Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.1 (alkaline phosphatase)
47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using polyclonal antibodies we have studied the distribution of protein kinase C in fetal mouse low thoracic vertebrae. By means of a pan protein kinase C antiserum recognizing the catalytic domain of the enzyme, we show that protein kinase C is markedly expressed in chondrocytes before birth. The enzyme seems to be very abundant in the more mature cells that are close to ossification centres as well as the periphery of the intervertebral disc, although it can also be detected in chondrocytes. In order to establish which protein kinase C isoenzyme(s) the chondrocytes produce, we employed polyclonal isoenzyme-specific antisera developed against three calcium-dependent isoforms (alpha, beta, gamma) and three calcium-independent isoforms (delta, epsilon, zeta). Secondary antibody conjugated to alkaline phosphatase revealed that chondrocytes markedly express the beta-isoform. Cells were also weakly stained by the anti-epsilon serum. The immunostaining was completely abolished by pre-incubating primary antibodies with the peptide antigens to which they were raised. These results suggest that protein kinase C (and particularly the beta isoform) could play an important role in mouse fetal chondrogenesis of the vertebral column.
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PMID:An immunohistochemical study of protein kinase C distribution in fetal mouse vertebral column. 798 11

Expression of ALP in F9 teratocarcinoma cells is induced by all-trans retinoic acid (ATRA) (Gianni' et al., Biochem. J. 274: 673-678, 1991). The specific ligand for retinoic acid related receptors (RXRs), 9-cis retinoic acid (9-cis RA), and three synthetic analogs binding to the alpha, beta and gamma forms of the retinoic acid receptors (RARs), AM580, CD2019, and CD437, were used to study their effects on alkaline phosphatase (ALP) enzymatic activity and mRNA levels. At concentrations close to the Kd for their respective receptors, 9-cis RA, AM580 (the RAR alpha agonist) and CD437 (the RAR gamma agonist) clearly upregulate the expression of the ALP gene, whereas the effect of CD2019 (the RAR beta agonist) is very modest. A specific inhibitor of the RAR alpha, Ro 41-5253, completely blocks the induction of ALP triggered by AM580, while it has minor effects on the upregulation caused by ATRA, 9-cis RA, CD437 and CD2019. The induction of ALP observed with the various retinoids is inhibited by the contemporaneous treatment with dibutyryl cAMP. The levels of the RAR alpha and gamma transcripts are unaltered, while RAR beta mRNAs are induced by ATRA, AM580, CD437 and to a lower extent by 9-cis RA and CD2019.
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PMID:Effects of synthetic retinoids and retinoic acid isomers on the expression of alkaline phosphatase in F9 teratocarcinoma cells. 821

Exogenous adenosine triphosphate (ATP) added to brush-border membrane vesicles was rapidly degraded mainly to inosine according to the high ecto-nucleotidase activities in these vesicles. In the absence of phosphate, inosine was slowly transformed into hypoxanthine, and xanthine oxidase and dehydrogenase activities were not detected. The presence of ecto-adenosine deaminase and ecto-adenosine monophosphate (AMP) nucleotidase was shown. The ecto-adenosine deaminase was inhibited by deoxycoformycin and was also detected in rat renal brush-border membrane vesicles. Using orthovanadate, levamisole, and alpha, beta-methylene adenosine diphosphate as possible inhibitors, alkaline phosphatase was shown to be the main agent responsible for ecto-AMP nucleotidase activity. In pig renal basolateral membrane vesicles and in whole cell extracts from pig renal cortex, ecto-AMP nucleotidase was the limiting factor in ATP degradation. Comparing the ATP catabolism in the whole cell cortical extract with the catabolism in the same sample precleared of membranes, it was shown that ectonucleotidase activity is mainly bound to the membranous components. It is also shown that the whole cell extract of pig renal cortex has hypoxanthine phosphoribosyl transferase activity, and it seems probable that the rapid and specific formation of luminal inosine and its transport into the cell in competition with adenosine may start the purine salvage pathway through the synthesis of IMP from hypoxanthine.
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PMID:Adenine nucleotides and adenosine metabolism in pig kidney proximal tubule membranes. 840 44

Treatment of eIF-2B and eIF-2 with NEM abolishes nucleotide exchange and GTP-binding activities of the proteins. Incubation of eIF-2B with [14C]NEM results in strong labeling of the 82- and 55-kDa subunits and with less labeling of the other subunits. Preincubation of eIF-2B with eIF-2 interferes with [14C]NEM labeling of the 82- and 55-kDa subunits. All three (alpha, beta, and gamma) subunits of eIF-2 are labeled strongly by [14C]NEM. Limited digestion of eIF-2B with trypsin inhibits nucleotide exchange activity but does not interfere with GTP binding. Under these conditions, the 65-kDa subunit is degraded completely while the other subunits remain intact. Treatment of eIF-2 with trypsin results in the generation of eIF-2 lacking the beta-subunit (eIF-2 alpha gamma). eIF-2(alpha gamma) binds [3H]GDP equally well as intact elf-2. In the presence of elf-2B, the exchange of [3H]GDP for GTP from elf-2. [3H]GDP prepared with eIF-2(alpha gamma) is diminished considerably. [3H]GTP binding to eIF-2(alpha gamma) is also four- to five-fold less than to intact eIF-2. In addition, the association of eIF-2B with intact eIF-2, but not with eIF-2(alpha gamma), reduces by two-fold the rate and extent of removal of 32P by alkaline phosphatase from CK-2-phosphorylated 82-kDa subunit.
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PMID:The interaction of rabbit reticulocyte guanine nucleotide exchange factor eIF-2B with chain initiation factor 2: studies with N-ethylmaleimide and trypsin. 868 43

17Beta-estradiol (E2) regulates growth plate chondrocyte differentiation in both a sex- and cell maturation-dependent manner, and the sex-specific effects of E2 appear to be mediated in part by membrane events. In this study, we examined whether E2 regulates protein kinase C (PKC) in a cell-maturation and sex-specific manner and whether E2 uses a nongenomic mechanism in regulating this enzyme. In addition, we determined if PKC mediates the E2-dependent stimulation of alkaline phosphatase activity seen in chondrocytes. Confluent, fourth passage resting zone (RC) and growth zone (GC) chondrocytes from male and female rat costochondral cartilage were treated with 10(-10) to 10(-7) M E2. E2 caused a dose-dependent increase in PKC in RC and GC cells from female rats. Peak stimulation was at 90 min. Increased PKC was evident by 3 min in both RC and GC and was still evident in RC cells at 720 min, but in GC cells activity returned to baseline by 270 min. Actinomycin D had no effect at 9, 90, 270, or 720 min, but there was a small decrease in E2-stimulated PKC in RC treated with cycloheximide at 90 and 270 min and in GC treated for 90 min. E2 increased cytosolic and membrane PKC at 9 min and by 90 min promoted translocation of PKC activity from the cytosol to the membranous compartment of female RC cells. Antibodies specific for the alpha, beta, delta, epsilon, and zeta isoforms of PKC revealed that PKCalpha in female GC and RC cells is activated by E2. There was a small, but statistically significant, increase in PKC in male RC cells in response to E2, but it was not dose-dependent, and no effect of E2 was noted in male GC cells. 17Alpha-estradiol, an inactive isomer of E2, did not affect PKC specific activity in RC or GC cells from either female or male rats. Chelerythrine, a specific inhibitor of PKC, inhibited E2-dependent alkaline phosphatase activity, indicating that E2 mediates its rapid effects on alkaline phosphatase via PKC.
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PMID:17beta-estradiol regulation of protein kinase C activity in chondrocytes is sex-dependent and involves nongenomic mechanisms. 964 31

Protein kinase C (PKC) signaling pathways play an important role in cell survival and anticancer drug-induced apoptosis. We observed in clonogenicity assays of BG-1 human ovarian cancer cells that gemcitabine cytotoxicity was increased synergistically when drug treatment was followed or preceded by a 24-h exposure to 10 nM 12-O-tetradecanoylphorbol-13-acetate (TPA). Coincubation of 10 nM TPA with pharmacological inhibitors of PKC abrogated the synergism of TPA and gemcitabine. These observations prompted further investigation of PKC signaling events linked to TPA and gemcitabine cytotoxicity in BG-1 cells. Because PKC isoforms are differentially expressed in various cell types, we determined that BG-1 cells express the alpha, beta, delta, epsilon, and zeta isoforms of PKC. In addition, 1-h exposures to 10 microM gemcitabine triggered cytosol to membrane translocation of PKC isoforms alpha, delta, and epsilon, indicating these isoforms were activated by gemcitabine. We also explored the PKC mechanism(s) responsible for the synergism of TPA and gemcitabine, and determined that treatment with 10 nM TPA for 24 h in BG-1 cells: 1) downregulated PKCdelta and PKCalpha, without affecting PKCepsilon, 2) did not affect cell cycle distribution into S phase. 3) increased extracellular signal-regulated kinase signaling, and 4) increased intracellular alkaline phosphatase activity, a biochemical marker of cellular differentiation. Chronic exposure (24 h) to TPA enhanced gemcitabine cytotoxicity, perhaps by inducing cellular differentiation pathways in BG-1 cells. Therefore, the use of differentiating agents in combination with gemcitabine may improve its clinical efficacy.
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PMID:The effects of gemcitabine and TPA on PKC signaling in BG-1 human ovarian cancer cells. 1006 71

BMS-189453 is a synthetic retinoid that acts as an antagonist at retinoic acid receptors alpha, beta, and gamma. In Sprague Dawley rats at daily oral doses of 15, 60, or 240 mg/kg for 1 month, BMS-189453 produced increases in leukocyte counts, alkaline phosphatase and alanine aminotransferase levels, and marked testicular degeneration and atrophy at all doses. Significant overt signs of toxicity and deaths occurred at 240 mg/kg, whereas body-weight and food-consumption decreases occurred at 60 and 240 mg/kg. When BMS-189453 was administered to male rats at daily doses ranging from 12.5 to 100 mg/kg for 1 week, only minimal testicular changes occurred at all doses, shortly after the dosing period. However, after a 1-month drug-free observation period, marked testicular atrophy was evident at all doses. BMS-189453 was then administered at doses of 2, 10, or 50 mg/kg to male rats for 1, 3, or 7 consecutive days. Dose- and duration-dependent testicular toxicity that occurred after a 1-month observation period did not recover, and, in some cases, was more severe 4 months after the last dose. In rabbits administered BMS-189453 at oral doses of 2, 10, or 50 mg/kg for 1 week, testicular degeneration and atrophy were evident in the high-dose group at 1 month following treatment. These studies indicate that retinoid antagonists can selectively produce progressive and prolonged testicular toxicity after single or repeated oral doses that are otherwise well tolerated.
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PMID:BMS-189453, a novel retinoid receptor antagonist, is a potent testicular toxin. 1115 23

Deer antlers are the only mammalian organs that can be repeatedly regenerated; each year, these complex structures are shed and then regrow to be used for display and fighting. To date, the molecular mechanisms controlling antler regeneration are not well understood. Vitamin A and its derivatives, retinoic acids, play important roles in embryonic skeletal development. Here, we provide several lines of evidence consistent with retinoids playing a functional role in controlling cellular differentiation during bone formation in the regenerating antler. Three receptors (alpha, beta, gamma) for both the retinoic acid receptor (RAR) and retinoid X receptor (RXR) families show distinct patterns of expression in the growing antler tip, the site of endochondral ossification. RAR alpha and RXR beta are expressed in skin ("velvet") and the underlying perichondrium. In cartilage, which is vascularised, RXR beta is specifically expressed in chondrocytes, which express type II collagen, and RAR alpha in perivascular cells, which also express type I collagen, a marker of the osteoblast phenotype. High-performance liquid chromatography analysis shows significant amounts of Vitamin A (retinol) in antler tissues at all stages of differentiation. The metabolites all-trans-RA and 4-oxo-RA are found in skin, perichondrium, cartilage, bone, and periosteum. The RXR ligand, 9-cis-RA, is found in perichondrium, mineralised cartilage, and bone. To further define sites of RA synthesis in antler, we immunolocalised retinaldehyde dehydrogenase type 2 (RALDH-2), a major retinoic acid-generating enzyme. RALDH-2 is expressed in the skin and perichondrium and in perivascular cells in cartilage, although chondroprogenitors and chondrocytes express very low levels. At sites of bone formation, differentiated osteoblasts which express the bone-specific protein osteocalcin express high levels of RALDH2. The effect of RA on antler cell differentiation was studied in vitro; all-trans-RA inhibits expression of the chondrocyte phenotype, an effect that is blocked by addition of the RAR antagonist Ro41-5253. In monolayer cultures of mesenchymal progenitor cells, all-trans-RA increases the expression of alkaline phosphatase, a marker of the osteoblastic phenotype. In summary, this study has shown that antler tissues contain endogenous retinoids, including 9-cis RA, and the enzyme RALDH2 that generates RA. Sites of RA synthesis in antler correspond closely with the localisation of cells which express receptors for these ligands and which respond to the effects of RA.
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PMID:A role for retinoic acid in regulating the regeneration of deer antlers. 1243 67

We have evaluated the role of the ADP-ribosyl cyclase, CD38, in bone remodeling, a process by which the skeleton is being renewed constantly through the coordinated activity of osteoclasts and osteoblasts. CD38 catalyzes the cyclization of its substrate, NAD+, to the Ca2+-releasing second messenger, cyclic ADP-ribose (cADPr). We have shown previously that CD38 is expressed both in osteoblasts and osteoclasts. Its activation in the osteoclast triggers Ca2+ release through ryanodine receptors (RyRs), stimulation of interleukin-6 (IL-6), and an inhibition of bone resorption. Here, we have examined the consequences of deleting the CD38 gene in mice on skeletal remodeling. We report that CD38-/- mice displayed a markedly reduced bone mineral density (BMD) at the femur, tibia, and lumbar spine at 3 months and at the lumbar spine at 4 months, with full normalization of the BMD at all sites at 5 months. The osteoporosis at 3 months was accompanied by a reduction in primary spongiosa and increased osteoclast surfaces on histomorphometric analysis. Hematopoetic stem cells isolated ex vivo from CD38-/- mice showed a dramatic approximately fourfold increase in osteoclast formation in response to incubation for 6 days with RANK-L and M-CSF. The osteoclasts so formed in these cultures showed a approximately 2.5-fold increase in resorptive activity compared with wild-type cells. However, when adherent bone marrow stromal cells were allowed to mature into alkaline phosphatase-positive colony-forming units (CFU-Fs), those derived from CD38-/- mice showed a significant reduction in differentiation compared with wild-type cells. Real-time RT-PCR on mRNA isolated from osteoclasts at day 6 showed a significant reduction in IL-6 and IL-6 receptor mRNA, together with significant decreases in the expression of all calcineurin A isoforms, alpha, beta, and gamma. These findings establish a critical role for CD38 in osteoclast formation and bone resorption. We speculate that CD38 functions as a cellular NAD+ "sensor," particularly during periods of active motility and secretion.
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PMID:Disordered osteoclast formation and function in a CD38 (ADP-ribosyl cyclase)-deficient mouse establishes an essential role for CD38 in bone resorption. 1263 76


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