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PubMed1996

Constitutive insulin-like growth factor-II expression interferes with the enterocyte-like differentiation of CaCo-2 cells.

In this study we have examined the role of insulin-like growth factor-II (IGF-II) in the differentiation of the CaCo-2 human colon carcinoma cell line. We have shown previously that IGF-II is an autocrine growth factor for CaCo-2 cells. IGF-II expression is high in proliferating, undifferentiated CaCo-2 cells and markedly decreases when cells become confluent and start to differentiate. To evaluate whether differentiation of CaCo-2 cells depends on an IGF-II related pathway, we treated cells with a blocking antibody to the IGF-I receptor that mediates most IGF-II biological effects. Treatment of preconfluent CaCo-2 cells with this antibody decreased by 40% autonomous cell proliferation and induced differentiation as shown by an increase in sucrase isomaltase activity and apolipoprotein A-I (apoA-I) mRNA levels. To examine the significance of autocrine IGF-II production in CaCo-2 cell differentiation, we generated stable CaCo-2 cell lines that constitutively express rat IGF-II under the control of a Rous sarcoma virus promoter. Sustained expression of IGF-II resulted in: (a) increased proliferative rate; (b) high IGF-I receptor number, even after reaching confluence; (c) increased capability of anchorage-independent growth; (d) inhibition of the expression of apoA-I and SI mRNAs. Analysis of several independent IGF-II-transfected clones showed an inverse correlation between IGF-II mRNA levels and expression of the differentiation markers, the cells expressing the higher levels of the transfected IGF-II being the less differentiated ones. Our data suggest that perturbation of IGF-II-mediated cell proliferation interferes with the enterocyte-like differentiation pathway of CaCo-2 cells.

Apolipoprotein A-I↗
PubMed2000

Roles of the histone H2A-H2B dimers and the (H3-H4)(2) tetramer in nucleosome remodeling by the SWI-SNF complex.

SWI-SNF is an ATP-dependent chromatin remodeling complex required for expression of a number of yeast genes. Previous studies have suggested that SWI-SNF action may remove or rearrange the histone H2A-H2B dimers or induce a novel alteration in the histone octamer. Here, we have directly tested these and other models by quantifying the remodeling activity of SWI-SNF on arrays of (H3-H4)(2) tetramers, on nucleosomal arrays reconstituted with disulfide-linked histone H3, and on arrays reconstituted with histone H3 derivatives site-specifically modified at residue 110 with the fluorescent probe acetylethylenediamine-(1,5)-naphthol sulfonate. We find that SWI-SNF can remodel (H3-H4)(2) tetramers, although tetramers are poor substrates for SWI-SNF remodeling compared with nucleosomal arrays. SWI-SNF can also remodel nucleosomal arrays that harbor disulfide-linked (H3-H4)(2) tetramers, indicating that SWI-SNF action does not involve an obligatory disruption of the tetramer. Finally, we find that although the fluorescence emission intensity of acetylethylenediamine-(1,5)-naphthol sulfonate-modified histone H3 is sensitive to octamer structure, SWI-SNF action does not alter fluorescence emission intensity. These data suggest that perturbation of the histone octamer is not a requirement or a consequence of ATP-dependent nucleosome remodeling by SWI-SNF.

Adenosine Triphosphatases↗
PubMed2003

Functional roles of loops 3 and 4 in the cyclic nucleotide binding domain of cyclic AMP receptor protein from Escherichia coli.

Cyclic AMP is a ubiquitous secondary message that regulates a large variety of functions. The protein structural motif that binds cAMP is highly conserved with the exception of loops 3 and 4, whose structure and length are variable. The cAMP receptor protein of Escherichia coli, CRP, was employed as a model system to elucidate the functional roles of these loops. Based on the sequence differences between CRP and cyclic nucleotide gated channel, three mutants of CRP were constructed: deletion (residues 54-56 in loop 3 were deleted), insertion (loop 4 was lengthened by 5 residues between Glu-78 and Gly-79) and double mutants. The effects of these mutations on the structure and function of CRP were monitored. Results show that the deletion and insertion mutations do not significantly change the secondary structure of CRP, although the tertiary and quaternary structures are perturbed. The functional data indicate that loop 3 modulates the binding affinities of cAMP and DNA. Although the lengthened loop 4 may have some fine-tuning functions, the specific function of the original loop 4 of CRP remains uncertain. The function consequences of mutation in loop 3 of CRP are similar to that of site A and site B in the regulatory subunits of cyclic AMP-dependent protein kinases. Thus, the roles played by loop 3 in CRP may represent a more common mechanism employed by cyclic nucleotide binding domain in modulating ligand binding affinity and intramolecular communication.

Amino Acid Sequence↗
PubMed2004

PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress.

The accumulation of unfolded proteins elicits a cellular response that triggers both pro-survival and pro-apoptotic signaling events. PERK-dependent activation of NF-E2-related factor-2 (Nrf2) is critical for survival signaling during this response; however, the mechanism whereby Nrf2 confers a protective advantage to stressed cells remains to be defined. We now demonstrate that Nrf2 activation contributes to the maintenance of glutathione levels, which in turn functions as a buffer for the accumulation of reactive oxygen species during the unfolded protein response. The deleterious effects of Nrf2 or PERK deficiencies could be attenuated by the restoration of cellular glutathione levels or Nrf2 activity. In addition, the inhibition of reactive oxygen species production attenuated apoptotic induction following endoplasmic reticulum stress. Our data suggest that perturbations in cellular redox status sensitize cells to the harmful effects of endoplasmic reticulum stress, but that other factors are essential for apoptotic commitment.

Animals↗
PubMed2004

Structure of the hepatocyte nuclear factor 6alpha and its interaction with DNA.

Hepatocyte nuclear factor 6 (HNF-6) belongs to the family of One Cut transcription factors (also known as OC-1) and is essential for the development of the mouse pancreas, gall bladder, and the interhepatic bile ducts. HNF-6 binds to DNA as a monomer utilizing a single cut domain and a divergent homeodomain motif located at its C terminus. Here, we have used NMR methods to determine the solution structures of the 162 amino acid residue DNA-binding domain of the HNF-6alpha protein. The resulting overall structure of HNF-6alpha has two different distinct domains: the Cut domain and the Homeodomain connected by a long flexible linker. Our NMR structure shows that the Cut domain folds into a topology homologous to the POU DNA-binding domain, even though the sequences of these two protein families do not show homology. The DNA contact sequence of the HNF-6alpha was mapped with chemical shift perturbation methods. Our data also show that a proposed CREB-binding protein histone acetyltransferase protein-recruiting sequence, LSDLL, forms a helix and is involved in the hydrophobic core of the Cut domain. The structure implies that this sequence has to undergo structural changes when it interacts with CREB-binding protein.

Acetyltransferases↗
PubMed2005

Protease-activated receptor-1 signaling by activated protein C in cytokine-perturbed endothelial cells is distinct from thrombin signaling.

Activated protein C (APC) has anti-inflammatory and vascular protective effects independent of anticoagulation. We previously identified the prototypical thrombin receptor, protease-activated receptor-1 (PAR1), as part of a novel APC-endothelial cell protein C receptor (EPCR) signaling pathway in endothelial cells. Experiments in wild-type and PAR1(-/-) mice demonstrated that intravenous injection of APC leads to PAR1-dependent gene induction in the lung. The vascular endothelium undergoes profound changes in severe sepsis, the approved therapeutic indication for APC. Similar to PAR1, APC activated PAR2 through canonical cleavage. Although PAR2 was up-regulated in cytokine-stimulated endothelial cells, APC signaling remained PAR1-dependent. Large scale gene expression profiling documented marked differences in both up- and down-regulated genes between APC and thrombin signaling in cytokine-stimulated cells. APC down-regulated transcripts for proapoptotic proteins including p53 and thrombospondin-1, but p53 was unchanged, and thrombospondin was even up-regulated by thrombin. Concordant PAR1-dependent effects on protein levels were found. Thus, by signaling through the same receptor PAR1, APC, and thrombin can exert distinct biological effects in perturbed endothelium. These data may explain how APC can be therapeutically protective through the EPCR-PAR1 signaling despite ongoing thrombin generation due to disseminated intravascular coagulopathy.

Animals↗
PubMed2004

Endocrine pancreatic dysfunction in HIV-infected children: association with growth alterations.

BACKGROUND: The pancreatic endocrine system normally guarantees a quick and efficient response to daily metabolic perturbations, but associated data for human immunodeficiency virus (HIV)-infected patients are lacking. A prospective study was performed to evaluate pancreatic endocrine secretion and its possible association with failure to thrive among HIV-infected children. METHODS: Fourteen well-nourished, prepubertal, HIV-infected children (6 boys and 8 girls; age range, 5-11 years), none of whom were receiving protease inhibitors, and 16 clinically healthy sex- and age-matched children formed the patient group and the control group, respectively. At yearly follow-up examinations, insulin, glucagon, C-peptide, and glucose levels were measured; the ratio of insulin to glucose, the ratio of insulin to glucagon, and the homeostasis model assessment (HOMA) index were calculated; the glucagon test was administered; and growth hormone, thyroid-stimulating hormone, adrenocorticotropic hormone, cortisol, and lipid patterns were evaluated. RESULTS: Insulin, glucagon, C-peptide, glucose, and HOMA measurements were significantly higher among patients, compared with control subjects, at all 3 follow-ups performed to date. The glucagon test revealed a normal glycemic response in all the healthy control subjects and a significantly impaired response in 11 patients. A significant correlation emerged between the ratio of insulin to glucagon and the growth velocity of HIV-infected children. CONCLUSION: To our knowledge, the present study provides the first evidence of altered pancreatic endocrine secretion and its association with growth failure among HIV-infected children.

Blood Glucose↗
PubMed2001

Comparison of the IAEA TRS-398 and AAPM TG-51 absorbed dose to water protocols in the dosimetry of high-energy photon and electron beams.

The International Atomic Energy Agency (IAEA TRS-398) and the American Association of Physicists in Medicine (AAPM TG-51) have published new protocols for the calibration of radiotherapy beams. These protocols are based on the use of an ionization chamber calibrated in terms of absorbed dose to water in a standards laboratory's reference quality beam. This paper compares the recommendations of the two protocols in two ways: (i) by analysing in detail the differences in the basic data included in the two protocols for photon and electron beam dosimetry and (ii) by performing measurements in clinical photon and electron beams and determining the absorbed dose to water following the recommendations of the two protocols. Measurements were made with two Farmer-type ionization chambers and three plane-parallel ionization chamber types in 6, 18 and 25 MV photon beams and 6, 8, 10, 12, 15 and 18 MeV electron beams. The Farmer-type chambers used were NE 2571 and PTW 30001, and the plane-parallel chambers were a Scanditronix-Wellhöfer NACP and Roos, and a PTW Markus chamber. For photon beams, the measured ratios TG-51/TRS-398 of absorbed dose to water Dw ranged between 0.997 and 1.001, with a mean value of 0.999. The ratios for the beam quality correction factors kQ were found to agree to within about +/-0.2% despite significant differences in the method of beam quality specification for photon beams and in the basic data entering into kQ. For electron beams, dose measurements were made using direct N(D,w) calibrations of cylindrical and plane-parallel chambers in a 60Co gamma-ray beam, as well as cross-calibrations of plane-parallel chambers in a high-energy electron beam. For the direct N(D,w) calibrations the ratios TG-51/TRS-398 of absorbed dose to water Dw were found to lie between 0.994 and 1.018 depending upon the chamber and electron beam energy used, with mean values of 0.996, 1.006, and 1.017, respectively, for the cylindrical, well-guarded and not well-guarded plane-parallel chambers. The Dw ratios measured for the cross-calibration procedures varied between 0.993 and 0.997. The largest discrepancies for electron beams between the two protocols arise from the use of different data for the perturbation correction factors p(wall) and p(dis) of cylindrical and plane-parallel chambers, all in 60Co. A detailed analysis of the reasons for the discrepancies is made which includes comparing the formalisms, correction factors and the quantities in the two protocols.

Air↗
PubMed1999

A cell signal pathway involving laminin-5, alpha3beta1 integrin, and mitogen-activated protein kinase can regulate epithelial cell proliferation.

Laminin-5 (LN5) is a matrix component of epithelial tissue basement membranes and plays an important role in the initiation and maintenance of epithelial cell anchorage to the underlying connective tissue. Here we show that two distinct LN5 function-inhibitory antibodies, both of which bind the globular domain of the alpha3 subunit, inhibit proliferation of epithelial cells. These same antibodies also induce a decrease in mitogen-activated protein kinase activity. Inhibition of proliferation by the function-perturbing LN5 antibodies is reversed upon removal of the antibodies and can be overcome by providing the antibody-treated cells with exogenous LN5 and rat tail collagen. Because epithelial cells use the integrin receptor alpha3beta1 to interact with both LN5 and rat tail collagen, we next investigated the possibility that integrin alpha3beta1 is involved in mediating the proliferative impact of LN5. Proliferation of human epithelial cells is significantly inhibited by a function-perturbing alpha3 integrin antibody. In addition, antibody activation of beta1 integrin restores the proliferation of epithelial cells treated with LN5 function-perturbing antibodies. These data indicate that a complex comprising LN5 and alpha3beta1 integrin is multifunctional and contributes not only to epithelial cell adhesion but also to the regulation of cell growth via a signaling pathway involving mitogen-activated protein kinase. We discuss our study in light of recent evidence that LN5 expression is up-regulated at the leading tips of tumors, where it may play a role in tumor cell proliferation.

Animals↗
PubMed2003

Functional genomics and proteomics as a foundation for systems biology.

Developments in high-throughput measurement technologies for biological molecules have created a paradigm shift in modern life science research. The field of systems biology attempts to provide a systems-level understanding by systematically organising the genomic, functional genomic and proteomic data obtained from genetic and environmental perturbations of interest and using the data to build a descriptive and mechanistic model of the biological phenomena. The goal is to build a mathematical framework with some predictive abilities. This review highlights the need for system-level understanding, lists some of the high-throughput measurement tools of importance in systems biology, reviews various types of experimental and computational approaches being used in systems biology research and attempts to address some of the challenges facing this research community.

Animals↗
PubMed1999

Magnetic critical behavior of two-dimensional random-bond Potts ferromagnets in confined geometries.

We present a numerical study of two-dimensional random-bond Potts ferromagnets. The model is studied both below and above the critical value Qc=4, which discriminates between second- and first-order transitions in the pure system. Two geometries are considered, namely cylinders and square-shaped systems, and the critical behavior is investigated through conformal invariance techniques that were recently shown to be valid, even in the randomness-induced second-order phase transition regime Q>4. In the cylinder geometry, connectivity transfer matrix calculations provide a simple test to find the range of disorder amplitudes that is characteristic of the disordered fixed point. The scaling dimensions then follow from the exponential decay of correlations along the strip. Monte Carlo simulations of spin systems on the other hand are generally performed on systems of rectangular shape on the square lattice, but the data are then perturbed by strong surface effects. The conformal mapping of a semi-infinite system inside a square enables us to take into account boundary effects explicitly and leads to an accurate determination of the scaling dimensions. The techniques are applied to different values of Q in the range 3-64.

Journal Article↗
PubMed2001

Nuclear quadrupole moment of 57Fe from microscopic nuclear and atomic calculations.

The nuclear quadrupole moment (NQM) of the Ipi = 3/2(-) excited nuclear state of 57Fe at 14.41 keV, important in Mössbauer spectroscopy, is determined from the large-scale nuclear shell-model calculations for 54Fe, 57Fe, and also from the electronic ab initio and density functional theory calculations including solid state and electron correlation effects for the molecules Fe(CO)(5) and Fe(C5H5)(2). Both independent methods yield very similar results. The recommended value is 0.15(2) e b. The NQM of the isomeric 10+ in 54Fe has also been calculated. The new NQM values for 54Fe and 57Fe are consistent with the perturbed angular distribution data.

Journal Article↗
PubMed2003

Optical conductivity of the Fröhlich polaron.

We present accurate results for optical conductivity of the three dimensional Fröhlich polaron in all coupling regimes. The systematic-error free diagrammatic quantum Monte Carlo method is employed where the Feynman graphs for the momentum-momentum correlation function in imaginary time are summed up. The real-frequency optical conductivity is obtained by the analytic continuation with stochastic optimization. We compare numerical data with available perturbative and nonperturbative approaches to the optical conductivity and show that the picture of sharp resonances due to relaxed excited states in the strong-coupling regime is "washed out" by large broadening of these states. As a result, the spectrum contains only a single-maximum broad peak with peculiar shape and a shoulder.

Journal Article↗
PubMed2005

A Bayesian framework for noise covariance estimation using the facet model.

In image processing literature, thus far, researchers have assumed the perturbation in the data to be white (or uncorrelated) having a covariance matrix sigma2I, i.e., assumption of equal variance for all the data samples and that no correlation exists between the data samples. However, there have been very few attempts to estimate noise characteristics under the assumption that there is a correlation between data samples. In this work, we propose a new and a novel approach for the simultaneous Bayesian estimation of the unknown colored or correlated noise (population) covariance matrix and the hyperparameters of the covariance model using the well-known facet model. We also estimate the facet model coefficients. We use the facet model because of its simple, yet elegant, mathematical formulation. We use the generalized inverted Wishart density as the prior model for the noise covariance matrix. We place a structure on the covariance matrix using the parameters of a correlation filter. These hyperparameters are estimated by a new extension of the expectation-maximization algorithm called the generalized constrained expectation maximization algorithm that we developed.

Algorithms↗
PubMed2005

A dual function for Munc-18 in exocytosis of PC12 cells.

Munc-18 interacts with the SNARE protein syntaxin and is supposed to influence transmitter release by controlling the formation of exocytosis-relevant SNARE complexes. Here, we used combined biochemical and physiological analyses to study the role of the Munc-18/syntaxin interaction in large dense core vesicle (LDCV) exocytosis of neuroendocrine PC12 cells. We compared two Munc-18 mutants carrying mutations in the syntaxin-binding region and show that Munc-18's membrane association depends on direct binding to syntaxin. The data suggest that perturbation of syntaxin binding inhibits neurotransmitter release upstream of the individual fusion event implying an essential role of the Munc-18/syntaxin complex leading to exocytosis. Furthermore, we show that a Munc-18 mutant lacking any syntaxin binding has a stimulatory effect on secretion, and provide evidence that the Munc-18/Mint1 interaction may constitute a second pathway for Munc-18 to regulate exocytosis. We propose that Munc-18 represents a dynamic link between syntaxin-related and Mint1-related mechanisms, both involved in the control of LDCV exocytosis in neuroendocrine cells.

Adaptor Proteins, Signal Transducing↗
PubMed1987

Effects of methylprednisolone and the combination of alpha-tocopherol and selenium on arachidonic acid metabolism and lipid peroxidation in traumatized spinal cord tissue.

Traumatic injury of the spinal cord leads to a series of pathological events that result in tissue necrosis and paralysis. Among the earliest biochemical reactions are hydrolysis of fatty acids from membrane phospholipids, production of biologically active eicosanoids, and peroxidation of lipids. This study examines the effect of agents purported to improve recovery following spinal cord trauma, methylprednisolone sodium succinate (MPSS) and the combination of alpha-tocopherol and selenium (Se), on the posttraumatic alterations of membrane lipid metabolism. Pretreatment with either MPSS or alpha-tocopherol and Se reduced the trauma-induced release of total FFA including arachidonate in the injured spinal cord tissue. In addition, these agents decreased the postinjury levels of prostanoids. Pretreatment with either MPSS or alpha-tocopherol and Se also completely prevented the trauma-induced loss of cholesterol while inhibiting the increase of a cholesterol peroxidation product, 25-hydroxycholesterol. These data suggest that: perturbation of membrane lipid metabolism may contribute to the tissue necrosis and functional deficit of spinal cord injury and MPSS or the combination of alpha-tocopherol and Se may protect injured spinal cord tissue, at least in part, by limiting these posttraumatic membrane lipid changes.

Animals↗
PubMedDate not supplied

Quantification of the control of carbohydrate catabolism in the tapeworm Hymenolepis diminuta.

The elasticities for the different steps of carbohydrate catabolism in the tapeworm Hymenolepis diminuta were estimated from perturbation experiments. These data were then used to calculate flux and metabolite control coefficients. Enzyme elasticities were also calculated from the rate equations and an independent estimate of the flux control coefficients for phosphoenolpyruvate carboxykinase was made by inhibitor titration. The values obtained for the flux control coefficients for carbohydrate breakdown in H. diminuta are consistent with how the pathway is thought to be controlled in vivo. A sensitivity analysis of the flux control coefficients of the important regulatory enzymes in the pathway shows that for hexokinase, phosphofructokinase, pyruvate kinase, and phosphoenolpyruvate carboxykinase there are three or four key elasticities which have a significant effect on the coefficient. For glycogen synthase, the major factor in determining the magnitude of the flux control coefficient is the relative flux through the branch.

Adenosine Triphosphate↗
PubMed2006

Phosphorylation of SIMPL modulates RelA-associated NF-kappaB-dependent transcription.

Epidemiological data have implicated perturbations in the regulation of NF-kappaB activity to diseases that affect a large number of Americans today. Specifically, chronic activation of genes involved in the inflammatory response is associated with the progression of and complications in diabetes, arthritis, atherosclerosis, and cancer. Insight into the mechanisms governing the regulation of NF-kappaB transcriptional activity will provide the molecular link between NF-kappaB and these pathological states. SIMPL (signaling molecule that associates with mouse Pelle-like kinase) is a component of a signaling pathway through which tumor necrosis factor-alpha (TNF-alpha) induces NF-kappaB-controlled gene transcription. SIMPL interacts with the nuclear pool of the NF-kappaB subunit, p65, in a TNF-alpha-dependent manner to enhance p65-dependent gene transcription. How SIMPL activity is regulated is unknown. Under basal as well as TNF-alpha-stimulated conditions, SIMPL phosphopeptides were identified. SIMPL mutants lacking sites that are phosphorylated under basal conditions diminished p65 transactivation activity but had no effect on SIMPL nuclear localization. SIMPL mutants lacking sites of TNF-alpha-enhanced phosphorylation impaired nuclear localization and prevented TNF-alpha-induced p65 transactivation activity. Together, these studies reveal that phosphorylation of the SIMPL protein plays a critical role in SIMPL regulation by affecting both SIMPL subcellular localization and the p65 coactivator function of SIMPL.

Carrier Proteins↗