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)

Niemann-Pick type C (NPC) disease is a severe cell lipidosis characterized by the accumulation of unesterified cholesterol in the endosomal/lysosomal system. Recently the primary disease-causing gene, NPC1, was identified, but few clues regarding its potential function(s) could be derived from its predicted amino acid sequence. Therefore, efforts were directed at characterizing the subcellular location of the NPC1 protein. Initial studies with a FLAG-tagged NPC1 cDNA demonstrated that NPC1 is a glycoprotein that associates with the membranes of a population of cytoplasmic vesicles. Immunofluorescence microscopy using anti-NPC1 polyclonal antibodies confirmed this analysis. Double-label immunofluorescence microscopy and subcellular fractionation studies indicated that NPC1 associates predominantly with late endosomes (Rab9 GTPase-positive vesicles) and, to a lesser extent, with lysosomes and the trans-Golgi network. When cholesterol egress from lysosomes was blocked by treatment of cells with U18666A, the NPC1 location shifted from late endosomes to the trans-Golgi network and lysosomes. Subcellular fractionation of liver homogenates from U18666A-treated mice confirmed these observations. These data suggest that U18666A may inhibit the retrograde transport of NPC1 from lysosomes to late endosomes for subsequent transfer to the trans-Golgi network.
Mol Genet Metab 1999 Sep
PMID:Niemann-Pick C1 is a late endosome-resident protein that transiently associates with lysosomes and the trans-Golgi network. 1047 77

Niemann-Pick disease Type C (NP-C) is a progressive neurodegenerative disorder caused by mutations in the NPC1 gene and characterized by intracellular accumulation of cholesterol and sphingo-lipids. The major neuronal storage material in NP-C consists of gangliosides and other glycolipids, raising the possibility that the accumulation of these lipids may participate in the neurodegenerative process. To determine if ganglioside accumulation is a crucial factor in neuropathogenesis, we bred NP-C model mice with mice carrying a targeted mutation in GalNAcT, the gene encoding the beta-1-4GalNAc transferase responsible for the synthesis of GM2 and complex gangliosides. Unlike the NP-C model mice, these double mutant mice did not exhibit central nervous system (CNS) accumulation of gangliosides GM2 or of glycolipids GA1 and GA2. Histological analysis revealed that the characteristic neuronal storage pathology of NP-C disease was substantially reduced in the double mutant mice. By contrast, visceral pathology was similar in the NP-C and double mutant mice. Most notably, the clinical phenotype of the double mutant mice, in the absence of CNS ganglioside accumulation and associated neuronal pathology, did not improve. The results demonstrate that complex ganglioside storage, while responsible for much of the neuronal pathology, does not significantly influence the clinical phenotype of the NP-C model.
Hum Mol Genet 2000 Apr 12
PMID:Alleviation of neuronal ganglioside storage does not improve the clinical course of the Niemann-Pick C disease mouse. 1076 33

A major obstacle in positional cloning is identifying the specific mutated gene from within a large physical contig. Here we describe the application of DNA microarray technology to a defined genomic region (physical map) to identify: (i) exons without a priori sequence data and (ii) the disease gene based on differential gene expression in a recessive disorder. The feasibility was tested using resources from the positional cloning of the Neimann-Pick Type C (NP-C) disease gene, NPC1. To identify NPC1 exons and optimize the technology, an array was generated from genomic fragments of the 110-kb bacterial artificial chromosome, 108N2, which encodes NPC1. First, as a test case for blindly identifying exons, fluorescently labeled NPC1 cDNA identified 108N2 fragments that contained NPC1 exons, many of which also contained intronic sequences and could be used to determine part of the NPC1 genomic structure. Second, to demonstrate that the NPC1 disease gene could be identified based upon differential gene expression, subarrays of 108N2 fragments were hybridized with fluorescently labeled cDNA probes generated from total RNA from hamster cell lines differentially expressing NPC1. A probe derived from the NP-C cell line CT60 did not detect NPC1 exons or other genomic fragments from 108N2. In contrast, several NPC1 exons were detected by a probe generated from the non-NP-C cell line 911D5A13, which was derived from CT60, and expressed NPC1 as a consequence of stable transduction with a YAC that contains NPC1 and encompasses 108N2. Thus, the array technology identified NPC1 as a candidate gene based on a physical contig and differential NPC1 expression between NP-C and non-NP-C cells. This technique should facilitate gene identification when a physical contig exists for a region of interest and mutations result in changes in the mRNA level of the disease gene or portions thereof.
Mol Genet Metab 2000 May
PMID:Positional cloning utilizing genomic DNA microarrays: the Niemann-Pick type C gene as a model system. 1083 27

Previous studies employing rabbit polyclonal anti-human liver ferritin have shown an absence of L ferritin immunoreactivity in liver and spleen tissue from patients with Niemann-Pick disease type C1 (NPC1). The great majority of NPC cases is caused by defects of the NPC1 gene, and a minority by those of another (NPC2). In this study using polyclonal and monoclonal antibodies we show the deficiency of H and L ferritin isoforms in various NPC tissues, including fetal NPC1, not previously described. In particular, evidence is provided for deficiency in H and L ferritins in tissues, except lung, from a patient with Niemann-Pick disease type C2 (NPC2). The present findings indicate that H and L ferritins are deficient in both NPC types characterized by accumulation of unesterified cholesterol and additional metabolites in the endosomal/lysosomal system. We hypothesize that the lesions in NPC1 and NPC2 block the intracellular utilization not only of cholesterol, but also that of iron for the synthesis of cytosolic ferritin.
Mol Genet Metab 2000 Jul
PMID:Deficient ferritin immunoreactivity in tissues from niemann-pick type C patients: extension of findings to fetal tissues, H and L ferritin isoforms, but also one case of the rare Niemann-Pick C2 complementation group. 1092 74

Niemann-Pick C (NPC) disease is a recessive cholesterol storage disorder characterized by severe, progressive neurodegeneration. The primary causative gene found on chromosome 18q11-12 was identified by a positional cloning approach. The NPC1 gene product is predicted to be a large polytopic glycoprotein with a cytoplasmic tail containing a dileucine endosome-targeting motif. The NPC1 protein sequence shares strong homology with a newly identified homologue, NPC1L1, and the morphogen receptor Patched. In addition, a group of five NPC1 transmembrane domains share homology with the sterol-sensing domain of proteins involved in cellular cholesterol homeostasis. Subcellular localization studies have shown NPC1 to reside in late endosomes and to transiently associate with lysosomes and the trans-Golgi network. Analysis of its topological arrangement in membranes suggests that NPC1 contains 13 transmembrane domains and three large, hydrophilic, lumenal loops. Currently, there is no direct evidence as to the function of the NPC1 protein; however, a number of observations suggest that NPC1 may be related to a family of prokaryotic efflux pumps and thus it may also act as a molecular pump.
Mol Genet Metab
PMID:The structure and function of the Niemann-Pick C1 protein. 1100 8

The Epstein-Barr virus (EBV) nuclear antigen 2 (EBNA2) has been shown to be required for promotion of cell-cycle progression in EBV-immortalized B-lymphocytes. However, other studies have indicated that EBNA2 alone, in the absence of other EBV genes, may retard cell growth. To resolve this discrepancy, we investigated the effect of EBNA2 on the growth of various cells, including EBV target nasopharyngeal carcinoma cells, NPC-TW01 and NPC-TW04. We found that EBNA2 could retard cell growth, in stable Vero, HEp-2, and U2OS cell clones expressing EBNA2, and in Vero, 293, NPC-TW01, and NPC-TW04 cells transiently transfected with EBNA2. While investigating the mechanism underlying the growth-retarding function of EBNA2, we found that EBNA2 induced p21(WAF1) expression in these cells. This induction of p21(WAF1) expression was mediated through p53. EBNA2 was found to stimulate p53 to bind to the p53-response element within the p21(WAF1) promoter, possibly by promoting p53 phosphorylation. This enhancement of p53 sequence-specific DNA-binding activity may be the mechanism through which EBNA2 activates the expression of p53-regulated genes, including p21(WAF1) and mdm-2. Together, these studies reveal a possible intrinsic function of EBNA2 in cell-growth regulation and elucidate a novel mechanism by which EBNA2 modulates transcription.
J Mol Biol 2000 Oct 13
PMID:Epstein-barr virus nuclear antigen 2 retards cell growth, induces p21(WAF1) expression, and modulates p53 activity post-translationally. 1102 66

Smad proteins have recently been shown to be downstream signaling molecules that transduce TGF-beta signals from cell surface to the nucleus. To determine the mechanisms of TGF-beta action in human trophoblast cells, we investigated the expression and regulation of Smad2,3,4, and 7 mRNAs in a normal trophoblast cell line, NPC, and a cell line derived from choriocarcinoma, JEG-3. Messenger RNAs for Smad2,3,4 and 7 were detected in both NPC and JEG-3 cells. TGF-beta1 induced modest increases in Smad2 and Smad4 mRNA levels without affecting Smad3 mRNA expression in both cell lines. Significant increases in Smad7 mRNA levels in both NPC and JEG-3 cells following TGF-beta1 treatment were observed. TGF-beta1 also induced promoter activity of the Smad7 gene, indicating a direct effect at the level of gene transcription. The transcriptional activity of TGF-beta was examined in JEG-3 cells using two TGF-beta responsive reporter constructs, p3TP-Lux and pAR3-Lux. We found that Smad3 and to a lesser extent, Smad2 and Smad4, enhanced, while Smad7 inhibited, TGF-beta1-induced transcriptional activities. The basal and TGF-beta1-induced transcription can be blocked by overexpression of a dominant negative TGF-beta type II receptor. Taken together, these findings demonstrate that in human trophoblast cell lines, the Smad pathway involved in TGF-beta signal transduction is functional and that TGF-beta plays an autocrine role in regulating gene expression.
Mol Cell Endocrinol 2001 Apr 25
PMID:Smads in human trophoblast cells: expression, regulation and role in TGF-beta-induced transcriptional activity. 1132 21

Studies of Niemann-Pick C (NPC) and Tangier diseases have led to the identification of the causative genes, NPC1 and ABCA1, respectively. Characterization of their protein products shows that NPC1 and ABCA1 are permeases that belong to two different superfamilies of efflux pumps, which might be important in subcellular lipid and cholesterol transport.
Nat Rev Mol Cell Biol 2001 Sep
PMID:Multidrug permeases and subcellular cholesterol transport. 1153 23

To analyze the contribution of vesicular trafficking pathways in cellular cholesterol transport we examined the effects of selected endosomal Rab proteins on cholesterol distribution by filipin staining. Transient overexpression of Rab11 resulted in prominent accumulation of free cholesterol in Rab11-positive organelles that sequestered transferrin receptors and internalized transferrin. Sphingolipids were selectively redistributed as pyrene-sphingomyelin and sulfatide cosequestered with Rab11-positive endosomes, whereas globotriaosyl ceramide and GM2 ganglioside did not. Rab11 overexpression did not perturb the transport of 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine-perchlorate-labeled low-density lipoprotein (LDL) to late endosomes or the Niemann-Pick type C1 (NPC1)-induced late endosomal cholesterol clearance in NPC patient cells. However, Rab11 overexpression inhibited cellular cholesterol esterification in an LDL-independent manner. This effect could be overcome by introducing cholesterol to the plasma membrane by using cyclodextrin as a carrier. These results suggest that in Rab11-overexpressing cells, deposition of cholesterol in recycling endosomes results in its impaired esterification, presumably due to defective recycling of cholesterol to the plasma membrane. The findings point to the importance of the recycling endosomes in regulating cholesterol and sphingolipid trafficking and cellular cholesterol homeostasis.
Mol Biol Cell 2002 Sep
PMID:Modulation of cellular cholesterol transport and homeostasis by Rab11. 1222 Nov 19

Niemann-Pick disease type C (NPC) is a neurodegenerative disorder with major visceral complications, including liver disease that can be fatal before onset of neurodegeneration. We have sought to determine the extent to which visceral disease contributes to neurodegeneration by making transgenic mice in which the wild-type NPC1 protein is expressed primarily in the CNS using the prion promoter. When the transgene was introduced into the npc1(-/-) animals neurodegeneration was prevented, a 'normal' lifespan occurred and the sterility of npc1(-/-) mice was corrected. The rescue did not provide complete neurological correction in the CNS as GM2 and GM3 gangliosides were observed to accumulate in some neurons and glia of transgenic animals. Two of three transgenic lines demonstrated some low-level ectopic expression resulting in correction of visceral phenotypes in liver and spleen. Interestingly, the third transgenic line continued to have moderate histocytosis in liver and spleen, yet had no detectable neurodegeneration. Thus, it is primarily the lack of NPC1 in the CNS and not the secondary effects of the visceral involvement that causes the neurological decline in NPC disease. In addition, the expression levels of NPC1 found in the CNS of transgenic animals were much greater than in normal littermates, demonstrating that overexpression of NPC1 is not harmful and allowing possibilities for genetic therapy interventions that utilize overexpression.
Hum Mol Genet 2002 Nov 15
PMID:Rescue of neurodegeneration in Niemann-Pick C mice by a prion-promoter-driven Npc1 cDNA transgene. 1241 32


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