restricted by insulin (1 microM) and H-89 (an inhibitor of protein kinase A; 50 microM) and seems to be primarily due to the inhibitory action of the phytoestrogen on cAMP phosphodiesterase in adipocytes. Genistein at the smallest concentration (0.01 mM) augmented epinephrine-stimulated (1 microM) lipolysis but failed to potentiate lipolysis induced by forskolin (1 microM) or dibutyryl-cAMP (1 mM). These results suggest genistein action on the lipolytic pathways before activation of adenylate cyclase. The restriction of lipolysis stimulated by several lipolytic agents--epinephrine, forskolin and dibutyryl-cAMP were observed when adipocytes were incubated with genistein at highest concentrations (0.1 and 1 mM). These results prove the inhibitory action of this phytoestrogen on the final steps of the lipolytic cascade, i.e. on protein kinase A or hormone sensitive lipase. Estradiol, added to the incubation medium, did not affect lipolysis. It can be concluded that genistein significantly affects lipogenesis and lipolysis in isolated rat adipocytes.
J Steroid Biochem Mol Biol 2000 Dec 31
PMID:Genistein affects lipogenesis and lipolysis in isolated rat adipocytes. 1128 81

The filamentous fungus Nectria haematococca (anamorph Fusarium solani f. sp. pisi) resides in soil, and attacks pea seedlings in the area of the underground epicotyl and upper tap root, causing foot rot disease. We detected lipase activity during in vitro growth of N. haematococca. Subsequently, a lipase gene was cloned and functionally characterised by heterologous expression in Saccharomyces cerevisiae. The full-length cDNA of 1152 bp was cloned using a 3' RACE-PCR approach coupled with cDNA library screening. The genomic clone, comprising an ORF of 999 bp interrupted by two introns of 56 and 64 bp, was isolated from a newly constructed lambda phage library. Analysis of the deduced protein sequence revealed the presence of a typical signal peptide at the N-terminus, and of the three conserved amino acids forming the active site of lipases. The lipase of N. haematococca has a low degree of similarity to the lipases from Humicola lanuginosa (37.2%), Rhizomucor miehei (21.6%), Rhizopus delemar (23.1%), Rhizopus niveus (25.9%), and to mono- and diacylglycerol lipase from Penicillium camembertii (30.8%), and very high similarity (94.6%) to a lipase from Fusarium heterosporum. The lipase from N. haematococca shows maximal activity at 37 degrees C and pH 8.0. Based on Southern analysis, the lipase clone represents a single-copy gene in N. haematococca. Expression analysis was performed by RT-PCR. In vitro, the lipase gene shows a low basal expression, but is highly inducible by lipase substrates, and repressed by glucose. During plant infection, transcripts of this fungal lipase gene were detected 4, 8, and 10 days after infection.
Mol Genet Genomics 2001 Apr
PMID:Cloning and expression analysis of NhL1, a gene encoding an extracellular lipase from the fungal pea pathogen Nectria haematococca MP VI (Fusarium solani f. sp. pisi) that is expressed in planta. 1136 31

Staphylococcus aureus is a major human pathogen that produces many virulence factors in a temporally regulated manner controlled by at least two global virulence regulatory loci (agr and sarA). We identified previously a two-component system, ArlS-ArlR, that modifies the activity of extracellular serine protease and may be involved in virulence regulation. Here, we show that mutations in either arlR or arlS increase the production of secreted proteins [alpha-toxin (Hla), beta-haemolysin, lipase, coagulase, serine protease (Ssp)] and especially protein A (Spa). Furthermore, the pattern of proteins secreted by both mutants was strikingly different from that of the wild-type strain. Transcriptional fusions showed that expression of hla, ssp and spa was higher in both mutants than in the wild-type strain, indicating that the arl operon decreases the production of virulence factors by downregulating the transcription of their genes. The arl mutation did not change spa expression in an agrA mutant or in a sarA mutant, suggesting that both the sarA and the agr loci are required for the action of arl on spa. Northern blot analyses indicated that the arl mutation increased the synthesis of both RNA II and RNA III, but decreased sarA transcription. Finally, arl was not autoregulated, but its expression was stimulated by agr and sarA. These results suggest that the Arl system interacts with both agr and sarA regulatory loci to modulate the virulence regulation network.
Mol Microbiol 2001 Jul
PMID:The two-component system ArlS-ArlR is a regulator of virulence gene expression in Staphylococcus aureus. 1145 17

Mucolipidosis type IV (MLIV) is a neurodegenerative lysosomal storage disorder characterized by psychomotor retardation and ophthalmological abnormalities, including corneal opacities, retinal degeneration, and strabismus. Severely affected as well as milder patients have been described. Over 80% of the MLIV patients are Ashkenazi Jews; the estimated heterozygote frequency in this population is 1/100. The disease is classified as a mucolipidosis due to the simultaneous lysosomal storage of lipids together with water-soluble substances. A broad spectrum of lipids and acid mucopolysaccharides were identified as the storage substances. Kinetic studies demonstrated that this heterogeneous storage stems from an abnormal endocytosis process in cells from MLIV patients of membrane components from late endosomes to the lysosomes and/or delayed efflux to the Golgi apparatus. The MLIV gene was mapped to chromosome 19p13.2--13.3 where a novel gene, MCOLN1, with MLIV-causing mutations, was identified. Two mutations were found among 95% of the Ashkenazi MLIV alleles, including an intronic acceptor splice-site mutation in 72% of the alleles and a partial gene deletion in 23%. Each of these mutations was associated with a defined haplotype in this chromosomal region. Other mutations were mostly identified in single, Ashkenazi and non-Ashkanazi patients, including missense, nonsense nucleotide deletions, and insertions. All mutations but one were identified in patients exhibiting the severe phenotype, an in-frame amino acid deletion was identified in a mild patient. MCOLN1 encodes a 580 aa protein, mucolipin 1, which is a member of a new protein family of unknown function at present, the mucolipins. Mucolipin 1 is a membrane protein with 6 transmembrane domains, a serine lipase, and nuclear localization signal motives. The protein shows homology to a group of calcium channels of the TRP/TRPL family. The involvement of this protein in the endocytosis process of membrane components is currently studied. A population screening operation among the Ashkenazi population for the detection of heterozygotes has been started in Israel as a prevention program.
Mol Genet Metab 2001 Jul
PMID:Mucolipidosis type IV. 1146 Nov 86


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