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At least 1,279 records · Page 71Linked to original sources
PubMed1993

Cysteamine gliopathy in situ: a cellular stress model for the biogenesis of astrocytic inclusions.

In cultured astroglia, cysteamine induces the accumulation of peroxidase-positive cytoplasmic inclusions in the context of a generalized cellular stress response. In the present study, systemic cysteamine administration over a 3 week period induced HSP27, 72, 90, and GRP94 (stress proteins) in astrocytes and significantly increased numbers of peroxidase-positive astrocytic inclusions in the various brain regions relative to controls. Similar patterns of HSP expression were also observed at 24 hours following cysteamine treatment indicating that cellular stress may be a very proximal event in the biogenesis of the astrocytic inclusions. The topography of glial peroxidase activity may provide a "map" of central nervous system regions particularly prone to oxidative stress during normal aging and under pathologic conditions.

Animals↗
PubMed1993

Membrane topology and biogenesis of eukaryotic signal peptidase.

The signal peptidase complex (SPC) is a hetero-oligomeric membrane protein containing subunits of 12, 18, 21, 22/23, and 25 kDa. The 18- and 21-kDa subunits are mammalian homologs of SEC11 protein, which is necessary for signal peptide processing and cell viability in the yeast Saccharomyces cerevisiae. The functional and/or structural contributions of the 12-, 22/23-, and 25-kDa subunits to SPC activity have not yet been elucidated. To explore the structure of SPC subunits and their relationships to signal peptide processing and protein translocation, we have examined their endoplasmic reticulum (ER) membrane topology and biogenesis. Signal peptidase activity and SPC subunits are resistant to protease treatment in intact and detergent-solubilized membranes. Heat-denatured SPC subunits and SPC subunits translated in vitro are, however, protease sensitive, suggesting that the assembly of the oligomeric complex confers protease resistance. To define the membrane topology of SPC subunits, both wild-type subunits and subunit fusion proteins containing additional sites for N-linked glycosylation were assembled into microsomal membranes in vitro. Despite the presence of multiple hydrophobic domains, each subunit is anchored to the ER membrane by a single amino-terminal transmembrane domain in an Ncytoplasmic Cexoplasmic (type II) orientation. This topology places the bulk of the protein mass in the ER lumen and positions a putative serine-containing active site domain in SPC 18 and 21 at the same relative distance from the membrane as the analogous region in Escherichia coli leader peptidase. These studies have also revealed that, in spite of the temporal and perhaps physical association of the SPC with the process of protein translocation, SPC subunits integrate into the ER membrane by a signal recognition particle-dependent pathway and, hence, rely on the existence of a preformed translocation apparatus for their own membrane assembly.

Amino Acid Sequence↗
PubMed1996

pH- and Ca(2+)-dependent aggregation property of secretory vesicle matrix proteins and the potential role of chromogranins A and B in secretory vesicle biogenesis.

Chromogranins A and B (CGA and CGB), the major proteins of the secretory vesicles of the regulated secretory pathway, have been shown to aggregate in a low pH and high calcium environment, the condition found in the trans-Golgi network where secretory vesicles are formed. Moreover, CGA and CGB, as well as several other secretory vesicle matrix proteins, have recently been shown to bind to the vesicle membrane at the intravesicular pH of 5.5 and to be released from it at a near physiological pH of 7.5. The pH- and Ca(2+)-dependent aggregation and interaction of chromogranins, as well as several other matrix proteins, with the vesicle membrane are considered essential in vesicle biogenesis. Therefore, to gain further insight into how vesicle matrix proteins find their way into the secretory vesicles, the pH- and Ca(2+)-dependent aggregation and vesicle membrane binding properties of the vesicle matrix proteins were studied, and it was found that most of the vesicle matrix proteins aggregated in the presence of Ca2+ at the intravesicular pH of 5.5. Furthermore, most of the vesicle matrix proteins bound not only to the vesicle membrane but also to CGA at pH 5.5, with the exception of a few matrix proteins that appeared to bind only to CGA or to vesicle membrane. Purified CGB was also shown to interact with CGA at pH 5.5. The extent and Ca(2+)-sensitivity of the aggregation of vesicle matrix proteins lay between those of purified CGB and CGA, CGB aggregation showing the highest degree of aggregation and being the most Ca2+ sensitive at a given protein concentration. Hence, in view of the abundance of chromogranins in secretory vesicles and their low pH- and high calcium-dependent aggregation property, combined with their ability to interact with both the vesicle matrix proteins and the vesicle membrane, CGA and CGB are proposed to play essential roles in the selective aggregation and sorting of potential vesicle matrix proteins to the immature secretory vesicles of the regulated secretory pathway.

Adrenal Medulla↗
PubMed1996

The peroxisome biogenesis disorder group 4 gene, PXAAA1, encodes a cytoplasmic ATPase required for stability of the PTS1 receptor.

In humans, defects in peroxisome assembly result in the peroxisome biogenesis disorders (PBDs), a group of genetically heterogeneous, lethal recessive diseases. We have identified the human gene PXAAA1 based upon its similarity to PpPAS5, a gene required for peroxisome assembly in the yeast Pichia pastoris. Expression of PXAAA1 restored peroxisomal protein import in fibroblasts from 16 unrelated members of complementation group 4 (CG4) of the PBD. Consistent with this observation, CG4 patients carry mutations in PXAAA1. The product of this gene, Pxaaa1p, belongs to the AAA family of ATPases and appears to be a predominantly cytoplasmic protein. Substitution of an arginine for the conserved lysine residue in the ATPase domain of Pxaaa1p abolished its biological activity, suggesting that Pxaaa1p is an ATPase. Furthermore, Pxaaa1p is required for stability of the predominantly cytoplasmic PTS1 receptor, Pxr1p. We conclude that Pxaaa1p plays a direct role in peroxisomal protein import and is required for PTS1 receptor activity.

Adenosine Triphosphatases↗
PubMed1996

Epoxide hydrolase in human and rat peroxisomes: implication for disorders of peroxisomal biogenesis.

To understand the basis of excretion of excessive amounts of epoxydicarboxylic fatty acids (EDFA) in urine of patients with disorders of peroxisomal biogenesis (Pitt, J. J., and A. Poulos. 1993. Clin. Chim. Acta. 223: 23-29), the activity of epoxide hydrolase (EH) was measured in cultured skin fibroblasts from control subjects and patients with peroxisomal disorders. EH activity was approximately 40% lower in fibroblasts that lack intact peroxisomes (Zellweger syndrome), whereas the activity in other peroxisomal disorders (X-adrenoleukodystrophy and rhizomelic chondrodysplasia punctata) with intact peroxisomes was similar to control. To identify the specific enzyme/organelle that represents the decrease in EH activity in Zellweger cells, we have analyzed this activity in different subcellular organelles from control and Zellweger skin fibroblasts. EH activity was enriched in peroxisomes from control fibroblast. EH activity in isolated mitochondria, microsomes, or cytosol from Zellweger fibroblast was similar to that of control fibroblast. These observations indicate that deficient activity of EH in cells from Zellweger patients is due to lack of peroxisomal EH activity. The peroxisomal EH is differentially induced to a higher degree by ciprofibrate, a hypolipidemic agent and peroxisome proliferator, than EH activity in other organelles and cytoplasm. The high specific activity of EH in peroxisomes and differential induction of EH activity in peroxisomes as compared to other organelles, and the excretion of EDFA in patients who lack peroxisomes suggests that peroxisomal EH may be responsible for the detoxification of EDFA, and that this enzyme in peroxisomes may be a different protein than the EH found in other organelles.

Animals↗
PubMed1996

Progress in the understanding of glycogen biogenesis in rat heart.

The sequence of glucosylation steps from "genesine", the naked initiation protein, to rat heart glycogen are described. During a pulse experiment with UDP-14C-glucose the radiolabelled 14C-glucosylated protein band of 38 and 42 kDa appeared first. Mn+2 stimulates the first transfer of glucoses to "genesine" and the 38 kDa and 42 kDa protein bands appear. Although further growth is inhibited by Mn+2, this inhibition is reversed by PMSF+Glc6P. In the absence of Mn+2, a major 14C-glucosylated protein band of 60 kDa and also a faint one in the location of 42 kDa appeared. Designing the synthetic and degradative processes it is possible to go from the 42 kDa 14C-glucosylated protein band through species of higher mw to glycogen and back to the 42 kDa one. In the "genesine" autoglucosylating process involved in the initiation of rat heart biogenesis, several dissimilar activities had to be distinguished. The first glycogen initiator 1 (GI1) is that with an activity stimulated by Mn+2 which transfers one or two glucoses. The other glycogen initiator 2 (GI2) is inhibited by Mn+2 and in its absence produces a glucosylated protein band of 60 kDa. Finally a third one, stimulated by Glc6P, we named it Elongator 1 (E1), which in the presence of mumolar concentration of UDPGlc originates a family of glucosylated protein bands almost from 42 kDa to 200 kDa.

Animals↗
PubMed1996

Human peroxisome assembly factor-2 (PAF-2): a gene responsible for group C peroxisome biogenesis disorder in humans.

Peroxisome-biogenesis disorders (PBD) are genetically heterogeneous and can be classified into at least ten complementation groups. We recently isolated the cDNA for rat peroxisome assembly factor-2 (PAF-2) by functional complementation using the peroxisome-deficient Chinese-hamster-ovary cell mutant, ZP92. To clarify the novel pathogenic gene of PBD, we cloned the full-length human PAF-2 cDNA that morphologically and biochemically restores peroxisomes of group C Zellweger fibroblasts (the same as group 4 in the Kennedy-Krieger Institute) and identified two pathogenic mutations in the PAF-2 gene in two patients with group C Zellweger syndrome. The 2,940-bp open reading frame of the human PAF-2 cDNA encodes a 980-amino-acid protein that shows 87.1% identity with rat PAF-2 and also restored the peroxisome assembly after gene transfer to fibroblasts of group C patients. Direct sequencing of the PAF-2 gene revealed a homozygous 1-bp insertion at nucleotide 511 (511 insT) in one patient with group C Zellweger syndrome (ZS), which introduces a premature termination codon in the PAF-2 gene, and, in the second patient, revealed a splice-site mutation in intron 3 (IVS3+1G-->A), which skipped exon 3, an event that leads to peroxisome deficiency. Chromosome mapping utilizing FISH indicates that PAF-2 is located on chromosome 6p21.1. These results confirm that human PAF-2 cDNA restores peroxisome of group C cells and that defects in the PAF-2 produce peroxisome deficiency of group C PBD.

ATPases Associated with Diverse Cellular Activitie↗
PubMed1996

[Polyunsaturated fatty acid biogenesis is impaired in spontaneously hypertensive rat in relation to the pathogenesis of hypertension].

This study was designed to investigate polyunsaturated fatty acid (PUFA) biogenesis in spontaneously hypertensive rats (SHR) during the onset of hypertension. We measured liver desaturase activities, limiting enzymes of linoleic (LA) biosynthesis into arachidonic acid (AA). Fifteen male SHR and 15 male Wistar Kyoto (WKY) normotensive rats were killed at 7.9 or 13 week-old (5 per group). Systolic blood pressure was measured by plethysmography. Liver microsomes were obtained after ultracentrifugation and 5 mg of microsomal proteins incubated during 5 minutes at 37 degrees C with 0.04 mumoles of (1-14C) LA or (2-14C) dihomo-gamma-linolenic acid (DGLA). After fatty acid saponification and methylation, the bioconversion of (1-14C) LA into (1-14C) gamma-linolenic acid (GLA; delta 6 desaturation) and of (2-14C) DGLA into (2-14C) AA (delta 5 desaturation) was determined by measuring the radioactivity shared out between substrate and product of desaturation, after HPLC partition. Fatty acid composition of liver total lipids was calculated after GLC partition. In 7 week-old SHR, blood pressure was closed to that of WKY rats, higher in the 9 week-olds, when hypertension was settled in the 13 week-olds. Delta 6 and delta 5 desaturase activities were lower in SHR than in corresponding WKY. Those impaired desaturase activities increased with the age of rats: delta 6 desaturase activity was 43, 70 and 61% lower in the 7, 9 and 13 week-old SHR, respectively; delta 5 desaturase activity was 14, 48 and 53% lower in the same conditions. We observed a liver storage of total lipids in the 3 groups of SHR. The fatty acid composition of liver total lipids shows a lower proportion of AA and a higher proportion of LA in SHR than in WKY rats, confirming the depletion of the enzymatic systems studied. In summary, LA bioconversion into AA is decreased in liver microsomes of SHR, via the desaturase impairments. This phenomenon is concomitant with the pathogenesis of hypertension and related to the liver fatty acid composition. Such results explain partly the effects of PUFA rich diets administered to hypertensive rats, and clarify the interpretation of such effects.

Animals↗
PubMed1977

[The nature of peptides firmly associated with the protein part of membrane lipoproteins in chloroplast biogenesis].

The biosynthesis of membrane lipoproteins in maize plastids at different stages of differentiation of the chloroplast lamellar system was studied. Prolamellar and lamellar system preparations were isolated from maize plastids and been or kidney bean chloroplasts, disintegrated by osmotic shock. Chloroplast lipoproteins are membraneous proteins of chloroplast lamellar systems. Peptids, lipids and carbohydrates "firmly" associated with the protein part of membrane lipoproteins were found at all stages of chloroplast ultrastructure formation. Incorporation of C14 amino acid increased with the time of incubation in "firmly" lipoprotein--bound peptids and in the polypeptid part of lipoproteins. Puromycin but not actidion D inhibited amino acid incorporation into the peptids and polypeptids of chloroplasts in vitro experiments. The maximal level of C14-peptids "firmly" associated with the protein part of membrane lipoproteins was observed in the membrane fraction of proplastids in vivo. It is pointed out that biogenesis process leads to the decrease of content of "firmly" lipoprotein--bound peptids in the chloroplast lamellae fraction.

Carbohydrate Metabolism↗
PubMed1997

Biogenesis of surface domains in fly photoreceptor cells: fine-structural analysis of the plasma membrane and immunolocalization of Na+, K+ ATPase and alpha-spectrin during cell differentiation.

Electron microscopic examination of pupal and adult blowfly (Calliphora erythrocephala) retina provides novel details on the biogenesis of the photoreceptor surface, particularly regarding the development of the microvillar rhabdomere and associated structures, such as the submicrovillar endoplasmic reticulum. Localization of the Na+, K(+)-ATPase on the surface of developing photoreceptors has also been examined by immunofluorescence confocal microscopy and immunogold electron microscopy. Na+, K(+)-ATPase has a nonpolarized distribution in midpupal photoreceptors that are determined by fate but that are not yet completely differentiated. Large amounts of Na+, K(+)-ATPase are synthesized and delivered to the cell surface throughout the second half of pupal life. At certain time points in late pupal development, specific membrane domains become cleared of Na+, K(+)-ATPase in the photoreceptors R1-R6. However, the distribution of Na+, K(+)-ATPase remains nonpolarized in R7/R8, even after eclosion. Because the membrane-associated cytoskeleton plays a direct role in the establishment and maintenance of membrane domains in a variety of systems, it is of interest to study the distribution of alpha-spectrin and its possible association with Na+, K(+)-ATPase. The localization of alpha-spectrin resembles the distribution pattern of Na+, K(+)-ATPase in midpupal and adult photoreceptors. However, changes in Na+, K(+)-ATPase localization in late pupal photoreceptors precede the redistribution of alpha-spectrin by several days. Biochemical studies of cellular membranes demonstrate further that Na+, K(+)-ATPase can be solubilized by Triton X-100, although alpha-spectrin remains in a macromolecular complex. These results indicate that the development and the maintenance of the polarized Na+, K(+)-ATPase distribution in blowfly photoreceptors are not tightly coupled to alpha-spectrin.

Animals↗
PubMed1998

Apolipoproteins in human fetal colon: immunolocalization, biogenesis, and hormonal regulation.

The present investigation aimed at defining the localization of apolipoproteins (apo) A-I, A-IV, B-48, and B-100 along the crypt-villus axis of the human fetal colon, their biogenesis during gestation, and their hormonal regulation. Using immunofluorescence, the distribution of apo A-I and A-IV appeared as a gradient, increasing from the developing crypt to the tip of the villus. On the other hand, apo B-100 staining was found in the crypt and the lower mid-villus region with varying intensities in the upper villus cells, while the 2D8 antibody which recognizes both apo B-100 and B-48, revealed uniform staining along the crypt-villus axis. Apolipoprotein synthesis, determined by [35S] methionine labeling, immunoprecipitation, and SDS-PAGE showed a predominance of apo A-IV (53%), followed by apo A-I (23.9%), apo B-48 (13.4%), and apo B-100 (9.7%). The synthesis of each apolipoprotein was significantly modulated by hydrocortisone, insulin and epidermal growth factor (EGF). Apart from a decrease in apo B-100 exerted by EGF and a reduction in apo A-I resulting from the addition of insulin, the other apolipoproteins were all enhanced. Our data confirm that the fetal colon has the capacity to synthesize apolipoprotein A-I, A-IV, B-48, and B-100 and establish that their synthesis are modulated by hormonal and growth factors known to be involved in the regulatory mechanism of the functional development of human jejunum.

Antibodies, Monoclonal↗
PubMed1995

Calcium concretions in the pineal gland of aged rats: an ultrastructural and microanalytical study of their biogenesis.

The genesis of calcium concretions in aged rats was studied by means of transmission and scanning electron microscopy. The potassium pyroantimonate method, combined with X-ray microanalysis, allowed us to study the distribution of cations and calcium. Notable accumulations of calcium (associated with phosphorus) were localized in vesicles, vacuoles, lipid droplets, lipopigments, and mitochondria of dark pinealocytes. The results obtained in the present investigation suggest that these organelles are involved in the genesis of the concretions. The presence of sulfur indicates the existence of an organic matrix. We propose that genesis takes place in dark pinealocytes, which contain more calcium than light pinealocytes. Mineralization foci are sometimes associated with cellular debris and enlarge by further apposition of material. Two types of concretions, as determined by electron microscopy and confirmed by electron diffraction, could be observed: the "amorphous" type with concentric layers and the crystalline type with needle-shaped crystals. Once formed, the concretions reach the extracellular space and the cell breaks down. Possible extracellular calcification is suggested in the extracellular calcium-rich floculent material. The mineralization process is interpreted as being an age-related phenomenon and mainly a consequence of the degeneration of pinealocytes.

Aging↗