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At least 721 records · Page 40Linked to original sources
PubMed2002

The regulation of HIV-1 gene expression: the emerging role of chromatin.

Host and viral factors that regulate the expression of the human immunodeficiency virus type 1 (HIV-1) 5' long terminal repeat (LTR) promoter have been studied since the recognition that HIV is the cause of the acquired immunodeficiency syndrome (AIDS). However, complex modifications of nucleosomes within chromatin has been recently recognized as an important mechanism of gene regulation. Nucleosome remodelling can alter the accessibility of DNA to specific activators or repressors, general transcription factors, and RNA polymerase. Emerging data now suggests that dynamic regulation of chromatin structure in the vicinity of the LTR promoter adds an additional level of complexity to the regulation of HIV expression. A better understanding of the role of chromatin in the regulation of HIV expression could lead to much-needed therapies against proviral genomes that are being actively transcribed, and those that are quiescent and persistent.

Chromatin↗
PubMed2003

Hypochlorite action on plasma fibronectin promotes its extended conformation in complexes with antibodies.

We investigated the influence of hypochlorite (HOCl/OCl-) on plasma fibronectin (Fn) aggregation and examined an affinity of Fn aggregates to Fn specific antibodies. Human plasma Fn HOCl/OCl(-)-mediated modification was monitored with differential OD method and with measurements of tryptophan fluorescence followed by acrylamide quenching of tryptophan emission. Antibody fibronectin complex formation was examined in ELISA systems with chemiluminescence (CL) detection. Results were expressed as an average of three experiments performed in triplicate. Fn aggregation/fragmentation was monitored with dynamic light scattering method. It was showed that HOCl/OCl- mediated chlorination promotes Fn aggregation/fragmentation with concomitant oxidation of tryptophan moieties and dichlorotyrosine formation. Quenching experiments revealed that in chlorinated Fn the percentage of intact tryptophan moieties buried in the hydrophobic Fn core increases as compared to unchlorinated Fn. In general, ELISA experiments showed that chlorination of plasma Fn diminished the number of available epitopes but for lower HOCl/OCl- concentrations (1-2 mM) the reverse effect is observed--the number of accessible fibronectin epitopes is increased when Fn adopts extended conformation in complex with antibody. Our results suggest that HOCl/OCl(-)-mediated plasma Fn chlorination leads to the formation of soluble aggregates and is followed by refolding processes. Fn chlorination with low doses of HOCl/OCl- promotes extended Fn conformation which in turn increases affinity toward specific antibodies and may promote Fn-IgG cluster formation. Thus it seems possible that mildly chlorinated plasma Fn promotes formation of IgG clusters which in turn may activate neutrophils.

Acrylamide↗
PubMed2005

Leptin promoter mutations affect leptin levels and performance traits in dairy cows.

Leptin concentrations in body fluids and tissues undergo dynamic changes during the periparturient period. Polymorphisms in the leptin gene have been shown to be associated with differences in leptin concentration during late pregnancy but not during lactation. As the promoter of leptin regulates the expression of leptin, polymorphisms in this region could play an important role in the differences in leptin expression observed during the periparturient period. We sequenced the leptin promoter and discovered 20 SNP in a 1.6-kbp region of the bovine leptin promoter. Fourteen of these SNP were genotyped for all animals and these were found to be associated with leptin concentrations during late pregnancy but not during lactation. Three of these SNP are located in a 135-bp promoter region and together explained 14.3% of the variance in prepartum leptin concentrations which indicates that this region might be important for pregnancy-induced leptin synthesis. In the association study of the 14 SNP with dairy traits three were separately found to be associated with fertility, energy balance and protein yield. These might serve as markers for future breeding programmes for better fertility and energy balance without significantly influencing milk yield in dairy cattle.

Animals↗
PubMed2006

BAL1 and BBAP are regulated by a gamma interferon-responsive bidirectional promoter and are overexpressed in diffuse large B-cell lymphomas with a prominent inflammatory infiltrate.

BAL1 is a transcription modulator that is overexpressed in chemoresistant, diffuse large B-cell lymphomas (DLBCLs). BAL1 complexes with a recently described DELTEX family member termed BBAP. Herein, we characterized BAL1 and BBAP expression in primary DLBCL subtypes defined by their comprehensive transcriptional profiles. BAL1 and BBAP were most abundant in lymphomas with a brisk host inflammatory response, designated host response (HR) tumors. Although these DLBCLs include significant numbers of tumor-infiltrating lymphocytes and interdigitating dendritic cells, BAL1 and BBAP were expressed primarily by malignant B cells, prompting speculation that the genes might be induced by host-derived inflammatory mediators such as gamma interferon (IFN-gamma). In fact, IFN-gamma induced BAL1 and BBAP expression in DLBCL cell lines; doxycycline-induced BAL1 also increased the expression of multiple IFN-stimulated genes, directly implicating BAL1 in an IFN signaling pathway. We show that BAL1 and BBAP are located on chromosome 3q21 in a head-to-head orientation and are regulated by a IFN-gamma-responsive bidirectional promoter. BBAP regulates the subcellular localization of BAL1 by a dynamic shuttling mechanism, highlighting the functional requirement for coordinated BBAP and BAL1 expression. IFN-gamma-induced BAL1/BBAP expression contributes to the molecular signature of HR DLBCLs and highlights the interplay between the inflammatory infiltrate and malignant B cells in these tumors.

Base Sequence↗
PubMed2000

Structural transitions at microtubule ends correlate with their dynamic properties in Xenopus egg extracts.

Microtubules are dynamically unstable polymers that interconvert stochastically between growing and shrinking states by the addition and loss of subunits from their ends. However, there is little experimental data on the relationship between microtubule end structure and the regulation of dynamic instability. To investigate this relationship, we have modulated dynamic instability in Xenopus egg extracts by adding a catastrophe-promoting factor, Op18/stathmin. Using electron cryomicroscopy, we find that microtubules in cytoplasmic extracts grow by the extension of a two- dimensional sheet of protofilaments, which later closes into a tube. Increasing the catastrophe frequency by the addition of Op18/stathmin decreases both the length and frequency of the occurrence of sheets and increases the number of frayed ends. Interestingly, we also find that more dynamic populations contain more blunt ends, suggesting that these are a metastable intermediate between shrinking and growing microtubules. Our results demonstrate for the first time that microtubule assembly in physiological conditions is a two-dimensional process, and they suggest that the two-dimensional sheets stabilize microtubules against catastrophes. We present a model in which the frequency of catastrophes is directly correlated with the structural state of microtubule ends.

Animals↗
PubMed2005

Stochastic dynamics of metastasis formation.

Tumor metastasis accounts for the majority of deaths in cancer patients. The metastatic behavior of cancer cells is promoted by mutations in many genes, including activation of oncogenes such as RAS and MYC. Here, we develop a mathematical framework to analyse the dynamics of mutations enabling cells to metastasize. We consider situations in which one mutation is necessary to confer metastatic ability to the cell. We study different population sizes of the main tumor and different somatic fitness values of metastatic cells. We compare mutations that are positively selected in the main tumor with those that are neutral or negatively selected, but faster at forming metastases. We study whether metastatic potential is the property of all (or the majority of) cells in the main tumor or only the property of a small subset. Our theory shows how to calculate the expected number of metastases that are formed by a tumor.

Computer Simulation↗
PubMed2003

Differential distribution of DNA methylation within the RASSF1A CpG island in breast cancer.

Aberrant DNA methylation of promoter CpG islands is associated with transcriptionally repressive heterochromatin in neoplasia. The dynamics of this epigenetic process in mediating the transition from an active to an inactive state of transcription remains to be elucidated, however. Here, we used the methylation-specific oligonucleotide microarray to map the methylation patterns of a CpG island, located within the promoter and the first exon regions of RASSF1A, in normal breast tissue controls, primary tumors, and breast cancer cell lines. Oligonucleotide pairs, spaced along the CpG island region, were designed to discriminate between methylated and unmethylated alleles of selected sites. The methylation-specific oligonucleotide data indicate that the majority of test samples show widespread methylation in the first exon of RASSF1A. In contrast, the promoter area was usually undermethylated in normal controls and in 32% of the primary tumors tested, whereas the rest of the primary tumors and breast cancer cell lines showed various degrees of methylation in the region. Methylation profiling of individual tumors further suggest that DNA methylation progressively spreads from the first exon into the promoter area of this gene. Functional analysis indicates that increased density of RASSF1A promoter methylation is associated with altered chromatin, marked by a depletion of acetylated histones and methylated histone 3-lysine 4 and an enrichment of methylated histone 3-lysine 9 in the studied area. The combination of these epigenetic modifications may engender a stable silencing of the gene in breast cancer cells. Thus, this study underscores the importance of detailed mapping of methylation patterns within a CpG island locus that may provide insights into the progressive nature of aberrant DNA methylation and its relationship with transcriptional silencing during the neoplastic process.

Acetylation↗
PubMed2005

Molecular dynamics simulation of truncated bovine adrenodoxin.

The 128 amino acid long soluble protein adrenodoxin (Adx) is a typical member of the ferredoxin protein family that are electron carrier proteins with an iron-sulfur cofactor. Adx carries electrons from adrenodoxin reductase (AdR) to cytochrome P450s. Its binding modes to these proteins were previously characterized by site-directed mutagenesis, by X-ray crystallography for the complex Adx:AdR, and by NMR. However, no clear evidence has been provided for the driving force that promotes Adx detachment from AdR upon reduction. Here, we characterized the conformational dynamics of unbound Adx in the oxidized and reduced forms using 2-20 ns long molecular dynamics simulations. The most noticeable difference between both forms is the enhanced flexibility of the loop (47-51) surrounding the iron-sulfur cluster in the reduced form. Together with several structural displacements at the binding interface, this increased flexibility may be the key factor promoting unbinding of reduced Adx from AdR. This points to an intrinsic property of reduced Adx that drives dissociation.

Adrenodoxin↗
PubMed2006

Diverse DNA methylation statuses at alternative promoters of human genes in various tissues.

We characterized the DNA methylation status at 144 tissue-biased and 37 non-tissue-biased alternative promoters of 61 human genes in five normal tissues. Analysis of the collected data revealed that (i) DNA methylation status differed greatly among alternative promoters belonging to the same gene; (ii) DNA methylation status differed between tissues for the majority of the individual promoters, and (iii) 80-90% of CpG-island-containing promoters were not methylated on either allele throughout the five tissues examined. Furthermore, although the statistical significance was not as clear as for the above features, we also found that (iv) the DNA methylation patterns of tissue-biased promoters changed more drastically than those of non-tissue-biased promoters; (v) tissue-biased promoters tended to be less methylated than their respective alternative promoters in the tissues where they were preferentially expressed, and (vi) the 'null' methylation pattern of a given promoter was enriched in the tissues where the transcription was most active. These findings together indicate that there are dynamic physiological changes of DNA methylation. DNA methylation appears to play a significant role in differential usage of alternative promoters and may be related to functional diversification between CpG-island-containing promoters and CpG-island-less promoters.

Brain↗
PubMed2000

Dynamics of gene targeting and chromatin remodelling by nuclear receptors.

Activation of the murine-mammary-tumour virus (MMTV) promoter by the glucocorticoid receptor (GR) is associated with a chromatin structural transition in the B nucleosome region of the viral long terminal repeat (LTR). We have reconstituted this nucleoprotein transition with chromatin assembled on MMTV LTR DNA with Drosophila embryo extracts, purified GR, and HeLa nuclear extract. Chromatin remodelling in vitro is ATP-dependent and maps to a region identical with that found in vivo. We demonstrate specific, glucocorticoid response element dependent, binding of purified GR to a large, multi-nucleosome MMTV chromatin array and show that GR-dependent chromatin remodelling is a multistep process. In the absence of ATP, GR binds to multiple sites on the chromatin array and inhibits nuclease access to GR recognition sites. On the addition of ATP, GR induces remodelling resulting in a large increase in access of enzymes to their sites within the transition region. These findings are complemented by studies in living cells; using a tandem array of MMTV-Ras reporter elements and a form of GR labelled with the green fluorescent protein, we have observed direct targeting of the receptor to response elements in live mouse cells. Whereas the ligand-activated receptor is associated with the MMTV promoter for observable periods, photobleaching experiments provide direct evidence that the hormone-occupied receptor undergoes rapid exchange between chromatin and the nucleoplasmic compartment. The results both in vitro and in vivo are consistent with a dynamic model ('hit and run') in which GR first binds to chromatin after ligand activation, recruits a remodelling activity and is then lost from the template.

Adenosine Triphosphate↗
PubMed2003

Correlation of intimal hyperplasia development and shear stress distribution at the distal end-side-anastomosis, in vitro study using particle image velocimetry.

Low shear areas at the distal anastomosis of peripheral bypasses are thought to promote neointimal hyperplasia. In this study we evaluated the fluid dynamic environment at the distal anastomosis of peripheral bypasses by means of a new method for in vitro flow visualization and quantitative velocity field measurement. A silastic model of a distal end-side anastomosis was attached to a mock circulation loop driven by an artificial heart. High resolution velocity fields were measured by means of particle image velocimetry (PIV). The velocity vector data were used to calculate vorticity omega, strain rates ex, shear rates h and shear stresses tau. Two separations and a stagnation zone were identified by means of flow visualization. Measured velocities inside the three zones were significantly lower than in the high velocity mainstream. Calculated shear rates and shear stresses inside the zones were significantly lower than human wall shear rates. At the transition between the effective mainstream and the boundary layers high vorticity and compressive strain fields existed, indicating the presence of high shear forces. The locations of these areas corresponded to the well known zones of intimal hyperplasia. The high resolution shear stress analysis supports the low shear theory of intimal hyperplasia development. A wall diversion angle greater than 6 degrees leads to flow separation and presumed IH promotion until high shear transition areas are reached.

Anastomosis, Surgical↗
PubMed2002

Fluid dynamics, wall mechanics, and oxygen transfer in peripheral bypass anastomoses.

Intimal hyperplasia at vascular anastomoses seems to be promoted by altered flow conditions and stress distributions within the anastomotic region. In order to gain deeper insight into postoperative disease processes, and subsequently, to contribute to the development of improved vascular reconstructions, detailed studies, also on local flow dynamics and related mass transport and wall mechanical effects, are required. In context with in vivo studies, computer simulation based on casts of femoro-popliteal bypasses implanted into sheep were performed to analyze the flow dynamics, the oxygen transport, and the wall and suture mechanics in anatomically correct bypass configurations related to three established surgical techniques and resulting geometries (conventional type anastomosis, Taylor-patch and Miller-cuff anastomoses with venous interposition grafts of different modifications). The influence of geometry, compliance of the graft, the interponated vein patch and vein cuff, and of the artery was included. Time-dependent, three-dimensional Navier-Stokes equations describing the flow field, and a nonlinear shell structure for the vessel walls were coupled using finite element methods. The numerical results demonstrate nonphysiological flow patterns in the anastomotic region. Strongly skewed axial velocity profiles and secondary velocities occur in the junction region. In the Miller-cuff a vortex may induce a wash-out effect which protects the host artery. On the artery floor opposite the junction flow separation and zones of recirculation were found. The analysis of oxygen transport illustrates a correlation between zones of low wall shear stress and reduced oxygen flux into the wall. Wall mechanics show that increased compliance mismatch leads to increased and discontinuous intramural stresses. Comparison to histomorphological findings on intimal hyperplasia shows certain correlations, particularly increased compliance mismatch has a proliferate influence on suture line hyperplasia. The reduction of compliance mismatch using vein interposition results in decreased generation of intimal hyperplasia, and therefore, contributes to improvement of patency rates, while the geometrical modification and the resulting change of the flow pattern seems to be less important for the growth of anastomotic intimal hyperplasia.

Anastomosis, Surgical↗
PubMed2004

Comparison of molecular dynamics averaged structures for complexes of normal and oncogenic ras-p21 with SOS nucleotide exchange protein, containing computed conformations for three crystallographically undefined domains, suggests a potential role of these domains in ras signaling.

ras-p21 protein binds to the son-of-sevenless (SOS) guanine nucleotide-exchange promoter that allows it to exchange GDP for GTP. Previously, we performed molecular dynamics calculations on oncogenic (Val 12-) and wild-type ras-p21 bound to SOS. By superimposing the average structures of these two complexes, we identified four domains (residues 631-641, 676-691, 718-729, and 994-1004) in SOS that change conformation and were candidates for being effector domains. These calculations were performed in the absence of three crystallographically undefined loops (i.e., residues 591-596, 654-675, and 742-751). We have now modeled these loops into the SOS structure and have re-performed the dynamics calculations. We find that all three loop domains undergo large changes in conformation that involve mostly changes in their positioning and not their individual conformations. We have also identified another potential effector domain (i.e., residues 980-989). Overall, our current results suggest that SOS interactions with oncogenic ras-p21 may enhance ras-p21 mitogenic signaling through prolonging its activation by maintaining its binding to GTP and by allowing its effector domains to interact with intracellular targets.

Animals↗
PubMed2006

Environmental discontinuity hypothesis: Buffer dysfunctions as a source of human disease.

Adaptive physiologic buffers enable organisms to respond to environmental variation with appropriate plasticity. Modern humans have substantially remodeled their environment such that many interactions with the environment have become relatively discontinuous functions compared to the past. Examples include sunlight, temperature, and altitude. We propose that environmental discontinuity represents a Darwinian maladaptation and may promote disease by inducing buffer dysfunctions. Skin pigmentation is an adaptive, dynamic buffer that normalizes sunlight exposure to balance the potential harm of damaging rays with the importance of sunlight in driving systemic biologic functions such as melatonin and vitamin D. Due to lifestyle characteristics such as indoor-outdoor living, well-intended sun-avoidance campaigns, and inhomogeneous use of apparel and sunblock techniques, modern humans increasingly experience sunlight variation as a discontinuous function. The resulting skin pigmentation buffer dysfunction may promote diseases associated with over- or under-exposure to sunlight, the most striking example being melanoma. In addition to promoting discontinuity of sunlight exposure, sun-avoidance campaigns may undermine sun-dependent biologic pathways such as melatonin and vitamin D that appear to protect against cancer. These issues may partly explain the rise in melanoma rates despite the implementation of sun-avoidance campaigns. Also discussed is the potential role that discontinuous temperature variation associated with modern lifestyles plays in diseases such as viral infection, heart failure, and acute coronary syndromes. Acute discontinuous changes in pressure and oxygen levels related to air travel may contribute to autonomic dysfunction, venous thromboembolism, and viral infections. Therapeutic implications are discussed.

Adaptation, Physiological↗
PubMed2006

Up-regulation of the KLF2 transcription factor by fluid shear stress requires nucleolin.

We have previously characterized the regulation of the KLF2 transcription factor gene by describing an induction complex that binds to and regulates its promoter. In the present study, by using DNA affinity chromatography and mass spectrometry, we have identified nucleolin as an additional protein that binds to a palindromic response region in the KLF2 promoter. The presence of nucleolin on the KLF2 promoter in macrophages was verified by electrophoretic mobility shift assays. Interestingly, in mouse and human endothelial cell lines, electrophoretic mobility shift assays and chromatin immunoprecipitation analyses indicated that nucleolin binds the KLF2 promoter only upon application of fluid shear stress. Pretreatment of the endothelial cells with LY294002, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K), blocked the shear stress-induced binding of nucleolin to the promoter, demonstrating its PI3K-dependent regulation. Additionally, nucleolin exhibited dynamic flow-specific, PI3K-dependent alterations in size. Anti-nucleolin antibodies interacted with a 110-kDa form in static endothelial cells and with several catalytic forms that changed in abundance after the application of shear stress. Immunoprecipitation experiments demonstrated that fluid flow induced the interaction of nucleolin with the p85 regulatory subunit of PI3K. Finally, introduction of small interfering RNAs targeting the nucleolin genetic sequence selectively reduced nucleolin expression and was sufficient to block the induction of KLF2 by shear stress. These data support a general role for nucleolin in gene regulation and identify it as a novel factor involved in regulation of KLF2 expression.

Amino Acid Sequence↗
PubMed2004

The beta-thymosin/WH2 domain; structural basis for the switch from inhibition to promotion of actin assembly.

The widespread beta-thymosin/WH2 actin binding domain has versatile regulatory properties in actin dynamics and motility. beta-thymosins (isolated WH2 domain) maintain monomeric actin in a "sequestered" nonpolymerizable form. In contrast, when repeated in tandem or inserted in modular proteins, the beta-thymosin/WH2 domain promotes actin assembly at filament barbed ends, like profilin. The structural basis for these opposite functions is addressed using ciboulot, a three beta-thymosin repeat protein. Only the first repeat binds actin and possesses the function of ciboulot. The region that shows the strongest interaction with actin is an amphipathic N-terminal alpha helix, present in all beta-thymosin/WH2 domains, which recognizes the ATP bound actin structure and uses the shear motion of actin linked to ATP hydrolysis to control polymerization. Crystallographic ((1)H, (15)N), NMR, and mutagenetic data reveal that the weaker interaction of the C-terminal region of beta-thymosin/WH2 domain with actin accounts for the switch in function from inhibition to promotion of actin assembly.

Actins↗
PubMed2000

[Dynamics of mitotic index of buckwheat root meristems, developing from seeds subjected to percussive wave treatment].

A method of percussive wave treatment of seeds, promoting activization of physiological processes in plants, was proposed. The influence of physical treatment on cell nuclei and phytohormones was investigated. We examined dynamics of mitotic indices (MI) of the root meristems of buckwheat seedlings 48-58 h after the treatment. The seeds were treated with pressures of 11, 23, 29 MPa. The synchrony of cell divisions was estimated according to the augmentation of maximum MI versus average MI. The maximum and the average MI of control seedlings was 9.6 and 8.1%, resp. After the treatment with the pressure of 11 MPa the average MI increased by 2.6 times, and synchrony raised by 50%. After the treatment by the pressure of 23 MPa the average value of MI did not change versus the control, but the synchrony enhanced by 2.8 times. After the treatment of the pressure of 29 MPa the average MI decreased by 31%, the synchrony increased by 33%. Examination of phase indexes allowed to reveal the damage of cytotomy, transition to metaphase, and mitotic apparatus formation. The MI of root meristems of the test seedling aged 8 days topped the control by 21, 156 and 20%. So, the pressure of 11 MPa promoted MI increase in 2 days, and those of 23 and 29 MPa in 8 days. The investigation of hormone balance allowed to detect a raising level of abscisic acid. Its influence on the plant growth depends on the content of zeatin. A hypothetical model of plant reaction mechanism was proposed, based on the obtained results. A momentary pressing in the percussive wave was a stressor, promoting the accumulation of ABA and "growth rest", that changed for an active growth induced by zeatin.

Fagopyrum↗