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Search Results: 1 - 10 of 14067 matches for " Varhaug Jan "
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Composition and biological significance of the human Nα-terminal acetyltransferases
Starheim Kristian K,Gromyko Darina,Velde Rolf,Varhaug Jan
BMC Proceedings , 2009, DOI: 10.1186/1753-6561-3-s6-s3
Abstract: Protein Nα-terminal acetylation is one of the most common protein modifications in eukaryotic cells, occurring on approximately 80% of soluble human proteins. An increasing number of studies links Nα-terminal acetylation to cell differentiation, cell cycle, cell survival, and cancer. Thus, Nα-terminal acetylation is an essential modification for normal cell function in humans. Still, little is known about the functional role of Nα-terminal acetylation. Recently, the three major human N-acetyltransferase complexes, hNatA, hNatB and hNatC, were identified and characterized. We here summarize the identified N-terminal acetyltransferase complexes in humans, and we review the biological studies on Nα-terminal acetylation in humans and other higher eukaryotes.
Incidental Detection of Internal Jugular Vein Thrombosis Secondary to Undiagnosed Benign Substernal Goiter
Mai Tone L nnebakken,Ole Martin Pedersen,Knut Sverre Andersen,Jan Erik Varhaug
Case Reports in Medicine , 2010, DOI: 10.1155/2010/645193
Abstract: Internal jugular vein thrombosis is a serious event with potentially fatal outcome, where the clinical symptoms may be vague or absent. This paper refers to a rare case where routine carotid Doppler ultrasound prior to coronary artery bypass grafting (CABG) and aortic valve replacement (AVR) in a 76-year-old man, incidentally revealed thrombosis of the right internal jugular vein. Thoracic CT demonstrated an underlying, large, benign substernal multinodular goiter, mainly involving the right lobe, causing compression and displacement of the great vessels. A successful, one-stage operation including ligation of the internal jugular vein to avoid pulmonary embolism and hemithyroidectomy, combined with the scheduled CABG and AVR, was performed. This case illustrates that benign substernal goiter may be associated with asymptomatic internal jugular vein thrombosis. Carotid Doppler ultrasound should involve evaluation of the internal jugular vein concerning thrombosis as its presence may reveal space-occupying lesions in the thorax.
A novel human NatA Nα-terminal acetyltransferase complex: hNaa16p-hNaa10p (hNat2-hArd1)
Thomas Arnesen, Darina Gromyko, Diane Kagabo, Matthew J Betts, Kristian K Starheim, Jan Varhaug, Dave Anderson, Johan R Lillehaug
BMC Biochemistry , 2009, DOI: 10.1186/1471-2091-10-15
Abstract: We here describe a novel human protein, hNaa16p (hNat2), with 70% sequence identity to hNaa15p (hNat1). The gene encoding hNaa16p originates from an early vertebrate duplication event from the common ancestor of hNAA15 and hNAA16. Immunoprecipitation coupled to mass spectrometry identified both endogenous hNaa15p and hNaa16p as distinct interaction partners of hNaa10p in HEK293 cells, thus demonstrating the presence of both hNaa15p-hNaa10p and hNaa16p-hNaa10p complexes. The hNaa16p-hNaa10p complex acetylates NatA type N-termini in vitro. hNaa16p is ribosome associated, supporting its potential role in cotranslational Nα-terminal acetylation. hNAA16 is expressed in a variety of human cell lines, but is generally less abundant as compared to hNAA15. Specific knockdown of hNAA16 induces cell death, suggesting an essential role for hNaa16p in human cells.At least two distinct NatA protein Nα-terminal acetyltransferases coexist in human cells potentially creating a more complex and flexible system for Nα-terminal acetylation as compared to lower eukaryotes.About 80% of all mammalian proteins and 50% of yeast proteins are estimated to be cotranslationally acetylated at their N-termini [1-6]. This clearly makes N-terminal acetylation one of the most common protein modifications in eukaryotic cells. In yeast, three complexes, NatA, NatB and NatC, express different substrate specificities and are responsible for the majority of N-terminal acetylation [6]. At present, the nomenclature of this class of enzymes is not coherent and later this year a revised nomenclature of this enzyme class will be presented (Polevoda B, Arnesen T and Sherman F, unpublished). In brief, for the proteins mentioned in this study the following names will apply: Naa10p (Ard1), Naa11p (Ard2), Naa15p (Nat1), Naa16p (Nat2) and Naa50p (Nat5). The yeast NatA complex contains the structural subunit Naa15p mediating ribosome association and the catalytic subunit Naa10p [7,8]. Deletion of yNAA15 and yNAA10 r
Inverse correlation between PDGFC expression and lymphocyte infiltration in human papillary thyroid carcinomas
Ove Bruland, ?ystein Fluge, Lars A Akslen, Hans G Eiken, Johan R Lillehaug, Jan E Varhaug, Per M Knappskog
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-425
Abstract: qRT-PCR was performed on PDGFA, PDGFB, PDGFC, PDGFD, PDGFRA PDGFRB and a selection of lymphocyte specific mRNA transcripts. Semiquantitative assessment of tumour-infiltrating lymphocytes was performed on the adjacent part of the biopsy used for RNA extraction for all biopsies, while direct quantitation by qRT-PCR of lymphocyte-specific mRNA transcripts were performed on RNA also subjected to expression analysis. Relative expression values of PDGF family members were combined with a cDNA microarray dataset and analyzed based on clinical findings and PDGF expression patterns. Ingenuity Pathway Analysis (IPA) was used to elucidate potential molecular interactions and networks.PDGF family members were differentially regulated at the mRNA level in PTC as compared to normal thyroid specimens. Expression of PDGFA (p = 0.003), PDGFB (p = 0.01) and PDGFC (p = 0.006) were significantly up-regulated in PTCs compared to non-neoplastic thyroid tissue. In addition, expression of PDGFC was significantly up-regulated in classical PTCs as compared to clinically aggressive PTCs (p = 0.006), and PDGFRB were significantly up-regulated in clinically aggressive PTCs (p = 0.01) as compared to non-neoplastic tissue. Semiquantitative assessment of lymphocytes correlated well with quantitation of lymphocyte-specific gene expression. Further more, by combining TaqMan and microarray data we found a strong inverse correlation between PDGFC expression and the expression of lymphocyte specific mRNAs.At the mRNA level, several members of the PDGF family are differentially expressed in PTCs as compared to normal thyroid tissue. Of these, only the PDGFC mRNA expression level initially seemed to distinguish classical PTCs from the more aggressive PTCs. However, further investigation showed that PDGFC expression level correlated inversely to the expression of several lymphocyte specific genes, and to the presence of lymphocytes in the biopsies. Thus, we find that PDGFC mRNA expression were down-regula
Associations between tamoxifen, estrogens, and FSH serum levels during steady state tamoxifen treatment of postmenopausal women with breast cancer
Jennifer Gjerde, Jürgen Geisler, Steinar Lundgren, Dagfinn Ekse, Jan Varhaug, Gunnar Mellgren, Vidar M Steen, Ernst A Lien
BMC Cancer , 2010, DOI: 10.1186/1471-2407-10-313
Abstract: Tamoxifen and its metabolites were measured by liquid chromatography-tandem mass spectrometry. Estrogen and FSH levels were determined using a sensitive radio- and chemiluminescent immunoassay, respectively.We observed significant correlations between the serum concentrations of tamoxifen, N-dedimethyltamoxifen, and tamoxifen-N-oxide and estrogens (p < 0.05). The genotype predicted CYP2C19 activity influenced the levels of both tamoxifen metabolites and E1.We have shown an association between tamoxifen and its metabolites and estrogen serum levels. An impact of CYP2C19 predicted activity on tamoxifen, as well as estrogen kinetics may partly explain the observed association between tamoxifen and its metabolites and estrogen serum levels. Since the role of estrogen levels during tamoxifen therapy is still a matter of debate further prospective studies to examine the effect of tamoxifen and estrogen kinetics on treatment outcome are warranted.Estrogens play a key role in breast cancer development. The selective estrogen receptor modulator (SERM) tamoxifen has been used in breast cancer treatment and prevention. It may act as a full estrogen agonist, partial agonist or antagonist depending on the dose, species, sex or target organ [1]. Tamoxifen is regarded as a pro-drug since two of its metabolites, 4-hydroxytamoxifen (4OHtam) and 4-hydroxy-N-demethyltamoxifen (4OHNDtam, endoxifen), both have estrogen receptor affinity markedly exceeding that of tamoxifen itself [2,3]. The 4OHNDtam is considered the main active metabolite of tamoxifen, since it has 100-fold higher affinity for the estrogen receptor (ER) than tamoxifen and is 10-fold higher in serum levels than 4OHtam [4-7]. These potent metabolites are converted from tamoxifen through the cytochrome P450 (CYP) enzymes 2C19, 2D6, and 3A5. They are conjugated and deactivated through sulfotransferase (SULT) 1A1 [8,9] and UDP-glucuronyltransferases. The inter-individual variations of the activity of these enzymes due to ge
1,25-Dihydroxyvitamin D and the Vitamin D Receptor Gene Polymorphism Apa1 Influence Bone Mineral Density in Primary Hyperparathyroidism
Monika H. E. Christensen, Ellen M. Apalset, Yngve Nordb?, Jan Erik Varhaug, Gunnar Mellgren, Ernst A. Lien
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0056019
Abstract: Objective Parathyroid hormone (PTH) and vitamin D are the most important hormones regulating calcium metabolism. In primary hyperparathyroidism (PHPT) excessive amounts of PTH are produced. Bone turnover is enhanced, leading to reduced bone mineral density and elevated levels of serum calcium. The aim of this study was to investigate relations between serum levels of 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)2D) and bone mineral density, as well as known genetic polymorphisms in the vitamin D receptor and enzymes metabolising vitamin D in patients with PHPT. Design/Subjects We conducted a cross-sectional study of 52 patients with PHPT. Results Mean level of 25(OH)D was 58.2 nmol/L and median 1,25(OH)2D level was 157 pmol/L. Among our patients with PHPT 36.5% had 25(OH)D levels below 50 nmol/L. Serum 1,25(OH)2D was inversely correlated to bone mineral density in distal radius (p = 0.002), but not to bone mineral density at lumbar spine or femoral neck. The vitamin D receptor polymorphism Apa1 (rs7975232) was associated with bone mineral density in the lumbar spine. Conclusions The results suggest that PHPT patients with high blood concentrations of 1,25(OH)2D may have the most deleterious skeletal effects. Randomized, prospective studies are necessary to elucidate whether vitamin D supplementation additionally increases serum 1,25(OH)2D and possibly enhances the adverse effects on the skeleton in patients with PHPT.
The Human N-Alpha-Acetyltransferase 40 (hNaa40p/hNatD) Is Conserved from Yeast and N-Terminally Acetylates Histones H2A and H4
Kristine Hole, Petra Van Damme, Monica Dalva, Henriette Aksnes, Nina Glomnes, Jan Erik Varhaug, Johan R. Lillehaug, Kris Gevaert, Thomas Arnesen
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0024713
Abstract: Protein Nα-terminal acetylation (Nt-acetylation) is considered one of the most common protein modification in eukaryotes, and 80-90% of all soluble human proteins are modified in this way, with functional implications ranging from altered protein function and stability to translocation potency amongst others. Nt-acetylation is catalyzed by N-terminal acetyltransferases (NATs), and in yeast five NAT types are identified and denoted NatA-NatE. Higher eukaryotes additionally express NatF. Except for NatD, human orthologues for all yeast NATs are identified. yNatD is defined as the catalytic unit Naa40p (Nat4) which co-translationally Nt-acetylates histones H2A and H4. In this study we identified and characterized hNaa40p/hNatD, the human orthologue of the yeast Naa40p. An in vitro proteome-derived peptide library Nt-acetylation assay indicated that recombinant hNaa40p acetylates N-termini starting with the consensus sequence Ser-Gly-Gly-Gly-Lys-, strongly resembling the N-termini of the human histones H2A and H4. This was confirmed as recombinant hNaa40p Nt-acetylated the oligopeptides derived from the N-termini of both histones. In contrast, a synthetically Nt-acetylated H4 N-terminal peptide with all lysines being non-acetylated, was not significantly acetylated by hNaa40p, indicating that hNaa40p catalyzed H4 Nα-acetylation and not H4 lysine Nε-acetylation. Also, immunoprecipitated hNaa40p specifically Nt-acetylated H4 in vitro. Heterologous expression of hNaa40p in a yeast naa40-Δ strain restored Nt-acetylation of yeast histone H4, but not H2A in vivo, probably reflecting the fact that the N-terminal sequences of human H2A and H4 are highly similar to each other and to yeast H4 while the N-terminal sequence of yeast H2A differs. Thus, Naa40p seems to have co-evolved with the human H2A sequence. Finally, a partial co-sedimentation with ribosomes indicates that hNaa40p co-translationally acetylates H2A and H4. Combined, our results strongly suggest that human Naa40p/NatD is conserved from yeast. Thus, the NATs of all classes of N-terminally acetylated proteins in humans now appear to be accounted for.
Primary Hyperparathyroidism Influences the Expression of Inflammatory and Metabolic Genes in Adipose Tissue
Monika H. E. Christensen,Simon N. Dankel,Yngve Nordb?,Jan Erik Varhaug,Bj?rg Alm?s,Ernst A. Lien,Gunnar Mellgren
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0020481
Abstract: Primary hyperparathyroidism (PHPT) is characterised by increased production of parathyroid hormone (PTH) resulting in elevated serum calcium levels. The influence on bone metabolism with altered bone resorption is the most studied clinical condition in PHPT. In addition to this, patients with PHPT are at increased risk of non-skeletal diseases, such as impaired insulin sensitivity, arterial hypertension and increased risk of death by cardiovascular diseases (CVD), possibly mediated by a chronic low-grade inflammation. The aim of this study was to investigate whether adipose tissue reflects the low-grade inflammation observed in PHPT patients.
Characterization of hARD2, a processed hARD1 gene duplicate, encoding a human protein N-α-acetyltransferase
Thomas Arnesen, Matthew J Betts, Frédéric Pendino, David A Liberles, Dave Anderson, Jaime Caro, Xianguo Kong, Jan E Varhaug, Johan R Lillehaug
BMC Biochemistry , 2006, DOI: 10.1186/1471-2091-7-13
Abstract: We here describe a human protein, hARD2, with 81 % sequence identity to hARD1. The gene encoding hARD2 most likely originates from a eutherian mammal specific retrotransposition event. hARD2 mRNA and protein are expressed in several human cell lines. Immunoprecipitation experiments show that hARD2 protein potentially interacts with NATH, suggesting that hARD2-NATH complexes may be responsible for protein N-α-acetylation in human cells. In NB4 cells undergoing retinoic acid mediated differentiation, the level of endogenous hARD1 and NATH protein decreases while the level of hARD2 protein is stable.A human protein N-α-acetyltransferase is herein described. ARD2 potentially complements the functions of ARD1, adding more flexibility and complexity to protein N-α-acetylation in human cells as compared to lower organisms which only have one ARD.Protein acetylation is a very common modification with a significant impact on several cellular processes. Acetylation occurs both at lysine residues within proteins (Nε-acetylation) and at the N-terminus of proteins (Nα-acetylation). In yeast, N-acetyltransferase 1 (Nat1p) complexes with Arrest defective 1 (Ard1p) to generate a functional NatA protein Nα-acetyltransferase [1], Ard1p being the catalytic subunit. Proteins with Ser-, Thr-, Gly-, or Ala- N-termini are described to be substrates of NatA after methionine cleavage [2]. The yeast NatB and NatC complexes acetylates different subsets of methionine N-termini [2-4]. Almost all known N-terminally acetylated yeast proteins are products of one of these Nat complexes[5]. Protein N-terminal acetylation is generally believed to be a cotranslational process linked to the ribosome [6-10]. hARD1, the human protein with highest sequence similarity to yeast ARD1, has been described on the genomic (TE2, GenBank [NM_003491]) [11], mRNA [12], protein, and enzyme activity levels [6]. Endogenous hARD1 was demonstrated to interact with NATH and express protein Nα-acetyltransferase activity. T
Haze of surface random systems: An approximate analytic approach
Ingve Simonsen,Age Larsen,Erik Andreassen,Espen Ommundsen,Katrin Nord-Varhaug
Physics , 2009, DOI: 10.1103/PhysRevA.79.063813
Abstract: Approximate analytic expressions for haze (and gloss) of Gaussian randomly rough surfaces for various types of correlation functions are derived within phase-perturbation theory. The approximations depend on the angle of incidence, polarization of the incident light, the surface roughness, $\sigma$, and the average of the power spectrum taken over a small angular interval about the specular direction. In particular it is demonstrated that haze(gloss) increase(decrease) with $\sigma/\lambda$ as $\exp(-A(\sigma/\lambda)^2)$ and decreases(increase) with $a/\lambda$, where $a$ is the correlation length of the surface roughness, in a way that depends on the specific form of the correlation function being considered. These approximations are compared to what can be obtained from a rigorous Monte Carlo simulation approach, and good agreement is found over large regions of parameter space. Some experimental results for the angular distribution of the transmitted light through polymer films, and their haze, are presented and compared to the analytic approximations derived in this paper. A satisfactory agreement is found. In the literature haze of blown polyethylene films has been related to surface roughness. Few authors have quantified the roughness and other have pointed to the difficulty in finding the correct roughness measure.
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