Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tyrosine hydroxylase (TH) catalyzes the conversion of L-tyrosine to L-dihydroxyphenylalanine (L-DOPA), the rate-limiting step in the biosynthesis of dopamine. This report describes a missense point mutation in the human TH (hTH) gene in a girl presenting parkinsonian symptoms in early infancy and a very low level of the dopamine metabolite homovanillic acid in the CSF. DNA sequencing revealed a T614-to-C transition in exon 5 (L205P). Both parents and the patient's brother are heterozygous for the mutation. Site-directed mutagenesis and expression in different systems revealed that the recombinant mutant enzyme had a low homospecific activity, i.e. approximately 1.5% of wt-hTH in E. coli and approximately 16% in a cell-free in vitro transcription-translation system. When transiently expressed in human embryonic kidney (A293) cells a very low specific activity (approximately 0.3% of wt-hTH) and immunoreactive hTH (< 2%) was obtained. The expression studies are compatible with the severe clinical phenotype of the L205P homozygous patient carrying this recessively inherited mutation. Treatment with L-DOPA resulted in normalisation of the CSF homovanillic acid concentration and a sustained improvement in parkinsonian symptoms.
Hum Mol Genet 1996 Jul
PMID:Recessively inherited L-DOPA-responsive parkinsonism in infancy caused by a point mutation (L205P) in the tyrosine hydroxylase gene. 881 41

Macrophage colony-stimulating factor (M-CSF) is a protein which is necessary for proliferation and differentiation of monocyte-macrophage precursor cells. We examined the effect of M-CSF on the cytokine production using BCG sensitized mice in vivo. On Day 0, BCG 1 mg/mouse was injected via the tail vein. Starting from Day 2, M-CSF 30 mu g/mouse (1 X 10(8) U/mg) was injected every 2 days for a total of six times (Day 2, 4, 6, 8, 10 and 12). On Day 14. LPS 25 mu g/mouse was injected via the tail vein, and Interferon (IFN)/Tumor necrosis factor-alpha (TNF-alpha) in serum were determined. The productions of IFN and TNF-alpha were suppressed significantly. These cytokine production-suppressive effects of M-CSF were found also in the in vitro experimental system using spleen cells collected. On Day 14, spleen cells were collected and adjusted to 5 X 10(6) cells/ml. 20 micro-grams of LPS was added to 2ml of spleen cells and they were incubated in a C02 incubator for 24 hours. IFN and TNF-alpha in the supernatant were determined. In the experiment using nude mice, the cytokine suppressive effect of M-CSF was not observed. MLR test was performed with spleen cells of C57BL/6 treated with M-CSF as the responder cells, and spleen cells of C3H were treated with mitomycin C as the stimulator cells. MLR was suppressed significantly by administration of M-CSF. These results might possibly reflect the actual effect of M-CSF in the living body, and the T-cell and cellular immunity might be concerned with the mechanism of the cytokine production-suppressive effect of M-CSF.
Res Commun Mol Pathol Pharmacol 1996 Feb
PMID:Cytokine production-suppressive effect by macrophage colony-stimulating factor (M-CSF). 883 8

Amyloidoses are a group of diseases where abnormal fibrillar protein deposits accumulate in patients' tissues. In familial amyloidosis of the Finnish type (FAF), or gelsolin-related amyloidosis, the amyloid subunit protein consists of gelsolin peptides of amino acids 173-243 with the disease causing substitution at Asp187. Gelsolin is an actin-modulating protein and exists in both secretory and intracellular forms both encoded by a single gene in chromosome 9. We have previously shown that the FAF-associated forms of secretory gelsolin carrying the Asp187Asn or Asp187Tyr mutations are abnormally processed in cells, resulting in the secretion of an aberrant 68 kDa carboxyterminal fragment. Here we demonstrate by N-terminal sequencing that the amino terminus of this abnormal fragment is the amino acid 173 and thus represents the N-terminus of the FAF amyloid. We also provide evidence that the same truncated gelsolin can be found among the aberrant gelsolin fragments detected in patients' CSF. Finally, we also expressed the FAF-associated forms of intracellular gelsolin in COS-1 cells, and found no abnormality in their processing opposite to secretory form. Our results provide strong evidence that the secretory gelsolin is solely responsible for the amyloid formation in FAF.
Hum Mol Genet 1996 Sep
PMID:In vitro expression analysis shows that the secretory form of gelsolin is the sole source of amyloid in gelsolin-related amyloidosis. 887 62

We investigated the contribution of hemopoietic progenitors to the accumulation of inflammatory cells in allergic airways disease. Using a multiparameter flow-cytometric method, the detection of peripheral blood (PB) and bone marrow (BM) cells expressing CD34, a progenitor cell marker, was explored. True CD34+ blast cells were detected as a discrete cluster exhibiting low intensity CD45 expression, low granularity, and low to intermediate cell size. A significantly greater number of CD34+ cells was detected in the PB of atopic individuals (1,438 +/- 347/10(6) nonadherent mononuclear cells [NAMNC], n = 19) compared with nonatopics (236 +/- 77/10(6) NAMNC, n = 13; P = 0.006). Similarly, in BM samples, a significantly greater number of CD34+ cells was detected in atopic (17,537 +/- 4,986/10(6) NAMNC, n = 7) compared with nonatopic subjects (6,422 +/- 1,853/10(6) NAMNC, n = 13, P = 0.02). Greater numbers of total colony-forming units (CFU) (granulocyte/macrophage [GM] and Eo/Baso) were present in cultures of PB NAMNC from atopics (24 +/- 5 CFU/10(6) NAMNC) cultured with recombinant human interleukin 5 (rhIL-5) (1 ng/ml) compared with nonatopics (5 +/- 2 CFU/10(6) NAMNC; P = 0.003). Analyses of colony subtypes showed significantly greater numbers of IL-5-responsive Eo/Baso-CFU in cultures from atopics (15 +/- 2 CFU/10(6) NAMNC) compared with nonatopics (5 +/- 2 CFU/10(6) NAMNC; P = 0.011). In contrast, no significant differences in colony counts were found between the two subject groups in cultures with rhIL-3 (1 ng/ml) or rhGM-CSF (10 ng/ml). A positive correlation was observed between PB CD34+ cell numbers and total CFU in cultures with rhIL-5 (r = 0.43, n = 32, P = 0.01) and rhGM-CSF (r = 0.45, n = 32, P = 0.009). Purging BM NAMNC with an anti-CD34 monoclonal antibody completely abrogated in vitro colony growth, supporting the view that a subset of CD34+ cells represents the relevant population of progenitors growing in culture. These data indicate that flow cytometric estimation of CD34+ cells is predictive of the colony-forming capacity of the sample and may be a useful alternative tool to clonogenic assays for enumerating progenitors. In addition, raised levels of CD34+ cells and IL-5-responsive Eo/Baso-CFU in atopics, including patients with atopic asthma, indicate a role for progenitors in allergic airways disease.
Am J Respir Cell Mol Biol 1996 Nov
PMID:Increased levels of CD34+ hemopoietic progenitor cells in atopic subjects. 891 71

Airway epithelial cells are known to produce a granulocyte/macrophage colony-stimulating factor (GM-CSF), which induces eosinophilic inflammation in bronchial asthma. Interleukin-4 (IL-4), IL-10, and IL-13 produced by Th2 cells are involved in the pathogenesis of bronchial asthma. To assess their contributions to airway inflammation, we examined their effects on GM-CSF production by bronchial epithelial cells. Human bronchial epithelial cells were obtained under bronchoscopy from 21 patients with various respiratory diseases and incubated with or without IL-4, IL-10, or IL-13. Then the GM-CSF concentrations in the cell-free supernatants were measured by enzyme-linked immunosorbent assay. Results showed that IL-4 and IL-13 stimulated GM-CSF production by the epithelial cells dose-dependently, whereas IL-10 did not. The eosinophil survival-stimulating activity in the culture supernatants was closely correlated with GM-CSF concentration and was neutralized by anti-GM-CSF antibody. Thus, IL-4 and IL-13 may contribute to airway inflammation by upregulating GM-CSF production by bronchial epithelial cells.
Am J Respir Cell Mol Biol 1996 Nov
PMID:Upregulatory effects of interleukin-4 and interleukin-13 but not interleukin-10 on granulocyte/macrophage colony-stimulating factor production by human bronchial epithelial cells. 891 75

Cytokine stimulation of mouse and rat macrophages has previously been shown to enhance their capacity to phagocytose and inhibit the growth of Cryptococcus neoformans. To extend these observations to primary human macrophages, we investigated the anticryptococcal activity of human alveolar macrophages stimulated with interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), or macrophage-colony stimulating factor (M-CSF). Neither TNF-alpha nor M-CSF had any effect on fungal growth inhibition compared with unstimulated macrophages. Alveolar macrophages stimulated with IFN-gamma demonstrated reduced fungistasis for C. neoformans compared with controls (49% +/- 15% versus 75% +/- 12%; mean % growth inhibition +/- SD, P < 0.001). Confocal laser scanning microscopy was used to assess binding and phagocytosis of yeast. No difference was observed between unstimulated macrophages and macrophages stimulated with any of the cytokines tested. These data suggest that the cytokine regulation of anticryptococcal macrophage functions in humans differs from the rat and mouse. Conclusions drawn from these models may not necessarily be applicable to human cryptococcosis. In particular, the effects of IFN-gamma on the interaction of human alveolar macrophages with C. neoformans was not predicted based on the mouse and rat macrophage responses.
Am J Respir Cell Mol Biol 1996 Dec
PMID:Interferon-gamma reduces the capacity of human alveolar macrophages to inhibit growth of Cryptococcus neoformans in vitro. 896 64

Colony-stimulating factor-1 (CSF-1), also known as macrophage colony-stimulating factor, controls the survival, proliferation, and differentiation of mononuclear phagocytes and regulates cells of the females reproductive tract. It appears to play an autocrine and/or paracrine role in cancers of the ovary, endometrium, breast, and myeloid and lymphoid tissues. Through alternative mRNA splicing and differential post-translational proteolytic processing, CSF-1 can either be secreted into the circulation as a glycoprotein or chondroitin sulfate-containing proteoglycan or be expressed as a membrane-spanning glycoprotein on the surface of CSF-1-producing cells. Studies with the op/op mouse, which possesses an inactivating mutation in the CSF-1 gene, have established the central role of CSF-1 in directly regulating osteoclastogenesis and macrophage production. CSF-1 appears to preferentially regulate the development of macrophages found in tissues undergoing active morphogenesis and/or tissue remodeling. These CSF-1 dependent macrophages may, via putative trophic and/or scavenger functions, regulate characteristics such as dermal thickness, male fertility, and neural processing. Apart from its expression on mononuclear phagocytes and their precursors, CSF-1 receptor (CSF-1R) expression on certain nonmononuclear phagocytic cells in the female reproductive tract and studies in the op/op mouse indicate that CSF-1 plays important roles in female reproduction. Restoration of circulating CSF-1 to op/op mice has preliminarily defined target cell populations that are regulated either humorally or locally by the synthesis of cell-surface CSF-1 or by sequestration of the CSF-1 proteoglycan. The CSF-1R is a tyrosine kinase encoded by the c-fms proto-oncogene product. Studies by several groups have used cells expressing either the murine or human CSF-1R in fibroblasts to pinpoint the requirement of kinase activity and the importance of various receptor tyrosine phosphorylation sites for signaling pathways stimulated by CSF-1. To investigate post-CSF-1R signaling in the macrophage, proteins that are rapidly phosphorylated on tyrosine in response to CSF-1 have been identified, together with proteins associated with them. Studies on several of these proteins, including protein tyrosine phosphates 1C, the c-cbl proto-oncogene product, and protein tyrosine phosphatase-phi are discussed.
Mol Reprod Dev 1997 Jan
PMID:Biology and action of colony--stimulating factor-1. 898 57

Proliferation, differentiation, and survival of monocytes, macrophages, and their immediate progenitors is regulated by the macrophage colony-stimulating factor (CSF-1). CSF-1 initiates a mitogenic response by binding to its receptor (CSF-1R), thereby activating the receptor's intrinsic tyrosine kinase activity and initiating signaling via multiple effector-mediated pathways. CSF-1 is required throughout G1 to ensure entry of bone marrow-derived macrophages into S phase, and persistent CSF-1R kinase activity is necessary to the expression of both immediate early (e.g., c-fos, c-jun, and c-myc) and delayed early (e.g., D-type cyclins) response genes. Ectopic expression of human CSF-1R in different mouse cell lines, including fibroblasts, IL-3-dependent myeloid cells, and early pre-B cells, confers CSF-1 responsiveness by replacing the cells' requirements for other mitogenic growth factors. NIH-3T3 fibroblasts engineered to express a human CSF-1 receptor point mutant (CSF-1R [Y809F]) fail to proliferate in response to CSF-1 and remain arrested in the early G1 phase of the cell cycle. Despite CSF-1-dependent transcription of fos and jun family members, c-myc, D-type, and E-type G1 cyclin mRNAs are not expressed in the latter cells in response to growth factor stimulation. However, enforced expression of c-myc or D-type cyclins, but not cyclin E, resensitizes cells bearing CSF-1R (Y809F) to the mitogenic effects of CSF-1, enabling them to proliferate continuously in liquid culture and to form colonies in agar in response to the growth factor. D-type cyclin mutants defective in binding to the retinoblastoma protein (pRB) were unable to rescue mutant receptor signaling, suggesting that the ability of D-type cyclin-dependent kinases to cancel pRB's growth-suppressive function is necessary for CSF-1-induced G1 exit. By contrast, cyclin E must function in a different pathway. Cells rescued by c-myc were prevented from entering S phase by microinjection of antibodies to cyclin D1. Conversely, cyclin D1-rescued cells were inhibited from forming CSF-1-dependent colonies in agar when challenged with either a dominant-negative c-myc mutant or mad, a transcription factor which competes with myc for max, its requisite heterodimeric partner. Thus, although the expression of c-myc and D-type cyclins is rate limiting for G1 phase progression, their functions are interdependent, with both activities being required for mitogenicity.
Mol Reprod Dev 1997 Jan
PMID:Regulation of cell cycle entry and G1 progression by CSF-1. 898 58

Control of cell proliferation involves a finely interwoven network of positive and negative cell cycle regulators. Signal transduction pathways linking c-fms (CSF-1R) to cellular proliferation and differentiation are being explored. Part of the strategy is to use a series of G1 inhibitors to help pinpoint relevant targets. Several inhibitors-8Br-cAMP, interferon gamma (IFN gamma), INF alpha/beta, lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF alpha), and dimethylamiloride-suppress CSF-1-stimulated proliferation in murine bone marrow-derived macrophages (BMM) even when added in the mid- to late-G1 phase of the cell cycle. The down-modulating effects of the inhibitors on the expression of the following cell cycle regulators have been examined: c-myc, cyclin D1 and D2, cdk4, Rb phosphorylation, E2F binding activity, ribonucleotide reductase subunits, and PCNA. Some differences in the negative control of such regulators were found, for example, in the manner in which IFN gamma and cAMP down-regulate c-myc expression. Using blocking antibodies and BMM from type I IFN receptor knockout mice, it appears that one of these inhibitors, IFN alpha/beta, acts as an endogenous inhibitor in CSF-1-treated BMM and is also responsible, at least in part, for the inhibition of cell cycle progression by LPS and TNF alpha. Another strategy has been to attempt to relate early biochemical changes induced by CSF-1 to later changes in the G1 phase, partly by studying cycling versus noncycling macrophages and partly by using cells expressing c-fms with tyrosine mutations in the intracytoplasmic region. CSF-1-mediated effects on the following signal transduction molecules in these systems will be described: PI3-kinase, myelin basic protein kinases, Erks, and STAT transcription factors.
Mol Reprod Dev 1997 Jan
PMID:CSF-1 and cell cycle control in macrophages. 898 59

M-CSF (CSF-1) can be produced in a variety of structural forms that may affect function in vivo. Truncated, nonglycosylated forms of recombinant M-CSF (rM-CSF) from E. coli have been refolded in vitro in high yield and shown to be functionally equivalent in vitro to glycosylated rM-CSF secreted from mammalian cells. An N-terminal domain of 149 amino acids is produced by all of the known M-CSF mRNA splice variants and is the region responsible for bioactivity observed in vitro. Heterodimeric rM-CSFs from different splice variants containing this domain were produced in pure form by refolding in vitro, and are fully active, but have yet to be observed in vivo. The circulating half-life of truncated M-CSF forms injected intravenously into rats increased with the MW of the M-CSF used. Large increases in half-life in vivo were observed following chemical addition of a single molecule of 10 kD polyethylene glycol to rM-CSF in vitro. The crystal structure of rM-CSF revealed that M-CSF is a member of a family of molecules related by having a distinctive four-helical-bundle structural core. Site-directed mutagenesis showed that residues in or near helix A and helix C are involved in receptor binding, as reflected by decreased bioactivity and receptor binding of certain mutants. A soluble form of the M-CSF receptor, c-fms, was produced in a baculovirus/Sf9 expression system and purified to homogeneity. The MW of rM-CSF saturated with this soluble receptor was determined by molecular sieve chromatography and light scattering. Each dimeric M-CSF molecule appears to bind two soluble receptor molecules in vitro, supporting the observation that M-CSF signaling is linked to receptor dimerization.
Mol Reprod Dev 1997 Jan
PMID:Structure-function studies on human macrophage colony-stimulating factor (M-CSF). 898 61


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