Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The thyroid hormone, retinoic acid (RA), and vitamin D regulate gene expression by binding to similar receptors which act as ligand-inducible transcription factors. Incubation of pituitary GH4C1 cells with nanomolar concentrations of vitamin D markedly reduces the response of the rat growth hormone mRNA to thyroid hormone triiodothyronine (T3) and RA. The stimulation of growth hormone gene expression by both ligands is mediated by a common hormone response element (TREGH) present in the 5'-flanking region of the gene, and the inhibition caused by vitamin D is due to transcriptional interference of the vitamin D receptor on this DNA element. No inhibition of the basal promoter activity by the vitamin was observed. The response to T3 and RA of a heterologous promoter containing this element, the palindromic T3- and RA-responsive sequence TREPAL, or a direct repeat of the same motif is also inhibited by vitamin D. In contrast, vitamin D strongly induces the activity of constructs containing a vitamin D response element, and neither T3 nor RA reduces vitamin D-mediated transactivation. Transfection with an expression vector for the retinoid X receptor alpha (RXR alpha) increases transactivation by T3 and RA but does not abolish the inhibition caused by the vitamin. Gel retardation experiments show that the vitamin D receptor (VDR) as a heterodimer with RXR weakly binds to the T3- and RA-responsive elements. Additionally, VDR displaces binding of T3 and RA receptors in a dose-dependent manner. Our data suggest the formation of TR-VDR and RAR-VDR heterodimers with RXR. The fact that the same response element mediates opposite effects of at least four different nuclear receptors provides a greater complexity and flexibility of the transcriptional responses to their ligands.
Mol Cell Biol 1996 Jan
PMID:Vitamin D interferes with transactivation of the growth hormone gene by thyroid hormone and retinoic acid. 852 11

During the fetal and suckling periods of mammalian development, the mother serves as the sole nutritional source for the offspring. As such, the quality of the maternal diet effects growth and development of the offspring during these periods. This study sought to determine if a maternal vitamin D deficiency altered the well characterized development of the neonatal heart. Weaned rat pups (21-day-old) were obtained from mothers who had consumed either a vitamin D-supplemented diet (3000 IU of vitamin D/kg) or a low vitamin D diet (< 200 IU of vitamin D/kg) prior to becoming pregnant and throughout pregnancy and suckling. These pups were sacrificed, hearts excised, and the hearts biochemically analysed for metabolic and contractile protein properties. The pups of dams fed the low vitamin D diet were slightly hypocalcemic relative to those on the supplemented diet (2.28 v 2.41 mumol/l, P < 0.05), had significantly lower body weights (43 v 55 g), heart weights (143 v 174 mg), citrate synthase activity (106 v 147 mumol g-1 min-1), and 3-hydroxyacyl CoA dehydrogenase activity (59 v 91 mumol g-1 min-1). Hexokinase activity (1.98 v 2.02 mumol g-1 min-1), and the distribution of cardiac myosin among its three isoforms (> 85% V1), were unaffected by this dietary deficiency, however myofibrillar protein content was approximately 15% lower in the experimental hearts. These data demonstrate that maternal consumption of a low vitamin D diet results in a general but significant slowing of neonatal cardiac development.
J Mol Cell Cardiol 1995 Jun
PMID:Maternal consumption of a low vitamin D diet retards metabolic and contractile development in the neonatal rat heart. 853 Dec 6

Estradiol is active in proliferation and differentiation of sex-related tissues like ovary and breast. Glandular steroid metabolism was for a long time believed to dominate the estrogenic milieu around any cell of the organism. Recent reports verified the expression of estrogen receptors in "non-target" tissues as well as the extraglandular expression of steroid metabolizing enzymes. Extraglandular steroid metabolism proved to be important in the brain, skin and in stromal cells of hormone responsive tumors. Aromatase converts testosterone into estradiol and androstenedione into estrone, thereby activating estrogen precursors. The group of 17 beta-hydroxysteroid dehydrogenases catalyzes the oxidation and/or reduction of the forementioned compounds, e.g. estradiol/estrone, thereby either activating or inactivating estradiol. Aromatase is expressed and regulated in the human THP 1 myeloid leukemia cell line after vitamin D/GMCSF-propagated differentiation. Aromatase expression is stimulated by dexamethasone, phorbolesters and granulocyte/macrophage stimulating factor (GMCSF). Exons I.2 and I.4 are expressed in PMA-stimulated cells only, exon I.3 in both PMA- and dexamethasone-stimulated cells. Vitamin D-differentiated THP 1 cells produce a net excess of estradiol in culture supernatants, if testosterone is given as aromatase substrate. In contrast, the 17 beta-hydroxysteroid dehydrogenase type 4 (17 beta-HSD 4) is abundantly expressed in unstimulated THP 1 cells and is further stimulated by glucocorticoids (2-fold). The expression is unchanged after vitamin D/GMCSF-propagated differentiation. 17 beta-HSD 4 expression is not altered by phorbolester treatment in undifferentiated cells but is abolished after vitamin D-propagated differentiation along with downregulation of beta-actin. Protein kinase C activation therefore appears to dissociate the expression of aromatase and 17 beta-HSD 4 in this differentiation stage along the monocyte/phagocyte pathway of THP 1 myeloid cells. The expression of steroid metabolizing enzymes in myeloid cells is able to create a microenvironment which is uncoupled from dominating systemic estrogens. These findings may be relevant in the autocrine, paracrine or iuxtacrine cellular crosstalk of myeloid cells in their respective states of terminal differentiation, e.g. in bone metabolism and inflammation.
J Steroid Biochem Mol Biol 1995 Dec
PMID:Expression and regulation of aromatase and 17 beta-hydroxysteroid dehydrogenase type 4 in human THP 1 leukemia cells. 854 82

The hormonal form of vitamin D, 1 alpha,25-dihydroxyvitamin D3 [1,25- (OH)2D3], transiently stimulates the transcription of the c-fos proto-oncogene in osteoblastic cells. We have identified and characterized a vitamin D response element (VDRE) in the promoter of c-fos. The 1,25-(OH)2D3-responsive region was delineated between residues -178 and -144 upstream of the c-fos transcription start site. A mutation that inhibited binding to the sequence concomitantly abolished 1,25-(OH)2D3-induced transcriptional responsiveness; similarly, cloning to the site upstream of a heterologous promoter conferred copy-number-dependent vitamin D responsiveness to a reporter gene, demonstrating that we have identified a functional response element. The structure of the c-fos VDRE was found to be unusual. Mutational analysis revealed that the c-fos VDRE does not conform to the direct repeat configuration in which hexameric core-binding sites are spaced by a few nucleotide residues. In contrast, the entire 36-bp sequence was essential for binding. We identified the vitamin D receptor and the retinoid X receptor alpha as components of the complex that bound the c-fos VDRE. However, our results also show that a putative CCAAT-binding transcription factor/nuclear factor 1 (CTF/NF-1) family member bound the response element in conjunction with the nuclear hormone receptors. The expression of this CTF/NF-1 family member appeared restricted to bone cells. These data hint at new molecular mechanisms of action for vitamin D.
Mol Cell Biol 1996 Feb
PMID:A composite element binding the vitamin D receptor, retinoid X receptor alpha, and a member of the CTF/NF-1 family of transcription factors mediates the vitamin D responsiveness of the c-fos promoter. 855 86

It is a well established fact that the calcium-binding protein, calbindin-D28k, is influenced by vitamin D in intestine and kidney. However, very little is known concerning the regulation of calbindin-D28k in brain. Although few genes that are regulated by retinoic acid (RA) have been identified in the nervous system, we now report that the human medulloblastoma cell line D283 (which is derived from cerebellum and has a distinctly neuronal phenotype) contains calbindin-D28k endogenously and that calbindin protein and mRNA can be induced 10- to 15-fold in these cells by 10(-7) M RA. These findings are the first evidence of RA-mediated regulation of calbindin. The time course of response, as determined by Northern blot analysis, indicated that the first significant increase in calbindin-D28k mRNA is at 12 h with a plateau of calbindin mRNA induction at 72 h after RA treatment. The induction of calbindin mRNA by RA was preceded by an induction of retinoic acid receptor-alpha mRNA and was accompanied by an induction of retinoid X receptor-alpha mRNA. Calbindin-D28k mRNA levels in D283 medulloblastoma cells as well as the induction of calbindin mRNA by RA were not significantly affected by 1,25-dihydroxyvitamin D3 treatment. Deletion mutant analysis of the native calbindin-D28k promoter and cotransfection of CV-1 or D283 medulloblastoma cells in the presence of retinoic acid receptor-alpha and/or retinoid X receptor-alpha expression vectors as well as results of nuclear transcription assays did not indicate transcriptional regulation of calbindin-D28k by RA. Studies of calbindin-D28k mRNA in control and RA-pretreated D283 medulloblastoma cells at various times (3-24 h) after treatment with 4 micrograms/ml actinomycin D indicated that the half-life of calbindin-D28k mRNA was significantly increased in the presence of RA, suggesting regulation of calbindin-D28k mRNA stability by RA. Thus, calbindin-D28k is one of the few known targets of RA action in cells that express a neuronal phenotype. In addition, our findings present further evidence of an interrelationship between the actions of 1,25-dihydroxyvitamin D3 and the active metabolites of vitamin A.
Mol Endocrinol 1995 Nov
PMID:Retinoic acid regulates the expression of the calcium binding protein, calbindin-D28K. 858 29

1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3] is the principal mediator of a wide array of biological responses through the far reaching network of the vitamin D endocine system (VDE). The steroid hormone 1 alpha,25(OH)2D3 is delivered to the various target organs of the VDE via a specific plasma transport protein, the vitamin D binding protein (DBP). Also 1 alpha,25(OH)2D3 is known to initiate biological responses through a nuclear receptor, the nVDR (50 kDa) which regulates selected gene transcription and, in addition in some target tissues, through a second receptor located in the cell membrane, the mVDR (approximately 60 kDa), which is linked to protein kinase C and/or voltage-gated Ca2+ channels so as to generate biological responses very rapidly. 1 alpha,25(OH)2D3 as a ligand is unusually conformationally flexible due to the eight carbon side chain, the seco B-ring which permits rotation about the 6-7 single carbon bond, and the A-ring which undergoes chair-chair conformational interconversion characteristic of cyclohexane rings. This paper reviews the evidence that different shapes of the 1 alpha,25(OH)2D3 satisfy the optimal requirements of the ligand binding domains of the DBP, nVDR and mVDR. The presence of a relatively rigid side chain (composed by the presence of an aromatic ring) enhances ligand interaction 2-3 fold with the DBP, but diminishes ligand affinity for the nVDR by 100 fold. The mVDR responds effectively to analogs of 1 alpha,25(OH)2D3 which are 6-s-cis locked [e.g. 1 alpha,25(OH)2-previtamin D3 or 1 alpha,25(OH)2-provitamin D3], but these same analogs have only 1-2% of the activity of 1 alpha,25(OH)2D3 in regulating gene transcription. Finally the 6-s-trans analog, 1 alpha,25(OH)2-tachysterol3, had <0.1% of the activity of 1 alpha,25(OH)2D3 in regulating gene transcription.
J Steroid Biochem Mol Biol 1996 Jan
PMID:Differing shapes of 1 alpha,25-dihydroxyvitamin D3 function as ligands for the D-binding protein, nuclear receptor and membrane receptor: a status report. 860 33

A number of analogs of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] have been synthesized that act as more potent inducers of cellular differentiation and inhibitors of cell growth than the natural ligand; at the same time, many of the analogs have reduced hypercalcemic properties. This combination makes these compounds attractive candidates for clinical use. The mechanism by which the analogs act, however, is unclear. Potentially, the analogs could be taken up more readily, be more slowly catabolized, or have higher binding affinities for the vitamin D receptor (VDR). Analogs of 1,25-(OH)2D3 could also differentially modulate one or more of the activities of VDR, namely dimerization, DNA binding, and/or transcriptional regulation. To directly examine this latter possibility, we used a sensitive assay for the kinetics of dimerization and DNA binding, surface plasmon resonance, and report here that three 1,25-(OH)2D3 analogs, 1,25-(OH)2-16-ene-23-yne-D3, 1,25-(OH)2-16-ene-23-yne-26,27-di home-D3, and 1,25-(OH)2-26,27-hexafluoro-16-ene-23-yne-D3, all confer distinct rate and equilibrium constants for VDR-retinoid X receptor heterodimerization and DNA binding to a specific vitamin D response element relative to the natural ligand. In response to the hexafluoro analog, the apparent Kd for DNA binding by VDR was significantly lower than that for 1,25-(OH)2D3, and correspondingly, in vivo transactivation from a responsive reporter was greater. Interestingly, solution heterodimerization was not affected by this analog. These results suggest that vitamin D analogs do indeed confer biological effects by acting directly and differentially at the level of VDR, and that specific vitamin D analogs can act on distinct receptor functions.
Mol Endocrinol 1995 Dec
PMID:Vitamin D3-retinoid X receptor dimerization, DNA binding, and transactivation are differentially affected by analogs of 1,25-dihydroxyvitamin D3. 861 17

Steroid/nuclear hormone receptors are ligand-regulated transcription f factors that play key roles in cell regulation, differentiation, and oncogenesis. Many nuclear receptors, including the human 1,25-dihydroxyvitamin D3 receptor (VDR), bind cooperatively to DNA either as homodimers or as heterodimers with the 9-cis retinoic acid (RA) receptor (retinoid X-receptor [RXR]). We have previously reported that the ligands for VDR and RXR can differentially modulate the affinity of the receptors' interaction with DNA in vitro, primarily by modulating the dimerization status of these receptors. These experiments suggested a complex interaction between VDR and RXR and their respective ligands on inducible target genes in vivo. To examine these effects in cells, we used a transient-transfection strategy whereby we simultaneously introduced two different reporter plasmids that are selectively inducible by each ligand. Although VDR can bind as a homodimer to the osteopontin gene vitamin D response element, we find that a RXR-VDR heterodimer must be the transactivating species from the element in vivo, since RXR enhances and 9-cis RA and other RXR-specific ligands attenuate this induction. Conversely, when VDR is overexpressed, vitamin D3 attenuates 9-cis RA induction from an RXR-responsive element. These effects, however, appear to be very sensitive to both the relative ratios of the two receptors and their respective target elements. Functional RXR-VDR complexes are strictly dependent on the DNA-binding polarity. Chimeric versions of VDR and RXR were also constructed to examine the putative activities of homodimeric receptors; a VDR chimera can transactivate in the absence of RXR, demonstrating that VDR has intrinsic transactivation properties. Taken together, these results establish a complex, sensitive cross talk in vivo between two ligands and their receptors that signal through two distinct endocrine pathways.
Mol Cell Biol 1996 Mar
PMID:Selective effects of ligands on vitamin D3 receptor- and retinoid X receptor-mediated gene activation in vivo. 862 45

We previously demonstrated that feeding rats the Steenbock and Black rickets-inducing diet produces remarkable changes in the metabolic pattern of intestinal mucosa, kidney, liver, cerebral cortex and heart. We have now determined the levels of calcium, phosphorus and citrate in cerebral cortex and the activity of some enzymes in synaptosomes and cerebral cortex mitochondria of three rat groups: control (Group A), fed a vitamin D-deficient diet (Group B), fed a vitamin D-deficient diet and treated with 1,25-dihydroxyvitamin D3 (Group C). While calcium content increased in Groups B and C, phosphorus concentration increased only in Group C and citrate in Group B in comparison with control. The increase in acetylcholinesterase and citrate synthase registered in Group B was restored to control values by 1,25-dihydroxyvitamin D3 treatment, while, neither the decrease in cytochrome c oxidase, nor the increase in glucose-6-phosphate dehydrogenase, acid phosphatase and NADP+(-)isocitrate dehydrogenase observed in Group B were corrected by 1,25-dihydroxyvitamin D3 supply. Acyl phosphatase showed a remarkable increase in consequence of 1,25-dihydroxyvitamin D3 administration.
Biochem Mol Biol Int 1995 Nov
PMID:Vitamin D--related modification of enzyme activities in synaptosomes and mitochondria isolated from rat cerebral cortex. 862 85

Evidence regarding the nature of the regulatory factors which directly act upon liver cells and extra-hepatic tissues to alter CBG synthesis is scarce. The present study used cultured rat fetal hepatocytes to investigate the involvement and possible interplay in this process of several members of the nuclear receptors superfamily: vitamin D (VDR), retinoic acids (RAR/RXR) and thyroid hormones (TR). Treatment of cells with 1alpha,25-(OH)2D3 (1,25-D) elicited a dose-dependent inhibition of basal CBG concentration in culture medium. Maximum inhibition to about 15% of control level was achieved with 0.1-1.0 nM, with an IC50 of 3.8 x 10(-12) M and with no significant change in binding affinity. Differential activation of RAR and RXR with either 9-cis-retinoic acid (9-cis-RA) or the RAR-selective synthetic retinoid TTNPB revealed that high doses of both drugs diminished CBG expression, though the former proved about 10-times more potent than the latter in this regard. Amplification by triiodothyronine (T3) of CBG synthesis failed to block the inhibitory effects of either 1,25-D or retinoids, as revealed by both binding capacity and mRNA measurements. Relative to CBG, 1,25-D similarly depressed the synthesis of alpha-fetoprotein (AFP), while on the contrary, retinoids and T3 were shown to cause opposite effects, as 9-cis-RA and TTNPB elevated and T3 decreased AFP expression. The present findings identify for the first time ligands of VDR and RAR/RXR as powerful negative regulators of both basal and T3-stimulated CBG biosynthesis in fetal hepatocytes and suggest lack of a functional interplay between TR and VR or RAR/RXR in these processes.
J Steroid Biochem Mol Biol 1996 Jan
PMID:Regulation of corticosteroid-binding globulin synthesis by 1alpha,25-dihyroxy-vitamin D3 (calcitriol), 9-cis-retinoic acid and triiodothyronine in cultured rat fetal hepatocytes. 864 9


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