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)

17 beta-Estradiol (E(2)) regulates growth plate cartilage cells via classical nuclear receptor mechanisms, as well as by direct effects on the chondrocyte membrane. These direct effects are stereospecific, causing a rapid increase in protein kinase C (PKC) specific activity, are only found in cells from female rats and are mimicked by E(2)-bovine serum albumin (BSA), which cannot penetrate the cell membrane. E(2) and E(2)-BSA stimulate alkaline phosphatase specific activity and proteoglycan sulfation in female rat costochondral cartilage cell cultures, but traditional nuclear receptors do not appear to be involved. This study examined the effect of the anti-estrogen tamoxifen on these markers of chondrocyte differentiation; the gender-specificity of tamoxifen's effect on PKC, if tamoxifen has an effect on vitamin D metabolite-stimulated PKC, which is mediated via specific membrane receptors (1,25-mVDR; 24,25-mVDR) and whether the effect of tamoxifen is mediated by nuclear estrogen receptors. Tamoxifen dose-dependently inhibited the effect of E(2)-BSA on PKC, alkaline phosphatase and proteoglycan sulfation in confluent cultures of female resting zone (RC) cells and growth zone (GC) (prehypertrophic/upper hypertrophic zones) cells, suggesting that its action is at the membrane and not cell maturation-dependent. Neither the estrogen receptor (ER) antagonist ICI 182780 nor the ER agonist diethylstilbesterol affected E(2) or E(2)-BSA-stimulated PKC in female chondrocytes. Tamoxifen also inhibited the increase in PKC activity due to 1 alpha,25-(OH)(2)D(3) or 24R,25-(OH)(2)D(3) in growth plate cells derived from either female or male rats. Inhibition of PKC by tamoxifen may be a general property of membrane receptors involved in rapid responses to hormones.
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PMID:Tamoxifen elicits its anti-estrogen effects in growth plate chondrocytes by inhibiting protein kinase C. 1198 87

Microarray analysis of gene expression has become a powerful approach for exploring the biological effects of drugs and other chemicals. In toxicology research, gene expression profiling may help identify hazards by comparing results for an experimental compound with a database, and establish mechanistic hypotheses through examination of discrete gene changes. Here we examine the hepatic effects of a thienopyridine inhibitor of NF-kappa B-mediated expression of cellular adhesion proteins. In a 3-day toxicity study in Sprague-Dawley rats, A-277249 induced hypertrophy of the liver and elevated serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP). To investigate mechanism, microarray analysis was done on RNA from livers of A-277249-treated rats. Gene expression profiles from A-277249 were compared with a database of profiles from fifteen known hepatotoxins. Agglomerative hierarchical cluster analysis showed A-277249 to have a profile most similar to the aromatic hydrocarbons Aroclor 1254 and 3-methylcholanthrene (3MC), two known activators of the aryl hydrocarbon nuclear receptor (AhR). Several genes regulated by the AhR, including cytochrome P450 1A1, were upregulated by A-277249. In addition, several genes involved in apoptosis and cell cycle were differentially expressed consistent with cell turnover, hypertrophy and hyperplasia observed by histology. Results from this study indicate that A-277249 hepatic toxicity is mediated by the AhR either directly or through effects on NF-kappa B, and demonstrate the utility of microarray analysis for the rapid identification of toxic hazards for new chemical entities.
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PMID:Identifying toxic mechanisms using DNA microarrays: evidence that an experimental inhibitor of cell adhesion molecule expression signals through the aryl hydrocarbon nuclear receptor. 1250 64

Assessment of the risk of human exposure to man-made chemicals that bind to hormone receptors has emerged as a major public health issue. Among hormone receptors, nuclear receptors tend to be targets of xenobiotics because their endogenous ligands are small, fat-soluble molecules. Nuclear receptors are ligand-inducible transcriptional factors and regulate the transcriptional activity of various target genes. At the start of the initiation step of transcription, nuclear receptors interact with coactivators (TIF2, SRC1, ACTR, CBP/p300, etc.) in an agonist-dependent manner. Using the interaction of the nuclear receptor with a coactivator, we have developed a novel rapid ligand in vitro screening method that is easy to use and has high sensitivity. This method, called by us the CoA-BAP system, is applicable to most nuclear receptors and is suitable for high-throughput screening because the entire experimental operation can be carried out on a microplate. We used human TIF2 as a coactivator including LXXLL motifs expressed in Escherichia coli as a fusion protein with BAP and nuclear receptor LBD expressed in E. coli as a fusion protein with GST. On a GSH-coupled microplate these proteins were incubated with chemicals and the protein-protein interactions were detected as alkaline phosphatase activity. To date we have examined seven nuclear receptors (ERalpha/beta, TRalpha, RARalpha/gamma, RXRalpha,and VDR) and confirmed that the method works well.
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PMID:Basis of a high-throughput method for nuclear receptor ligands. 1286 36

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is critical for phenotype determination at early differentiation stages of mesenchymal cells. Activation of this nuclear receptor inhibits gene expression in part by antagonizing the activities of several transcription factors. In this study we examined inhibitory mechanisms of osteoblast differentiation markers by activating PPAR-gamma. Our data indicate that the PPAR-gamma natural ligand 15d-PGJ2 dose-dependently inhibits expression of alkaline phosphatase and mineral deposition by primary stromal cells and by cell lines such as ST2 and MC3T3-E1. We next show that PPAR-gamma nuclear translocation coincides with duration and doses of ligand addition, indicating that 15d-PGJ2-activated PPAR-gamma rapidly translocates to the nuclear component where it exerts its biological effects. Further examination of downstream osteogenic signaling pathways induced by beta-glycerophosphate and ascorbic acid reveals that induction of osteoblast differentiation by these agents involves activation of the transcription factors Cbfa1 and NF-kappaB. The former is critical for osteoblast differentiation. To test whether inhibition of alkaline phosphatase expression and mineral deposition by activated PPAR-gamma reflects attenuation of transcriptional activity, we performed DNA protein-binding assays for NF-kappaB and Cbfa1. Our findings indicate that 15d-PGJ2-induced PPAR-gamma abrogates beta-glycerophosphate-activated Cbfa1 and NF-kappaB. These findings were consistent in primary and stromal cell lines, ST2 and MC3T3-E1. Thus activation of PPAR-gamma by 15d-PGJ2 inhibits DNA-binding activity of the transcription factors Cbfa1 and NF-kappaB, leading to diminished expression of osteoblast/stromal differentiation markers.
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PMID:Activation of peroxisome proliferator-activated receptor-gamma inhibits differentiation of preosteoblasts. 1287 83

Thiazolidinediones (TZDs) increase peripheral tissue insulin sensitivity in patients with type 2 diabetes mellitus by activating the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma). In bone marrow stromal cell cultures and in vivo, activation of PPARgamma by high doses (20 mg/kg/day) of TZDs has been reported to alter stem cell differentiation by promoting commitment of progenitor cells to the adipocytic lineage while inhibiting osteoblastogenesis. Here, we have examined the in vivo effects of low-dose rosiglitazone (3 mg/kg/day) on bone, administered to mice by gavage for 90 days. Rosiglitazone-treated mice had increased weight when compared with controls, with no significant alterations in serum levels of glucose, calcium or parathyroid hormone (PTH). Bone mineral density (BMD) at the lumbar vertebrae (L1-L4), ilium/sacrum, and total body was diminished by rosiglitazone treatment. Histologically, bone was characterized by decreased trabecular bone volume and increased marrow space with no significant change in bone marrow adipocity. Decreased osteoblast number and activity due to increased apoptotic death of osteoblasts and osteocytes was apparent while osteoclast parameters and serum levels of osteocalcin, alkaline phosphatase activity, and leptin were unaltered by rosiglitazone treatment. Therefore, the imbalance in bone remodeling that follows rosiglitazone administration arises from increased apoptotic death of osteogenic cells and diminished bone formation leading to the observed decrease in trabecular bone volume and BMD. These novel in vivo effects of TZDs on bone are of clinical relevance as patients with type 2 diabetes mellitus and other insulin resistant states treated with these agents may potentially be at increased risk of osteoporosis.
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PMID:Rosiglitazone impacts negatively on bone by promoting osteoblast/osteocyte apoptosis. 1552 88

Placental efflux transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) protect the developing fetus from exposure to potentially toxic xenobiotics. However, little is known about the expression of these transporters in human placentae of different gestational ages. Therefore, we quantified the expression of P-gp and BCRP in human placentae of different gestational ages. We also measured the expression of various nuclear regulatory factors such as the pregnane xenobiotic factor to determine whether their expression also changes with gestational age. Syncitial microvillous plasma membranes were isolated from human placentae of various gestational ages (60-90 days, 90-120 days, and full-term C-section placentae). P-gp and BCRP expression (protein) in these preparations were measured by Western blot analysis followed by an ELISA. Expression (mRNA) of P-gp, BCRP, and nuclear regulatory factors in the placentae were quantified by quantitative real-time PCR. P-gp expression (relative to that of alkaline phosphatase) was significantly (P < 0.05) higher (44.8-fold as protein; 6.5-fold as mRNA) in early gestational age human placentae (60-90 days) vs. term placentae. In contrast, BCRP (protein and mRNA) and nuclear regulatory factors (mRNA) expression in placental tissue did not change significantly with gestational age. However, placental expression of P-gp and human chorionic gonadotropin-beta (hCG-beta) transcripts was highly correlated (r = 0.73; P < 0.0001; Spearman rank correlation). Expression of P-gp, but not BCRP, decreases dramatically with gestational age in human placentae. This decrease in P-gp expression is not caused by a change in expression of nuclear receptor transcripts but appears to be related to hCG-beta expression. The placental P-gp expression appears to be upregulated in early pregnancy to protect the fetus from xenobiotic toxicity at a time when it is most vulnerable to such toxicity.
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PMID:P-glycoprotein and breast cancer resistance protein expression in human placentae of various gestational ages. 1596 34

Estrogens are known to cause hepatotoxicity such as intrahepatic cholestasis in susceptible women during pregnancy, after administration of oral contraceptives, or during postmenopausal replacement therapy. Enterohepatic nuclear receptors including farnesoid X receptor (FXR), pregnane X receptor (PXR), and constitutive active/androstane receptor (CAR) are important in maintaining bile acid homeostasis and protecting the liver from bile acid toxicity. However, no nuclear receptor has been implicated in the mechanism for estrogen-induced hepatotoxicity. Here Era(-/-), Erb(-/-), Fxr(-/-), Pxr(-/-), and Car(-/-) mice were employed to show that Era(-/-) mice were resistant to synthetic estrogen 17alpha-ethynylestradiol (EE2)-induced hepatotoxicity as indicated by the fact that the EE2-treated Era(-/-) mice developed none of the hepatotoxic phenotypes such as hepatomegaly, elevation in serum bile acids, increase of alkaline phosphatase activity, liver degeneration, and inflammation. Upon EE2 treatment, estrogen receptor alpha (ERalpha) repressed the expression of bile acid and cholesterol transporters (bile salt export pump (BSEP), Na(+)/taurocholate cotransporting polypeptide (NTCP), OATP1, OATP2, ABCG5, and ABCG8) in the liver. Consistently, biliary secretions of both bile acids and cholesterol were markedly decreased in EE2-treated wild-type mice but not in the EE2-treated Era(-/-) mice. In addition, ERalpha up-regulated the expression of CYP7B1 and down-regulated the CYP7A1 and CYP8B1, shifting bile acid synthesis toward the acidic pathway to increase the serum level of beta-muricholic acid. ERbeta, FXR, PXR, and CAR were not involved in regulating the expression of bile acid transporter and biosynthesis enzyme genes following EE2 exposure. Taken together, these results suggest that ERalpha-mediated repression of hepatic transporters and alterations of bile acid biosynthesis may contribute to development of the EE2-induced hepatotoxicity.
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PMID:Estrogen receptor alpha mediates 17alpha-ethynylestradiol causing hepatotoxicity. 1660 10

Dental epithelium comprises different cell populations, including ameloblasts and stratum intermedium cells. Ameloblasts are vitamin D targets, and at least five proteins undergo specific modulation of their expression following the addition of 1alpha,25(OH)2 vitamin D3[1alpha,25(OH)2D3]. Stratum intermedium cells have not been studied in any great detail regarding vitamin D impact. Interestingly, in these cells, the tissue non-specific alkaline phosphatase (TNAP) is overexpressed. On the other hand, TNAP is a reliable bone marker of vitamin D action, similar to calbindins in kidney and intestine, previously used for studies of vitamin D activity in ameloblasts. Here, TNAP expression and activity were investigated in vivo in the microdissected epithelium and mesenchyme of mandible incisors. Physiological doses of 1alpha,25(OH)2D3 injected in control rats failed to modify TNAP activity in both dental epithelium and mesenchyme. No significant differences were observed in the steady-state levels of TNAP mRNAs of dental tissues from wild-type and vitamin D nuclear receptor (VDRnuc)-deficient mice of the same litters. These data suggest that, in contrast to ameloblasts, stratum intermedium cells are not sensitive to 1alpha,25(OH)2D3. An explanation for such a responsiveness of stratum intermedium cells to 1alpha,25(OH)2D3 is proposed based on the respective expressions of both vitamin D receptors (VDRnuc and 1,25D3-[MARRS]) and the Dlx2 homeobox gene.
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PMID:Vitamin D and tissue non-specific alkaline phosphatase in dental cells. 1667 82

Bitter gourd (Momordica charantia L.) is a common vegetable in Asia that has been used in traditional medicine for the treatment of Diabetes. PPARs are ligand-dependent transcription factors that belong to the steroid hormone nuclear receptor family and control lipid and glucose homeostasis in the body. We previously reported that the ethyl acetate (EA) extract of bitter gourd activated peroxisome proliferator receptors (PPARs) alpha and gamma. To identify the active compound that activated PPARalpha, wild bitter gourd EA extract was partitioned between n-hexane and 90% methanol/10% H(2)O, and the n-hexane soluble fraction was further separated by silica gel column chromatography and finally by preparative HPLC. A transactivation assay employing a clone of CHOK1 cells stably transfected with a (UAS)(4)-tk-alkaline phosphatase reporter and a chimeric receptor of GAL4-rPPARalpha LBD was used to track the active component. Based on Mass, NMR, and IR spectroscopy, 9cis, 11trans, 13trans-conjugated linolenic acid (9c, 11t, 13t-CLN) was identified as a PPARalpha activator in wild bitter gourd. The isolated 9c, 11t, 13t-CLN rich fraction also significantly induced acyl CoA oxidase (ACO) activity in a peroxisome proliferator-responsive murine hepatoma cell line, H4IIEC3, implying that 9c, 11t, 13t-CLN was able to act on a natural PPARalpha signaling pathway as well. The content of 9c, 11t, 13t-CLN was estimated to be about 7.1 g/kg of our dried wild bitter gourd sample. The concentration of 9c, 11t, 13t-CLN and activation activity in the hydrolyzed EA extract of the seeds was higher than that of the flesh. The potential health benefits of 9c, 11t, 13t-CLN through the PPARalpha regulated mechanism are worthy to be further characterized in in vivo studies.
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PMID:Fractionation and identification of 9c, 11t, 13t-conjugated linolenic acid as an activator of PPARalpha in bitter gourd (Momordica charantia L.). 1695 49

Selective progesterone receptor modulators (SPRMs) have been suggested as therapeutic agents for treatment of gynecological disorders. One such SPRM, asoprisnil, was recently in clinical trials for treatment of uterine fibroids and endometriosis. We present the crystal structures of progesterone receptor (PR) ligand binding domain complexed with asoprisnil and the corepressors nuclear receptor corepressor (NCoR) and SMRT. This is the first report of steroid nuclear receptor crystal structures with ligand and corepressors. These structures show PR in a different conformation than PR complexed with progesterone (P4). We profiled asoprisnil in PR-dependent assays to understand further the PR-mediated mechanism of action. We confirmed previous findings that asoprisnil demonstrated antagonism, but not agonism, in a PR-B transfection assay and the T47D breast cancer cell alkaline phosphatase activity assay. Asoprisnil, but not RU486, weakly recruited the coactivators SRC-1 and AIB1. However, asoprisnil strongly recruited the corepressor NCoR in a manner similar to RU486. Unlike RU486, NCoR binding to asoprisnil-bound PR could be displaced with equal affinity by NCoR or TIF2 peptides. We further showed that it weakly activated T47D cell gene expression of Sgk-1 and PPL and antagonized P4-induced expression of both genes. In rat leiomyoma ELT3 cells, asoprisnil demonstrated partial P4-like inhibition of cyclooxygenase (COX) enzymatic activity and COX-2 gene expression. In the rat uterotrophic assay, asoprisnil demonstrated no P4-like ability to oppose estrogen. Our data suggest that asoprisnil differentially recruits coactivators and corepressors compared to RU486 or P4, and this specific cofactor interaction profile is apparently insufficient to oppose estrogenic activity in rat uterus.
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PMID:A structural and in vitro characterization of asoprisnil: a selective progesterone receptor modulator. 1735 70


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