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At least 1,099 records · Page 61Linked to original sources
PubMed2003

Structural control of endoplasmic reticulum-associated degradation: effect of chemical chaperones on 3-hydroxy-3-methylglutaryl-CoA reductase.

The endoplasmic reticulum (ER) quality control pathway destroys misfolded and unassembled proteins in the ER. Most substrates of this ER-associated degradation (ERAD) pathway are constitutively targeted for destruction through recognition of poorly understood structural hallmarks of misfolding. However, the normal yeast ER membrane protein 3-hydroxy-3-methylglutaryl-CoA reductase (Hmg2p) undergoes ERAD that is physiologically regulated by sterol pathway signals. We have proposed that Hmg2p ERAD occurs by a regulated transition to an ERAD quality control substrate. Consistent with this, we had previously shown that Hmg2p is strongly stabilized by chemical chaperones such as glycerol, which stabilize misfolded proteins. To understand the features of Hmg2p that permit regulated ERAD, we have thoroughly characterized the effects of chemical chaperones on Hmg2p. These agents caused a reversible, immediate, direct change in Hmg2p degradation consistent with an effect on Hmg2p structure. We devised an in vitro limited proteolysis assay of Hmg2p in its native membranes. In vitro, chemical chaperones caused a dramatic, rapid change in Hmg2p structure to a less accessible form. As in the living cell, the in vitro action of chemical chaperones was highly specific for Hmg2p and completely reversible. To evaluate the physiological relevance of this model behavior, we used the limited proteolysis assay to examine the effects of changing in vivo degradation signals on Hmg2p structure. We found that changes similar to those observed with chemical chaperones were brought about by alteration of natural degradation signal. Thus, Hmg2p can undergo significant, reversible structural changes that are relevant to the physiological control of Hmg2p ERAD. These findings support the idea that Hmg2p regulation is brought about by regulated alteration of folding state. Considering the ubiquitous nature of quality control pathways in biology, it may be that this strategy of regulation is widespread.

Endoplasmic Reticulum↗
PubMed2004

Asexuality: prevalence and associated factors in a national probability sample.

I used data from a national probability sample (N > 18,000) of British residents to investigate asexuality, defined as having no sexual attraction to a partner of either sex. Approximately 1% (n = 195) of the sample indicated they were asexual. A number of factors were related to asexuality, including gender (i.e., more women than men), short stature, low education, low socioeconomic status, and poor health. Asexual women also had a later onset of menarche relative to sexual women. The results suggest that a number of pathways, both biological and psychosocial, contribute to the development of asexuality.

Adolescent↗
PubMedDate not supplied

Toxicoproteomics: proteomics applied to toxicology and pathology.

Global measurement of proteins and their many attributes in tissues and biofluids defines the field of proteomics. Toxicoproteomics, as part of the larger field of toxicogenomics. seeks to identify critical proteins and pathways in biological systems that are affected by and respond to adverse chemical and environmental exposures using global protein expression technologies. Toxicoproteomics integrates 3 disciplinary areas: traditional toxicology and pathology, differential protein and gene expression analysis, and systems biology. Key topics to be reviewed are the evolution of proteomics, proteomic technology platforms and their capabilities with exemplary studies from biology and medicine, a review of over 50 recent studies applying proteomic analysis to toxicological research, and the recent development of databases designed to integrate -Omics technologies with toxicology and pathology. Proteomics is examined for its potential in discovery of new biomarkers and toxicity signatures, in mapping serum,plasma. and other biofluid proteomes, and in parallel proteomic and transcriptomic studies. The new field of toxicoproteomics is uniquely positioned toward an expanded understanding of protein expression during toxicity and environmental disease for the advancement of public health.

Animals↗
PubMed2006

Integration of genomic data for pharmacology and toxicology using Internet resources.

Genome based technologies such as sequencing and gene expression profiling using microarrays are creating massive amounts of data. Results from these studies have provided unique insights into targets, biochemical pathways, and biological systems affected by drug or xenobiotic chemical treatments. Moreover, these genomic technologies offer the potential to identify biomarkers for pharmacological development or toxicological prediction. Nonetheless, microarray studies involving a single compound produce useful although limited data. To gain further power from these individual studies, the ability to combine datasets through integration schemes has become imperative. In the current study, we describe and analyze currently available Internet resources designed to address this problem. Many functionalities, such as ability to cross reference orthologous genes across species or to combine same technology platform data, are present in these resources. Nonetheless, these resources are limited in the number of technology platforms they can support. While the ability to integrate all currently existing gene expression datasets remains enigmatic, the current tools provide a partial solution that may still yield unique insights into the affects of exogenous molecules at the level of gene expression.

Databases, Genetic↗
PubMed2006

Club drugs as causal risk factors for HIV acquisition among men who have sex with men: a review.

We reviewed medical and psychology databases for articles published between January 1980 and August 2005 demonstrating associations between HIV/Sexually Transmitted Infection risk and club drug use. Seventy-four articles were reviewed, of which 30 provided adjusted risk ratios for associations between HIV/sexually transmitted infection risk and club drug use among men who have sex with men. Definitions and lists of club drugs were broad and inconsistent. We constructed a conceptual framework of biologically plausible pathways for causation. Using Hill's criteria to examine club drugs as causal risk factors for HIV, we found the most evidence for methamphetamine and volatile nitrites; however, more studies are needed.

HIV Infections↗
PubMed1996

A simple procedure for large-scale purification of 9-cis beta-carotene from Dunaliella bardawil.

For experiments designed to obtain reliable data on the metabolic pathway and biological function of 9-cis beta-carotene, sufficient quantity of this substance in pure form is needed. For this purpose, we decided to purify 9-cis beta-carotene from the dry powder of the alga Dunaliella bardawil. By use of both silica gel and ODS open column chromatography and high-performance liquid chromatography (HPLC) on an ODS column and by treatment of the sample with ethanol, we could obtain this carotenoid as fine needle-shaped orange crystals. They were found to be highly pure as judged by analytical HPLC, absorption spectrum, and nuclear magnetic resonance analysis.

Chlorophyta↗
PubMed2005

Multiple angiopoietin recombinant proteins activate the Tie1 receptor tyrosine kinase and promote its interaction with Tie2.

The Tie1 receptor tyrosine kinase was isolated over a decade ago, but so far no ligand has been found to activate this receptor. Here, we have examined the potential of angiopoietins, ligands for the related Tie2 receptor, to mediate Tie1 activation. We show that a soluble Ang1 chimeric protein, COMP-Ang1, stimulates Tie1 phosphorylation in endothelial cells with similar kinetics and angiopoietin dose dependence when compared with Tie2. The phosphorylation of overexpressed Tie1 was weakly induced by COMP-Ang1 also in transfected cells that do not express Tie2. When cotransfected, Tie2 formed heteromeric complexes with Tie1, enhanced Tie1 activation, and induced phosphorylation of a kinase-inactive Tie1 in a ligand-dependent manner. Tie1 phosphorylation was also induced by native Ang1 and Ang4, although less efficiently than with COMP-Ang1. In conclusion, we show that Tie1 phosphorylation is induced by multiple angiopoietin proteins and that the activation is amplified via Tie2. These results should be important in dissecting the signal transduction pathways and biological functions of Tie1.

Angiopoietins↗
PubMed2002

Mechanisms for regulation of cellular responsiveness to human IFN-beta1a.

Interferons (IFNs) are potent, pleiotropic cytokines, and therefore it is likely that the cell has mechanisms to modulate IFN activity in response to excessive or prolonged IFN exposure. To investigate this question, Jurkat T cells were exposed to IFN-beta1a in vitro. The effect of dose and frequency of IFN treatment on receptor expression, the signal transduction pathway, and biologic activity was examined. Results demonstrate that at even modest doses of IFN (60 IU/ml), cell surface expression of the IFN receptor subunit, IFNAR-1, decreased significantly, and the cells were unresponsive to further IFN treatment. More interestingly, after an initial treatment with very low concentrations of IFN (<10 IU/ml), even when receptor levels remained normal and phosphorylation of signaling molecules occurred, cells were still refractory to further IFN treatment. After withdrawal of IFN, full cellular responsiveness was a progressive but surprisingly slow process. Cells retreated 2 days or 4 days after the initial IFN treatment were still refractory to even high doses (500 IU/ml) of IFN. Cells retreated 1 week after the initial IFN treatment were fully responsive. High levels of Stat1 and Stat2 correlated with the block in transcriptional activation of IFN-dependent genes and may be a mechanism by which cells can downmodulate an IFN response. Similar results were obtained when fresh peripheral blood mononuclear cells (PBMC) were treated with IFN and expression of the endogenous IFN-dependent gene, MxA, was examined. Cell surface levels of IFNAR-1 decreased and Stat1 levels increased after IFN-beta treatment, and retreatment with IFN resulted in an attenuated induction of Mx protein expression. In the context of using IFNs as therapeutic agents in the treatment of human disease, our data suggest that increasing the amount or frequency of IFN administration may not yield desired biologic effects. Thus, issues concerning the dosage and the frequency of IFN-beta administration deserve careful consideration.

Cells, Cultured↗
PubMed1999

Wasting in cancer.

Progressive weight loss is a common feature of many types of cancer and is responsible not only for a poor quality of life and poor response to chemotherapy, but also a shorter survival time than is found in patients with comparable tumors without weight loss. Although anorexia is common, a decreased food intake alone is unable to account for the changes in body composition seen in cancer patients, and increasing nutrient intake is unable to reverse the wasting syndrome. Although energy expenditure is increased in some patients, cachexia can occur even with a normal energy expenditure. Various factors have been investigated as mediators of tissue wasting in cachexia. These include cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interferon-gamma (IFN-gamma) and leukemia inhibitory factor (LIF), as well as tumor-derived factors such as lipid mobilizing factor (LMF) and protein mobilizing factor (PMF), which can directly mobilize fatty acids and amino acids from adipose tissue and skeletal muscle respectively. Induction of lipolysis by the cytokines is thought to result from an inhibition of lipoprotein lipase (LPL), although clinical studies provide no evidence for an inhibition of LPL in the adipose tissue of cancer patients. Instead there is an increased expression of hormone sensitive lipase, the enzyme activated by LMF. Protein degradation in cachexia is associated with an increased activity of the ATP-ubiquitin-proteasome pathway. The biological activity of both the LMF and PMF was shown to be attenuated by eicosapentaenoic acid (EPA). Clinical studies show that this polyunsaturated fatty acid is able to stabilize the rate of weight loss and adipose tissue and muscle mass in cachectic patients with unresectable pancreatic cancer. Knowledge of the mechanism of cancer cachexia should lead to the development of new therapeutic agents.

Anorexia↗
PubMed2002

Electron transfer in ferredoxin: are tunneling pathways evolutionarily conserved?

A theoretical study of electron transfer (ET) pathways in a recently crystallized Clostridium acidurici ferredoxin is reported. The electronic structure of the protein complex is treated at the semiempirical extended Hückel level, and the tunneling pathways are calculated with the rigorous quantum mechanical method of tunneling currents. The model predicts two pathways between the two [4Fe-4S] cubanes: a strong one running directly from Cys(14) to Cys(43) and a weaker one from Cys(14) via Ile(23) to Cys(18), whereas other amino acids do not play a significant role in the electron tunneling. The cysteine ligands conduct almost all of the current when Ile(23) is mutated to valine in silico, so that there is no appreciable change in the ET rate. The calculated value of the transfer matrix element is consistent with the experimentally determined rate of transfer. Results of the sequence analysis performed on this ferredoxin reveal that Ile(23) is a highly variable amino acid compared with the cubane-ligating cysteine amino acids, even though Ile(23) lies directly between the donor and acceptor complexes. We further argue that the homologous proteins with a [3Fe-4S] cofactor, which does not have one of the four cysteine ligands, use the same tunneling pathways as those in this ferredoxin, on the basis of the high homology as well as the absolute conservation of Cys(14) and Cys(43) which serve as the main tunneling conduit. Our results explain why mutation of amino acids around and between the donor and acceptor cubane clusters, including that of Ile(23), does not appreciably affect the rate of transfer and add support to the proposal that there exist evolutionarily conserved electron tunneling pathways in biological ET reactions.

Amino Acid Sequence↗
PubMed2006

Isolation of cDNAs for R2R3-MYB, bHLH and WDR transcriptional regulators and identification of c and ca mutations conferring white flowers in the Japanese morning glory.

The transcriptional regulators for anthocyanin biosynthesis include members of proteins containing an R2R3-MYB domain, a bHLH (basic helix-loop-helix) domain and conserved WD40 repeats (WDRs). Spacial and temporal expression of the structural genes encoding the enzymes for anthocyanin biosynthesis is thought to be determined by combinations of the R2R3-MYB, bHLH and WDR factors and their interactions. While the wild-type Japanese morning glory (Ipomoea nil) exhibits blue flowers with colored stems and dark-brown seeds, the c mutants display white flowers with red stems and colored seeds, and the ca mutants exhibit white flowers with green stems and ivory seeds. Here, we characterize the tissue-specific expression of three MYB genes, three bHLH genes and two WDR genes in I. nil. We also show that the recessive c-1 and ca alleles are frameshift mutations caused by a 2 bp deletion and 7 bp insertions in the genes for the R2R3-MYB and WDR transcriptional regulators designated as InMYB1 and InWDR1, respectively. In addition to defects in flower, stem and seed pigmentations, the ca mutants were found to show reduced trichome formation in seeds but to produce leaf and stem trichomes and root hairs normally. Except for the gene for chalcone synthase E in the ca mutant, all structural genes tested were coordinately reduced in both c-1 and ca mutant flower limbs. However, slight but significant expression of the genes for chalcone synthase D, chalcone isomerase and flavanone 3-hydroxylase in the pathway for flavonol biosynthesis was detectable in c-1 and ca mutants, whereas no such residual expression could be observed in other genes involved in the later anthocyanin biosynthesis pathway. The biological roles of the C-1 and Ca genes in I. nil epidermal traits and their evolutionary implications are also discussed.

Acyltransferases↗
PubMed2003

Role of the MET/HGF receptor in proliferation and invasive behavior of osteosarcoma.

Signal transduction downstream HGF receptor (MET) activation involves multiple pathways that account for mitogenesis, motility and morphogenesis in a cell type-dependent fashion. MET receptor is aberrantly expressed in almost 100% of human osteosarcomas. We analyzed the effect of the MET receptor activation in five human osteosarcoma cell lines evaluating the levels of HGF-dependent activation of MAPK and PKB/AKT as biochemical readouts of mitogenic and invasive responses, respectively. All the cell lines tested expressed high levels of the MET proto-oncogene. Four cell lines showed activation of the MAPK cascade upon HGF stimulation, suggesting that this growth factor serves a common proliferative function in osteosarcomas. Two lines showed activation of PKB/AKT that is known to be involved in migration mediated by HGF receptor. Accordingly, cell lines where MAPK cascade was activated responded to HGF with increased proliferation, while induction and inhibition of PKB/AKT activity corresponded to acquisition or block of the invasive-motile response to HGF, respectively. Both the HGF dependent responses were reverted by the specific MET inhibitor K252a. These data show that HGF activates both the mitogen and motogen machinery in osteosarcoma cells and suggest that HGF might promote their malignant behavior by concomitant activation of different pathways and biological functions.

Bone Neoplasms↗
PubMed2003

Rapid induction of distinct stress responses after the release of singlet oxygen in Arabidopsis.

The conditional fluorescent (flu) mutant of Arabidopsis accumulates the photosensitizer protochlorophyllide in the dark. After a dark-to-light shift, the generation of singlet oxygen, a nonradical reactive oxygen species, starts within the first minute of illumination and was shown to be confined to plastids. Immediately after the shift, plants stopped growing and developed necrotic lesions. These early stress responses of the flu mutant do not seem to result merely from physicochemical damage. Peroxidation of chloroplast membrane lipids in these plants started rapidly and led to the transient and selective accumulation of a stereospecific and regiospecific isomer of hydroxyoctadecatrieonic acid, free (13S)-HOTE, that could be attributed almost exclusively to the enzymatic oxidation of linolenic acid. Within the first 15 min of reillumination, distinct sets of genes were activated that were different from those induced by superoxide/hydrogen peroxide. Collectively, these results demonstrate that singlet oxygen does not act primarily as a toxin but rather as a signal that activates several stress-response pathways. Its biological activity in Arabidopsis exhibits a high degree of specificity that seems to be derived from the chemical identity of this reactive oxygen species and/or the intracellular location at which it is generated.

Acclimatization↗
PubMed2005

Interaction of serine acetyltransferase with O-acetylserine sulfhydrylase active site: evidence from fluorescence spectroscopy.

Serine acetyltransferase is a key enzyme in the sulfur assimilation pathway of bacteria and plants, and is known to form a bienzyme complex with O-acetylserine sulfhydrylase, the last enzyme in the cysteine biosynthetic pathway. The biological function of the complex and the mechanism of reciprocal regulation of the constituent enzymes are still poorly understood. In this work the effect of complex formation on the O-acetylserine sulfhydrylase active site has been investigated exploiting the fluorescence properties of pyridoxal 5'-phosphate, which are sensitive to the cofactor microenvironment and to conformational changes within the protein matrix. The results indicate that both serine acetyltransferase and its C-terminal decapeptide bind to the alpha-carboxyl subsite of O-acetylserine sulfhydrylase, triggering a transition from an open to a closed conformation. This finding suggests that serine acetyltransferase can inhibit O-acetylserine sulfhydrylase catalytic activity with a double mechanism, the competition with O-acetylserine for binding to the enzyme active site and the stabilization of a closed conformation that is less accessible to the natural substrate.

Acetyltransferases↗
PubMed2004

Interferons, interferon-like cytokines, and their receptors.

Recombinant interferon-alpha (IFN-alpha) was approved by regulatory agencies in many countries in 1986. As the first biotherapeutic approved, IFN-alpha paved the way for the development of many other cytokines and growth factors. Nevertheless, understanding the functions of the multitude of human IFNs and IFN-like cytokines has just touched the surface. This review summarizes the history of the purification of human IFNs and the key aspects of our current state of knowledge of human IFN genes, proteins, and receptors. All the known IFNs and IFN-like cytokines are described [IFN-alpha, IFN-beta, IFN-epsilon, IFN-kappa, IFN-omega, IFN-delta, IFN-tau, IFN-gamma, limitin, interleukin-28A (IL-28A), IL-28B, and IL-29] as well as their receptors and signal transduction pathways. The biological activities and clinical applications of the proteins are discussed. An extensive section on the evolution of these molecules provides some new insights into the development of these proteins as major elements of innate immunity. The overall structure of the IFNs is put into perspective in relation to their receptors and functions.

Animals↗
PubMed1991

Diversity in receptor signalling: cellular individuality and the search for selective drugs.

Recent developments in the molecular pharmacology of receptor signalling are reviewed. Receptors and other signalling molecules belong to superfamilies characterized by variations on given themes. A remarkable degree of diversity is generated by unique combinations of molecular entities, and there are also interactions between parallel signal transduction pathways. Molecular biology techniques have revealed new targets for drug development, as well as new methods of drug testing. However, it is not yet clear whether molecular and biochemical specificity always correspond to clinical selectivity.

Animals↗
PubMed1984

Changes in the haemolytic activity of bovine serum complement by Hypoderma lineatum (insect oestridae) larval proteinases in naive and immune cattle.

Three serine proteinases (hypodermin A, B and C) of the first instar larvae of Hypoderma lineatum have been assayed for their ability to deplete seric complement of naive or immune cattle. In naive cattle complement consumption is initiated by hypodermin B through the sequence C1-C3 at a concentration of 5 micrograms/ml of serum, and by hypodermin A through the sequence of C3-C9 at a higher concentration of 150 micrograms. The third enzyme presenting a collagenolytic activity has no anti-complementary activity even on C1q. In immune cattle a 70% complement depletion through the classical pathway is observed with 15 micrograms of hypodermin B per ml of serum. The two enzymes A and C appear to play a minor role in the complement depletion via the classical pathway. The biological role of each of these enzymes in the parasite-host interrelationships is discussed. The participation of these enzymes in the immediate hypersensitive reactions following systemic treatment of cattle infested by this endoparasite is considered.

Animals↗
PubMed1996

Ida Mann Lecture. Transduction in human photoreceptors.

Phototransduction (the process by which light triggers a neural response in retinal rod and cone photoreceptors) is now understood at a molecular level. Indeed, the G-protein cascade of phototransduction is one of the best understood of all biological signalling pathways. The diffusional interactions of the proteins underlying the cascade are described and are briefly analysed. In response to a single activated rhodopsin (R*), formed as a result of a single photon hit, it can be shown that molecules of the G-protein will be activated (to G*) at an approximately constant rate. This, in turn, will cause the number of activated molecules of the third protein (the effector protein, E*, a phosphodiesterase) also to rise linearly with time. These kinetics of protein activation lead to an accurate description of the time-course of the rising phase of the photoreceptor's electrical response, both in single-cell recordings and also in recordings of the human electroretinogram (ERG). By analysing the a-wave of the ERG it is possible to determine the 'amplification' of transduction within living photoreceptors, and to begin to localise the molecular site of dysfunction is cases of photoreceptor abnormality.

Electroretinography↗