Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027960 (mole)
 21,279 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This series presents six cases of a rare variant of dermatofibroma, characterized by marked clear cell change. All lesions occurred on the lower extremities of middle-aged adults (four women, two men), mostly with the clinical diagnosis of fibrohistiocytic lesion. Histological examination revealed well circumscribed, faintly stained dermal to subcutaneous lesions which were due to the overwhelming presence of clear cells (> 90%), some with prominent PAS-positive cytoplasmic granulation. Overlying epidermal hyperplasia as well as storiform arrangement of spindle cells, sclerotic collagen and some interspersed lympho-histiocytic infiltrate at the periphery of the lesion indicated the fibrohistiocytic origin. Individual histopathological peculiarities included: bizarre giant cells in two cases, perifollicular arrangement and haemangiopericytoma-like features with iron deposition in one case each. Immunohistochemically three of four lesions showed moderate reactivity for factor XIIIa and two of four with an anti-metallothionen marker E9, but were otherwise negative with a broad panel of markers. Electronmicroscopy in two cases revealed large pools of glycogen beside focal, prominent endoplasmic reticulum and lysosomes in some granular cells, but only optically translucent cells in cases of clear cells. Recognition of clear cell dermatofibroma is important as the differential diagnosis includes some entities with more serious outcome/considerations such as metastases of renal cell carcinoma, xanthogranulomatous reactions, balloon cell naevus/melanoma and clear cell sarcoma.
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PMID:Clear cell dermatofibroma. 902 59

The activity of BiP, the major chaperone of the endoplasmic reticulum (ER) lumen, is known to be Ca2+-regulated; however, the participation of this protein in the ER storage of the cation has not yet been investigated. Here such a role is demonstrated in human epithelial (HeLa) cells transiently transfected with the hamster BiP cDNA and incubated in Ca2+-free medium, as revealed by two different techniques. In the first, co-transfected aequorin was employed as a probe for assaying either the cytosolic of the mitochondrial free Ca2+ concentration. By this approach higher Ca2+ release responses were revealed in BiP-transfected cells by experiments in which extensive store depletion was induced either by repetitive stimulation with inositol 1,4,5-trisphosphate-generating agonists or by treatment with the Ca2+ ionophore, A23187. In the second technique the cells were loaded at the equilibrium with 45Ca, and the release of the tracer observed upon treatment with thapsigargin, a blocker of the ER Ca2+ ATPases, was larger in BiP-transfected than in control cells. The latter results were obtained also when BiP was overexpressed not via transfection but as a response to ER stress by tunicamycin. These results are sustained by increases of the ER Ca2+ storage capacity rather than by artifacts or indirect readjustments induced in the cells by the overexpression of the chaperone since (a) the exogenous and endogenous BiP were both confined to the ER, (b) the expression levels of other proteins active in the ER Ca2+ storage were not changed, and (c) effects similar to those of wild type BiP were obtained with a deletion mutant devoid of chaperone activity. The specificity of the results was confirmed by parallel 45Ca experiments carried out in HeLa cells transfected with two other Ca2+-binding proteins, calreticulin and CaBP2(ERp72), only the first of which induced increases of Ca2+ capacity. We conclude that BiP has a dual function, in addition to its chaperone role it is a bona fide ER lumenal Ca2+ storage protein contributing, under resting cell conditions, to around 25% of the store, with a stoichiometry of 1-2 moles of calcium/mole of BiP.
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PMID:BiP, a major chaperone protein of the endoplasmic reticulum lumen, plays a direct and important role in the storage of the rapidly exchanging pool of Ca2+. 938 33

The blind mole rat (Spalax ehrenbergi) is a fossorial solitary rodent which exhibits extensive intraspecific aggression and uses scent markings to deter contraspecific invaders. Mole rats of different ages were captured near Tel Aviv, Israel, and sacrificed by an overdose of Xylazine hydrochloride. Olfactory epithelium sites from the nasal cavity (NC) and the vomeronasal organ (VNO) were dissected and fixed for light and electron microscopy. The mole rat's olfactory epithelium of the NC consists of several cell types, of which two types are supporting cells that comprise both microvilli and cilia but differ in staining and the presence of rough endoplasmic reticulum. The third type has no cilia. Secretory goblet cells were frequent among supporting cells of adults alone. Two types of receptor cells protrude into the NC with olfactory knobs at their apical region; one type has up to 177.6 +/- 9.4 cilia per knob plus microvilli, while the other type has only microvilli. The third type of sensory cell has no knob and contains microvilli only. The basal epithelium layer consists of short-bodied cells with round nuclei. The VNO of the mole rat is situated beneath the nasal septum, consisting of supporting, sensory, and basal cell types, with many cilia at the apical portion. At its anterior part, the VNO is connected to the NC by narrow canals. The abundance of cilia and microvilli in the mole rat olfactory cells provides the first anatomical evidence for their olfactory acuity. Such acuity is important in mole rats, compensating for their loss of vision and enabling them to detect and avoid rivals prior to potential aggressive encounters as well as to select food plants during foraging.
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PMID:Morphology and cytology of the nasal cavity and vomeronasal organ in juvenile and adult blind mole rats (Spalax ehrenbergi). 971 84

Epidermal naevi are localized malformations of the epidermis consisting of verrucoid scaly papules and plaques following Blaschko's lines. Genetic mosaicism has been proposed to underlie the development of linear epidermal naevi. Rarely, epidermal naevi show acantholytic histology similar to Darier's disease, a dominantly inherited skin condition characterized by widespread warty papules. As patients with acantholytic dyskeratotic naevi often give a history of worsening after sun exposure and the lesions are typical of Darier's disease, numerous authors have proposed that these patients have segmental Darier's disease. The postulated relationship has not been proven, however. Recently, we identified ATP2A2, which encodes the sarco/endoplasmic reticulum Ca(2+) ATPase isoform 2 as the defective gene in Darier's disease. In this report, we investigated the involvement of ATP2A2 in acantholytic dyskeratotic naevi following Blaschko's lines in two patients. We identified a nonsense mutation (Y894X) in the first patient and a nonconservative glycine to arginine mutation at codon 769 (G769R) in the other patient. These mutations were present in affected skin, and were not detected in unaffected skin or in leukocytes. We conclude that acantholytic dyskeratotic naevi can arise from a somatic mutation in ATP2A2. These individuals are mosaics for the mutation, but the risk of transmission of generalized Darier's disease will depend on whether the germline is affected. Our findings provide further evidence that Blaschko's lines do reflect genetic mosaicism and that the term acantholytic dyskeratotic naevus might be replaced in the future by segmental Darier's disease induced by postzygotic mosaicism. J Invest Dermatol 115:1144-1147 2000
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PMID:Mosaicism for ATP2A2 mutations causes segmental Darier's disease. 1112 Nov 53

Modulation of cytosolic calcium levels in both plants and animals is achieved by a system of Ca2+-transport and storage pathways that include Ca2+ buffering proteins in the lumen of intracellular compartments. To date, most research has focused on the role of transporters in regulating cytosolic calcium. We used a reverse genetics approach to modulate calcium stores in the lumen of the endoplasmic reticulum. Our goals were two-fold: to use the low affinity, high capacity Ca2+ binding characteristics of the C-domain of calreticulin to selectively increase Ca2+ storage in the endoplasmic reticulum, and to determine if those alterations affected plant physiological responses to stress. The C-domain of calreticulin is a highly acidic region that binds 20-50 moles of Ca2+ per mole of protein and has been shown to be the major site of Ca2+ storage within the endoplasmic reticulum of plant cells. A 377-bp fragment encoding the C-domain and ER retention signal from the maize calreticulin gene was fused to a gene for the green fluorescent protein and expressed in Arabidopsis under the control of a heat shock promoter. Following induction on normal medium, the C-domain transformants showed delayed loss of chlorophyll after transfer to calcium depleted medium when compared to seedlings transformed with green fluorescent protein alone. Total calcium measurements showed a 9-35% increase for induced C-domain transformants compared to controls. The data suggest that ectopic expression of the calreticulin C-domain increases Ca2+ stores, and that this Ca2+ reserve can be used by the plant in times of stress.
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PMID:Expression of the high capacity calcium-binding domain of calreticulin increases bioavailable calcium stores in plants. 1187 98

Monoclonal antibody (mAb) therapy applications have been growing rapidly in recent years. Like other recombinant protein drugs, therapeutic mAb's need to be well characterized to ensure their structural and functional integrity. IgG mAb's are composed of two heavy and two light chains covalently linked by interchain disulfide bonds. Each domain of the heavy or light chain contains one additional disulfide bond. Native IgG mAb's, with completely formed disulfide bonds, should not bear any free sulfhydryl. This report describes detection and quantification of free sulfhydryl in recombinant mAb's produced in Chinese hamster ovary (CHO) cells using a fluorescent technique. The method utilizes the fluorescent probe N-(1-pyrenyl)maleimide (NPM). The purified mAb's appear to be homogeneous under native conditions with approximately 0.02 mol of free sulfhydryl per mole of protein. Upon denaturation, minor species related to the mAb's are observed on sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), and the free sulfhydryl level is determined to be approximately 0.1 mol/mol of protein. These results suggest that a small portion of these recombinant mAb's lack in intermolecular disulfide bonds but remain noncovalently associated under native conditions. The formation of the free sulfhydryl containing mAb species is likely to occur during the culture process and/or protein folding process in the endoplasmic reticulum (ER).
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PMID:Free sulfhydryl in recombinant monoclonal antibodies. 1205 67

Connective tissue consists of collagen, elastic fibers and ground substances produced by fibrocytes. These cells are usually spindle-shaped with slender nuclei and bipolar cytoplasmic extensions. Apart from labeling for vimentin and variable reactivity for factor XIIIa and CD34, fibrocytes are immunonegative. Electron microscopy reveals prominent endoplasmic reticulum, but is otherwise indistinct. Lesions with fibrocytic differentiation can be divided into five categories: scars, keloids, dermatofibromas, nodular fasciitis, and superficial fibromatoses are inflammatory lesions. Thereby, dermatofibromas and their subcutaneous/deep soft tissue counterpart nodular fasciitis can present with a wide variety of clinicopathologic variants which may be misinterpreted as malignancies. Prurigo nodularis, chondrodermatitis nodularis helicis, acanthoma fissuratum, and knuckle pads are hyperplasias; fibroma molle, fibrous papules, connective tissue nevi, and elastofibroma are hamartomas; and fibroma of tendon sheath, pleomorphic fibroma, and giant cell tumor of tendon sheath are benign neoplasms. Deep fibromatoses, dermatofibrosarcoma protuberans, giant cell fibroblastoma, giant cell angiofibroma, hyalinizing spindle cell tumor with giant rosettes, solitary fibrous tumor, myxofibrosarcoma, low-grade fibromyxoid sarcoma, acral myxoinflammatory fibroblastic sarcoma, and classical fibrosarcoma, are malignant neoplasms, that is fibrosarcomas of variable malignant potential. Lesions dominated by myocytes/ myofibroblasts, e.g. cutaneous myofibroma/infantile myofibromatosis, or by macrophages, e.g. xanthogranulomas, are not part of this chapter.
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PMID:Connective tissue tumors. 1207 32

A significant portion of brain phosphatidylethanolamine (PE) is synthesized by a pathway involving the mitochondrial enzyme phosphatidylserine decarboxylase (PSDC), in a process by which phosphatidylserine (PS) is transferred from the endoplasmic reticulum to mitochondria. Aging changes the fatty acid composition of brain phospholipids, PS and PE being the most affected. The present study was carried out to determine PSDC activity in cerebral cortex (CC) and cerebellum (CRBL) mitochondrial fraction from adult (4-month-old) and aged (30-month-old) rats and to compare these activities with that found in liver. To study the effect of 22:6n-3 content on the PSDC activity, PSs from different sources were prepared: rPS (from bovine retina, containing 36 mol % of 22:6n-3); adPS (from adult rat CC microsomal membranes, with 25 mole % 22:6n-3 content) and agPS (from aged rat CC microsomal membranes, with 21 mole % 22:6n-3 content). For aged CC PSDC, the preferred substrate was agPS (the physiological substrate for aged animals), whereas in adult CC PSDC the substrate preference was inverse (rPS > adPS > agPS). Furthermore, CRBL PSDC does not show any substrate preference based on 22:6n-3 content. CRBL PSDC activity in aged membranes using agPS as substrate is lower than PSDC activity in adult membranes in the presence of adPS. These results indicate that under physiological conditions, cerebellar PSDC is inhibited during aging. Liver PSDC activity showed the same substrate preference in adult and aged rats as adult CC PSDC. These findings lead us to conclude that PSDC activity has a differential tissue-dependent substrate preference characteristic of the aging process.
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PMID:Age-related changes in central nervous system phosphatidylserine decarboxylase activity. 1239 87

Mammalian enzymes in late cholesterol biosynthesis have been localized uniformly over the endoplasmic reticulum by enzymatic methods. We report here the first mammalian cholesterol biosynthetic enzyme unequivocally localized at the surface of intracellular lipid storage droplets. NAD(P)H steroid dehydrogenase-like protein (Nsdhl), a mammalian C-3 sterol dehydrogenase involved in the conversion of lanosterol into cholesterol, was localized on lipid droplets by immunofluorescence microscopy and subcellular fractionation. Nsdhl was localized on lipid droplets even when cell growth exclusively depended on cholesterol biosynthesis mediated by this enzyme. Depletion of fatty acids in culture medium reduced the development of lipid droplets and caused Nsdhl redistribution to the endoplasmic reticulum. Elevating oleic acid in medium induced well developed, Nsdhl-positive lipid droplets, and simultaneously caused a reduction in cellular conversion of lanosterol into cholesterol. Manipulated human NSDHL with a missense mutation (G205S) causing a human embryonic developmental disorder, congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD) syndrome, could no longer be localized on lipid droplets. Although the expression of wild-type NSDHL could restore the defective growth of a CHO cholesterol auxotroph, LEX2 in cholesterol-deficient medium, the expression of NSDHL(G205S) failed to do so. These results point to functional significance of the localization of Nsdhl on lipid droplets. Functional significance was also suggested by the colocalization of Nsdhl on lipid droplets with TIP47, a cargo selection protein for mannose 6-phosphate receptors from late endosomes to the trans-Golgi network. These results add to the growing notion that the lipid droplet is an organelle endowed with more complex roles in various biological phenomena.
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PMID:Localization of mammalian NAD(P)H steroid dehydrogenase-like protein on lipid droplets. 1283 64

NSDHL, for NAD(P)H steroid dehydrogenase-like, encodes a sterol dehydrogenase or decarboxylase involved in the sequential removal of two C-4 methyl groups in post-squalene cholesterol biosynthesis. Mutations in this gene are associated with human CHILD syndrome (congenital hemidysplasia with ichthyosiform nevus and limb defects), an X-linked, male lethal disorder, as well as the mouse mutations bare patches and striated. In the present study, we have investigated the subcellular localization of tagged proteins encoded by wild-type and selected mutant murine Nsdhl alleles using confocal microscopy. In addition to an ER localization commonly found for enzymes of post-squalene cholesterol biosynthesis, we have identified a novel association of NSDHL with lipid droplets, which are endoplasmic reticulum (ER)-derived cytoplasmic structures that contain a neutral lipid core. We further demonstrate that trafficking through the Golgi is necessary for ER membrane localization of the protein and propose a model for the association of NSDHL with lipid droplets. The dual localization of NSDHL within ER membranes and on the surface of lipid droplets may provide another mechanism for regulation of the levels and sites of accumulation of intracellular cholesterol.
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PMID:NSDHL, an enzyme involved in cholesterol biosynthesis, traffics through the Golgi and accumulates on ER membranes and on the surface of lipid droplets. 1450 30


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