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:3.2.1.23 (beta-galactosidase)
14,648 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The vitamin D receptor (VDR) binds to the vitamin D response element (VDRE) and mediates the effects of the biologically active form of vitamin D, 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], on gene expression. The VDR binds to the VDRE as a heterodimeric complex with retinoid X receptor. In the present study, we have used a yeast two-hybrid system to clone complementary DNA that codes for VDR-interacting protein(s). We found that the human steroid receptor coactivator-1 (SRC-1) interacts with the VDR in a ligand-dependent manner, as demonstrated by beta-galactosidase production. The interaction of the VDR and the SRC-1 takes place at physiological concentrations of 1,25(OH)2D3. A 48.2-fold stimulation of beta-galactosidase activity was observed in the presence of 10(-10) M 1,25-(OH)2D3. In addition, a direct interaction between the ligand-activated glutathione-S-transferase-VDR and 35S-labeled SRC-1 was observed in vitro. Deletion-mutation analysis of the VDR established that the ligand-dependent activation domain (AF-2) of the VDR is required for the interaction with SRC-1. One deletion mutant, pGVDR-(1-418), bound the ligand but failed to interact with the SRC-1, whereas another deletion mutant, pGVDR-(1-423), bound the ligand and interacted with the SRC-1. We demonstrated that all the deletion mutants were expressed as analyzed by a Gal4 DNA-binding domain antibody. Deletion mutation analysis of the SRC-1 demonstrated that 27 amino acids (DPCNTNPTPMTKATPEEIKLEAQSQFT) of the SRC-1 are essential for interaction with the AF-2 motif of the VDR.
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PMID:Mapping the domains of the interaction of the vitamin D receptor and steroid receptor coactivator-1. 944 Aug 10

The active hormonal form of vitamin D3, 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3), has been described as a principal mediator of skeletal homeostasis. Treatment of rat osteosarcoma (ROS)17/2.8, an osteoblast-like cell line, with 1alpha,25(OH)2D3 results in a ligand-dependent increase in transcription of the bone-specific osteocalcin gene. We isolated permanent cell lines that were established by transfecting ROS 17/2.8 cells with plasmids consisting of the human osteocalcin gene promoter containing the vitamin D responsive element linked to a bacterial beta-galactosidase gene. In one of many cell lines, especially in clone NK-31, 1alpha,25(OH)2D3 strongly stimulated beta-galactosidase activity. Reverse transcription-polymerase chain reaction analysis also showed endogenous osteocalcin gene expression and beta-galactosidase gene expression in clone NK-31 cells, which paralleled the increase in beta-galactosidase activity. Using a synthetic analogue of 1alpha,25(OH)2D3, 24,24-difluoro-1alpha,25-dihydroxyvitamin D3, we found that the levels of this activity and these gene expressions were nearly parallel to those of 1alpha,25(OH)2D3. 24R,25-dihydroxyvitamin D3 and 25-hydroxyvitamin D3 at high doses (concentration: 10(-7) M) also induced beta-galactosidase activity in clone NK-31. These cell lines, harboring the plasmid-carrying beta-galactosidase gene under the control of the osteocalcin gene promoter, may contribute to studies on the regulation by 1alpha,25(OH)2D3 or to the development of synthetic analogues of 1alpha,25(OH)2D3.
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PMID:Establishment of permanent cell lines exhibiting vitamin D-dependent expression of beta-galactosidase activity. 1042 66

Modulation of transgene expression by exogenous agents is an optimal goal in gene therapy. Successful keratinocyte gene therapy requires a promoter-enhancer cassette to regulate expression of the therapeutic gene in vivo. In this study, we first transferred plasmids, constructed by introducing inducible promoters fused to the beta-galactosidase gene (LAC Z), into keratinocytes in vitro. Metallothionein (MT) and 1,24-vitamin D(3)(OH)(2) dehydroxylase (VDH) promoters responded to the inducing agents, Cadmium and 1,25-vitamin D(3)(OH)(2) (VitD(3)), respectively. The plasmids were then introduced in vivo using a naked DNA method and the inducible promoters were evaluated by measuring beta-gal activity in rat keratinocytes. Zinc induced the transferred MT promoter activity by approximately 2-fold or 10-fold when administered systemically and topically, respectively. In addition, VitD(3) induced the transferred VDH promoter activity approximately 10-fold when administered topically. These data are useful for developing inducible promoters for keratinocyte gene therapy.
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PMID:Keratinocyte gene therapy: inducible promoters and in vivo control of transgene expression. 1167 83

Early in vitro cell culture studies suggested that testicular orphan nuclear receptor 2 (TR2), a member of the nuclear receptor superfamily, may play important roles in the control of several pathways including retinoic acids, vitamin D, thyroid hormones, and ciliary neurotrophic factor. Here we report the surprising results showing that mice lacking TR2 are viable and have no serious developmental defects. Male mice lacking TR2 have functional testes, including normal sperm number and motility, and both male and female mice lacking TR2 are fertile. In heterozygous TR2(+/-) male mice we found that beta-galactosidase, the indicator of TR2 protein expression, was first detected at the age of 3 weeks and its expression pattern was restricted mainly in the spermatocytes and round spermatids. These protein expression patterns were further confirmed with Northern blot analysis of TR2 mRNA expression. Together, results from TR2-knockout mice suggest that TR2 may not play essential roles in spermatogenesis and normal testis development, function, and maintenance. Alternatively, the roles of TR2 may be redundant and could be played by other close members of the nuclear receptor superfamily such as testicular orphan receptor 4 (TR4) or unidentified orphan receptors that share many similar functions with TR2. Further studies with double knockouts of both orphan nuclear receptors, TR2 and TR4, may reveal their real physiological roles.
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PMID:Spermatogenesis and testis development are normal in mice lacking testicular orphan nuclear receptor 2. 1205 74

The hypothesis that cross-talk between membrane-active beta-adrenergic agonists and estrogens includes beta-adrenergic modulation of estrogen receptor (ER)-regulated gene expression was investigated. Vascular smooth muscle-derived A7r5 cells were transfected with an ERalpha expression plasmid (pCR3.1-hERalpha), the estrogen response element (ERE)-linked reporter pERE-E1b-luciferase (ERE-Luc), and pCMV-beta-galactosidase using a lysine-conjugated adenovirus transfection method. Hormone or agonist treatment and harvest followed 6 hours and 24 hours later, respectively. Treatment with 17beta-estradiol (E(2), 1 nmol/L) significantly stimulated ERE-Luc activity. Isoproterenol (10-9 to 10-6 mol/L) treatment alone did not stimulate ERE-Luc activity. Cotreatment with both E(2) and isoproterenol resulted in complete inhibition of E(2)-stimulated ERE-Luc activity. This isoproterenol effect was prevented by the beta-adrenergic antagonist propanolol (10-6 mol/L). Adrenomedullin treatment in these cells (1-50 nmol/L) did not inhibit ER/ERE-Luc activity, whether in the presence or absence of E(2). Moreover, isoproterenol did not affect vitamin D-stimulated VDRE-Luc expression, indicating that the inhibitory effect of isoproterenol on E(2)-directed ERE-Luc expression is specific among nuclear transcription factor receptors. Moreover, in MCF-7 breast cancer cells, there was no effect of isoproterenol on ER/ERE-directed transcription in the absence or presence of E(2), demonstrating tissue specificity of this isoproterenol effect. These studies demonstrate cross-talk between the beta-adrenergic agonist isoproterenol and ER-directed reporter gene expression in A7r5 cells. Furthermore, this cross-talk is specific with respect to agonist, nuclear receptor species, and cell type. These observations may have important implications both for the use of beta-adrenergic agents to treat hypertension and for possible gender-related differences in cardiovascular regulation.
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PMID:Cross-talk between beta-adrenergic stimulation and estrogen receptors: isoproterenol inhibits 17beta-estradiol-induced gene transcription in A7r5 cells. 1288 32

The hormonally active form of vitamin D(3),1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], is synthesized in the kidney through a tightly regulated reaction catalyzed by 25-hydroxyvitamin D(3)-1alpha-hydroxylase (1alpha-hydroxylase), the product of the CYP27B1 gene. Through gene targeting in embryonic stem cells, we engineered a mouse strain in which the coding region of the 1alpha-hydroxylase gene is replaced by the genes for beta-galactosidase (lacZ) and neomycin resistance. Null mice produced no detectable 1alpha-hydroxylase transcript. The mice grew normally when maintained on a balanced diet containing 1,25(OH)(2)D(3) but rapidly developed rickets when phosphorus and 1,25(OH)(2)D(3) were restricted. Rickets was curable through administration of 1,25(OH)(2)D(3) but not its biological precursor, 25-hydroxyvitamin D(3). Upon administration of a diet low in calcium and devoid of any form of vitamin D(3), beta-galactosidase activity was detected in the kidneys of the -/- and +/- mice and in placentas harvested from -/- females bred with -/- males. No beta-galactosidase activity was detected in skin sections or in primary keratinocyte cultures from -/- animals. Our results demonstrate we have generated 1alpha-hydroxylase null mice that display phenotypes characteristic of vitamin D-dependency rickets type I. From the histochemical analysis of reporter gene expression in these mice, we conclude that acute 1,25(OH)(2)D(3) deficiency in otherwise healthy animals does not stimulate local production of 1,25(OH)(2)D(3) in the skin. These findings stand in contrast to previously published reports of 1,25(OH)(2)D(3) production in keratinocytes.
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PMID:CYP27B1 null mice with LacZreporter gene display no 25-hydroxyvitamin D3-1alpha-hydroxylase promoter activity in the skin. 1637 65

Serum Gc protein (known as vitamin D(3)-binding protein) is the precursor for the principal macrophage-activating factor (MAF). The MAF precursor activity of serum Gc protein of prostate cancer patients was lost or reduced because Gc protein was deglycosylated by serum alpha-N-acetylgalactosaminidase (Nagalase) secreted from cancerous cells. Therefore, macrophages of prostate cancer patients having deglycosylated Gc protein cannot be activated, leading to immunosuppression. Stepwise treatment of purified Gc protein with immobilized beta-galactosidase and sialidase generated the most potent MAF (termed GcMAF) ever discovered, which produces no adverse effect in humans. Macrophages activated by GcMAF develop a considerable variation of receptors that recognize the abnormality in malignant cell surface and are highly tumoricidal. Sixteen nonanemic prostate cancer patients received weekly administration of 100 ng of GcMAF. As the MAF precursor activity increased, their serum Nagalase activity decreased. Because serum Nagalase activity is proportional to tumor burden, the entire time course analysis for GcMAF therapy was monitored by measuring the serum Nagalase activity. After 14 to 25 weekly administrations of GcMAF (100 ng/week), all 16 patients had very low serum Nagalase levels equivalent to those of healthy control values, indicating that these patients are tumor-free. No recurrence occurred for 7 years.
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PMID:Immunotherapy for Prostate Cancer with Gc Protein-Derived Macrophage-Activating Factor, GcMAF. 1863 61

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