Collective nomenclature for LAP proteins.
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Amino Acid Motifs↗
Biomedical subjects
E Jansen
Publications and source records attributed to E Jansen.
Regulation of pancreatic PC1 and PC2 associated with increased glucagon-like peptide 1 in diabetic rats.
The pancreatic processing enzymes, PC1 and PC2, convert proinsulin to insulin and convert proglucagon to glucagon and glucagon-like peptide 1 (GLP-1). We examined the effect of streptozotocin (STZ) treatment on the regulation of these enzymes and the production of insulin, glucagon, and GLP-1 in the rat. Pancreatic PC1 and PC2 mRNA increased >2-fold and >4-fold, respectively, in rats receiving intraperitoneal STZ (50 mg/kg) daily for 5 days. Immunocytochemistry revealed that, although pancreatic islet cells in the STZ-treated rats were sparse and atrophic PC1, PC2, glucagon, and GLP-1 immunoreactivity increased dramatically in the remaining islet cells. Heightened PC1 and PC2 expression was seen in cells expressing glucagon but not in insulin-expressing cells. Furthermore, in STZ-treated rats, bioactive GLP-1(7-36 amide) accumulated in pancreatic extracts and serum 3- and 2.5-fold, respectively, over control animals. This treatment also caused a 2-fold increase in the ratio of amidated forms of GLP-1 immunoreactivity to total glucagon immunoreactivity in the pancreas but did not affect the ratio of proinsulin to insulin. We conclude that hyperglycemic rats have an increased expression of prohormone converting enzymes in islet alpha cells, leading to an increase in amidated GLP-1, which can then exert an insulinotropic effect on the remaining beta cells.
Animals↗
Regulation of prohormone convertase 1 (PC1) by gp130-related cytokines.
The processing of pro-opiomelanocortin (POMC) to generate bioactive ACTH in the anterior pituitary is mediated by prohormone convertase 1 (PC1). Leukemia inhibitory factor (LIF) and interleukin 6 (IL-6), two cytokines sharing the common gp130 receptor subunit and functioning through activation of the intracellular JAK/STAT pathway, induce POMC synthesis and ACTH release. We investigated the effects of LIF and IL-6 on PC1 expression and its subsequent processing of POMC. A significant time-dependent up-regulation of both PC1 protein and mRNA by LIF and IL-6 was seen in mouse corticotroph AtT-20 cells. IL-6 or LIF increased the synthesis of ACTH-related products with a concomitant increase in bioactive 5 and 13 kDa ACTH indicating coordinated regulation of substrate and processing enzyme. AtT-20 cells transiently transfected with a human PC1-promoter-luciferase reporter construct and treated with LIF or IL-6 showed significantly increased luciferase activity. Additionally, lipopolysaccharide (LPS) administration to rats resulted in an increase in both pituitary PC1 and POMC mRNA. These findings suggest that the ACTH increase induced by LIF and IL-6 is due to both increased POMC synthesis as well as increased POMC processing by up-regulation of PC1. These two coordinately regulated processing events probably exert central roles in the pathophysiological response to some stresses, such as inflammatory stress.
Animals↗
Regulation of HMGIC expression: an architectural transcription factor involved in growth control and development.
The HMGIC gene has been implicated in the control of cell proliferation and development. We show here that HMGIC has multiple mRNA isoforms that arise by transcription initiation from alternative tandem promoters. These transcripts are not only differentially expressed between cell lines, but they can also differ within an individual cell line, in response to particular stimuli. Whereas quiescent 3T3-L1 preadipocytes express low levels of HMGIC mRNA, stimulation by serum results in a dramatic upregulation with the characteristics of a delayed-early response gene. Characterization of involved signal transduction pathways showed that both FGF-1 and PDGF-BB are strong inducers of HMGIC expression mediated via both the PI-3 kinase and MAP kinase pathways. In order to characterize the regulatory elements, sequences upstream of the translation initiation site of HMGIC were assayed for promoter activity. The HMGIC 5' flanking sequences had constitutive promoter activity in all cell lines tested, suggesting that HMGIC is regulated by negative regulatory elements that were not present in the 5'-flanking regions analysed here.
3T3 Cells↗
The nucleolar antigen Nop52, the human homologue of the yeast ribosomal RNA processing RRP1, is recruited at late stages of nucleologenesis.
We report the molecular characterization of a novel nucleolar protein, Nop52, and its subcellular distribution during the cell cycle and nucleologenesis. This protein was originally identified with human autoantibodies which were subsequently used to clone its corresponding cDNA. Transfection experiments in mammalian cells have confirmed that this cDNA encodes a nucleolar protein that accumulates in the nucleoli and at the periphery of the chromosomes. Nop52 is the putative human homologue of the yeast ribosomal RNA processing protein RRP1 which is involved in pre-rRNA processing from 27S to 25S and 5.8S. In nucleoli, Nop52 is excluded from the ribosomal RNA transcription sites, accumulates in the granular external domain and mainly colocalizes with nucleolar proteins involved in the late processing step such as hPop1 and protein B23. During the building process of the nucleolus at the end of mitosis, a sequential order was observed in the assembly of nucleolar proteins of early and late processing mainly via the prenucleolar body pathway. The order is the following: fibrillarin, nucleolin, Nop52 together with protein B23 in the prenucleolar bodies, and simultaneously with hPop1, and finally Ki-67. The evolutionary conservation of Nop52 and the lethal effects observed in gene disruption experiments, predict a critical role for Nop52 in the generation of 28S rRNA.
Amino Acid Sequence↗
Lysosomal enzyme activities in serum and leukocytes from patients with carbohydrate-deficient glycoprotein syndrome type IA (phosphomannomutase deficiency).
From 10 patients with carbohydrate-deficient glycoprotein (CDG) syndrome due to phosphomannomutase (PMM) deficiency, out of 10 lysosomal enzymes, 7 enzyme activities were measured in serum and 9 in leukocytes. In serum there was a 2-fold to 4-fold increase in activity of beta-glucuronidase, beta-hexosaminidase, beta-galactosidase, and arylsulphatase A. In leukocytes, however, several enzymes had reduced activity, particularly alpha-fucosidase, beta-glucuronidase and alpha-mannosidase. These abnormalities could result from missorting, defective reuptake and/or reduced stability of the enzymes due to the defective glycosylation.
Congenital Disorders of Glycosylation↗
Tolerance to head-up tilt and suspension with elevated legs.
OBJECTIVE: Orthostatic hypotension is usually a benign event. However, some patients are disabled by frequent syncopal events, and vertical transportation during helicopter rescue, for example, may even be fatal. Normal orthostatic tolerance is poorly defined, so we evaluated the response to 50 degrees head-up tilt. Also, the effect of leg elevation was examined in order to establish the influence of venous return, and a fatal accident associated with orthostasis is reported. METHODS: There were 79 volunteers who were subjected to 50 degrees head-up tilt, and 9 subjects performed 1 h of suspension by double strops placed around the thorax and knee bends, respectively. The time to presyncope and changes in BP, heart rate, thoracic electrical impedance, central venous pressure and central venous and muscle oxygen saturations were measured. RESULTS: Head-up tilt resulted in hypotension, bradycardia and presyncopal symptoms in 69 subjects within 1 h (87%; half time 27 min), but during suspension with elevated legs in only one subject (11%; p < 0.02). In presyncopal subjects the central blood volume was reduced as reflected by an elevated thoracic electrical impedance and reduced central venous and muscle oxygen saturations. CONCLUSIONS: During 50 degrees head-up tilt, half of 79 subjects near-fainted within 27 min, whereas elevation of the legs secured venous return to the heart and prevented presyncopal symptoms. The high rate of near-fainting in normal subjects should be taken into account during evaluation of patients with syncope, and it emphasizes the use of a position that secures venous return during transportation.
Adult↗
Regulation of human prohormone convertase 2 promoter activity by the transcription factor EGR-1.
Prohormone convertases are involved in the tissue-specific endoproteolytic processing of prohormones and neuropeptide precursors within the secretory pathway. In the present study, we have isolated genomic clones comprising the 5'-terminal region of the human prohormone convertase 2 (PC2) gene and established characteristics of the PC2 promoter region. The proximal promoter region is very G+C-rich and does not contain a canonical TATA box or a CAAT box. Transient expression assays with a set of human PC2 gene fragments containing progressive 5' deletions demonstrate that the proximal promoter region is capable of directing high levels of neuroendocrine-specific expression of reporter gene constructs. In addition, we show that the transcription factor EGR-1 interacts with two distinct elements within the proximal human PC2 promoter region. Transfection experiments also demonstrate that EGR-1 is able to enhance PC2 promoter activity.
Animals↗
The NNP-1 gene (D21S2056E), which encodes a novel nuclear protein, maps in close proximity to the cystatin B gene within the EPM1 and APECED critical region on 21q22.3.
We have cloned and molecularly characterized a novel human cDNA that encodes a protein of about 52 kDa that was shown by immunocytochemistry to have a nuclear localization. Northern blot analysis of a variety of human tissues revealed that the gene for this novel nuclear protein, designated NNP-1 (HGMW-approved symbol D21S2056E), is ubiquitously expressed as a 2.0-kb transcript. The NNP-1 protein displays significant sequence similarity to the C47E12.7 protein of Caenorhabditis elegans (38% identity and 58% similarity) and the YD78 protein of Saccharomyces cerevisiae (36% identity and 54% similarity). The human NNP-1 gene was mapped to a 15-kb DNA interval on chromosome 21q22.3, close to markers D21S1459 and D21S1953, that is 25 kb distal to the gene encoding cystatin B. Finally, an as-yet unknown gene that is highly related to NNP-1 was found proximal to the gene encoding cystatin B, near marker D21S1458, which is approximately 75 kb centromeric to the NNP-1 gene.
Amino Acid Sequence↗
Oral absorption and metabolism of quercetin and sugar-conjugated derivatives in specific transport systems.
The intestinal transport and metabolism of quercetin and various sugar-conjugates were quantified in in vitro and in vivo model systems. The nature of the sugar moiety at the C3 and C4' position had no significant effect on the rate of transport. At the 10 microM level, quercetin and glycosides with sugars at position 3 were determined to be glucose transport carrier inhibitors.
Absorption↗
Cell type-specific protein-DNA interactions at the cAMP response elements of the prohormone convertase 1 promoter. Evidence for additional transactivators distinct from CREB/ATF family members.
The proximal promoter region of the neuroendocrine-specific human prohormone convertase 1 (PC1) gene contains two distinct cAMP response elements (CRE-1 and CRE-2). Both elements are essential in directing the cAMP-mediated hormonal regulation of PC1 gene transcription. In this study, we have demonstrated that CRE-1 binds several trans-acting factors. In electrophoretic mobility shift assay experiments with nuclear extracts prepared from neuroendocrine AtT-20 and beta-TC3 cells and non-neuroendocrine COS-1 cells, three specific protein-DNA complexes (I-III) were detected. Complexes II and III were shown to contain CREB-1 and ATF-1, respectively. The most slowly migrating complex I was only detected with the neuroendocrine cell lines and appeared to comprise a c-Jun-containing heterodimer. In addition, CRE-2 was shown to bind a protein that was only detected in nuclear extracts derived from the neuroendocrine cell lines. Antibody supershift experiments indicated that both the c-Jun-interacting protein in CRE-1 complex I and the CRE-2-interacting protein are distinct from known members of the basic domain, leucine zipper family of transcription factors. UV cross-linking experiments demonstrated that these potential novel proteins are approximately 100 and 60 kDa in size, respectively. Site-specific mutagenesis experiments demonstrated that the formation of both CRE-1 and CRE-2 complexes is correlated with the transcriptional activity of the proximal PC1 promoter as has been shown in transient transfections with wild-type and mutant promoter constructs. In addition, it was shown that both CREB-1 and ATF-1 transactivate the human PC1 promoter in transient transfection experiments.
Activating Transcription Factor 1↗
Ectopic ICER expression in pituitary corticotroph AtT20 cells: effects on morphology, cell cycle, and hormonal production.
The products of the cAMP response element modulator (CREM) gene play an important role in the transcriptional response to cAMP in endocrine cells. By virtue of an alternative, intronic promoter within the gene, the inducible cAMP early repressor (ICER) isoform is generated. ICER was shown to act as a dominant negative regulator and to be cAMP-inducible in various neuroendocrine cells and tissues. ICER negatively autoregulates its own expression and has been postulated to participate in the molecular events governing oscillatory hormonal regulations. To elucidate ICER function in pituitary physiology, we have generated AtT20 corticotroph cell lines expressing the sense or antisense ICER transcript under the control of the cadmium-inducible human methallothionein IIA promoter. Here we demonstrate that changes in the regulated levels of ICER have drastic consequences on the physiology of the corticotrophs. Ectopic ICER expression induces remarkable modifications in AtT20 morphology. Cells with persistent, nonregulated high levels of ICER are blocked in the G2/M phase of the cell cycle, while the opposite effect is obtained in cells expressing an antisense ICER transcript. We show that the effect of ICER on the AtT20 cell cycle is correlated to a direct down-regulation of the cyclin A gene promoter by ICER. Finally, we show that ACTH hormonal secretion from the corticotrophs is completely blocked by ICER ectopic expression. Interestingly, this effect is not due to a direct regulation of the POMC gene, but is mediated by a transcriptional control of the prohormone convertase 1 gene. These results point to a key regulatory function of CREM in pituitary physiology.
Animals↗
Getting medications despite HMO cost cutting.
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Drug Industry↗
Identification of a transferable sorting domain for the regulated pathway in the prohormone convertase PC2.
The mammalian subtilisin-like endoproteases furin and PC2 catalyze similar reactions but in different parts of the cell: furin in the trans-Golgi network and PC2 in dense-core granules. To map targeting domains within PC2, chimeras were constructed of the pro-, catalytic, and middle domains of furin with the carboxyl-terminal domain of PC2 (F-S-P) or of the pro- and catalytic domains of furin with the middle and carboxyl-terminal domains of PC2 (F-N-P). Their behavior in stable transfected AtT-20 cells was compared to a furin mutant truncated after the middle domain (F-S), wild-type furin, and with wild-type PC2. F-S-P, F-N-P, and F-S were catalytically active and underwent post-translational proteolysis and N-glycosylation with similar kinetics to wild-type furin. The truncated furin mutant was not stored intracellularly, whereas both chimeras, like PC2, showed intracellular retention and regulated release. Immunofluorescence and immuno-electron microscopy showed the presence of the chimeras and PC2 in dense-cored secretory granules together with proopiomelanocortin immunoreactivity. PC2 was sorted more efficiently than F-S-P, and the inclusion of the middle domain (F-N-P) further enhanced intracellular retention. It is concluded that sorting of PC2 into the regulated pathway depends on its carboxyl terminus. The middle domain may provide additional sorting determinants or a conformational framework for expression of the sorting signal.
Animals↗
Neuroendocrine-specific expression of the human prohormone convertase 1 gene. Hormonal regulation of transcription through distinct cAMP response elements.
Prohormone convertases are involved in the tissue-specific endoproteolytic processing of prohormones and neuropeptide precursors within the secretory pathway. In the present study, we have isolated genomic clones comprising the 5'-terminal region of the human prohormone convertase 1 (PC1) gene and identified and characterized the PC1 promoter region. We found multiple transcription start sites located within a 15-base pair region, 205 base pairs upstream of the translation start codon. The promoter region is not G+C-rich and does not contain a canonical TATA box nor a CAAT box. Transient expression assays with a set of human PC1 gene fragments containing progressive 5' deletions demonstrate that the proximal promoter region is capable of directing high levels of neuroendocrine-specific expression of reporter gene constructs. In addition, the proximal promoter region confers both basal and hormone-regulated promoter activity. Site-specific mutagenesis experiments demonstrate that two closely spaced cAMP response elements within the proximal promoter region direct cAMP-mediated hormonal regulation of transcription of the PC1 gene.
Animals↗
Innovation and restrictive conformity among hospital employees: individual outcomes and organizational considerations.
Two factors characterize innovative organizational climates as perceived by nonmanagerial hospital employees. The first, innovation, comprises perceptions about the consequences or contingencies (e.g., punished, ignored, rewarded) of such proactive activities as implementing new ideas, questioning established methods, and communicating with other departments and the supervisor. The second, restrictive conformity, comprises perceptions about the consequences of risk-aversive, conflict-avoidant activities that suggest dysfunctional conformity (e.g., "sticking to the rules no matter what"). Positive personal outcomes--greater role clarity, organizational involvement, and satisfaction, and lower role conflict and willingness to leave the organization--are associated with innovation; negative personal outcomes are associated with restrictive conformity. The dialectical tension between conformity and innovation is discussed in terms of loose coupling and a reward systems perspective.
Adult↗
Technical evaluation of three second generation CA 125 assays.
The analytical performance of five CA 125 assays was studied using samples from apparently healthy women (n = 28) and from a group of patients with gynaecological malignancies (n = 260). Investigations were carried out on two homologous sandwich assays using the monoclonal antibody OC 125 (LIA-mat I and IRMA-mat I) and three heterologous assays using the monoclonal antibodies OC 125 and M11, both directed against the carcinoantigen CA 125 (LIA-mat CA 125 II, IRMA-mat CA 125 II, Centocor CA 125 II). The precision of the LIA-mat CA 125 II was better than that of the previously used LIA-mat I, the intra-assay coefficients of variation being 6.5% and 11.6% respectively. Using the new generation CA 125 II assays, only 0.5% of the duplicate measurements had to be rejected. The inter-assay coefficient of variation of the automated LIA-mat CA 125 II ranged from 7.1% to 11.2% while the IRMA-mat CA 125 II inter-assay CV ranged from 11.6% to 13.9%. Serum EDTA or heparin plasma did not give significantly different results. A carry-over of 0.02% was observed using the LIA-mat S 300 system. A high dose hook effect may be observed with concentrations over 20000 kU/l. All assays showed excellent linearity, and there was a good correlation between the assays.
Adult↗