Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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We describe here a novel class of cis-acting response elements for retinoid, vitamin D, and estrogen receptors which are widely spaced (10 to 200 bp) direct repeats (DRs) of the canonical 5'-AGGTCA half-site recognition motif (DR10 to DR200). In contrast to the specificity previously observed with shortly spaced DRs (DR1 to DR5), the different receptors bind promiscuously to these novel elements to activate transcription in the presence of retinoic acid (RA), vitamin D, or estrogen. The greatest RA-dependent transactivation, seen with DR15, was similar to that observed with the canonical DR5. Both RA receptors and retinoid X receptors contribute to transactivation through widely spaced DR elements. With the estrogen receptor, DR15 was one-third as efficient as the classical palindromic response element. A further increase of spacer lengths progressively decreased the efficiency of transactivation. No transactivation was seen with widely spaced DRs when the thyroid and retinoid X receptors were coexpressed in the presence of their ligands. The progesterone receptor was also unable to transactivate through a DR10 element composed of its cognate binding motifs. These results considerably extend the response element repertoire of nuclear receptors and suggest the existence of promiscuous transcriptional regulation through common response elements, as well as the possibility of receptor "cross-talk."
Mol Cell Biol 1995 Nov
PMID:Widely spaced, directly repeated PuGGTCA elements act as promiscuous enhancers for different classes of nuclear receptors. 756 38

The effects of the thyroid hormone (3,5,3'-triiodo-L-thyronine [T3]) on gene transcription are mediated by nuclear T3 receptors (T3Rs). alpha- and beta-isoform T3Rs (T3R alpha and -beta) are expressed from different genes and are members of a superfamily of ligand-dependent transcription factors that also includes the receptors for steroid hormones, vitamin D, and retinoids. Although T3 activates transcription by mediating a conformational change in the C-terminal approximately 220-amino-acid ligand-binding domain (LBD), the fundamental mechanisms of T3R-mediated transcriptional activation remain to be determined. We found that deletion of the 50-amino-acid N-terminal A/B domain of chicken T3R alpha (cT3R alpha) decreases T3-dependent stimulation of genes regulated by native thyroid hormone response elements about 10- to 20-fold. The requirement of the A/B region for transcriptional activation was mapped to amino acids 21 to 30, which contain a cluster of five basic amino acids. The A/B region of cT3R alpha is not required for T3 binding or for DNA binding of the receptor as a heterodimer with retinoid X receptor. In vitro binding studies indicate that the N-terminal region of cT3R alpha interacts efficiently with TFIIB and that this interaction requires amino acids 21 to 30 of the A/B region. In contrast, the LBD interacts poorly with TFIIB. The region of TFIIB primarily involved in the binding of cT3R alpha includes an amphipathic alpha helix contained within residues 178 to 201. Analysis using a fusion protein containing the DNA-binding domain of GAL4 and the entire A/B region of cT3R alpha suggests that this region does not contain an intrinsic activation domain. These and other studies indicate that cT3R alpha mediates at least some of its effects through TFIIB in vivo and that the N-terminal region of DNA-bound cT3R alpha acts to recruit and/or stabilize the binding of TFIIB to the transcription complex. T3 stimulation could then result from ligand-mediated changes in the LBD which may lead to the interaction of other factors with cT3R alpha, TFIIB, and/or other components involved in the initiation of transcription.
Mol Cell Biol 1995 Aug
PMID:A 10-amino-acid sequence in the N-terminal A/B domain of thyroid hormone receptor alpha is essential for transcriptional activation and interaction with the general transcription factor TFIIB. 762 41

The gene encoding parathyroid hormone-related protein (PTHrP), an autocrine/paracrine inhibitor of vascular and nonvascular smooth muscle contractility, is regulated by hormonal steroids including estrogens (E2), 1,25-dihydroxy vitamin D (Vit D3) and glucocorticoids. While E2 increases PTHrP gene expression, Vit D3 and glucocorticoids inhibit transcriptional activity of this gene. In the uterus of ovariectomized rats, E2-treatment increases both PTHrP mRNA levels and smooth muscle sensitivity to the action of PTHrP(1-34). To examine the action(s) of Vit D3 and glucocorticoids on these parameters, OVX rats were treated with E2, Vit D3 or the synthetic glucocorticoid, dexamethasone (Dex), alone, or with E2 following a 1 h pretreatment with Vit D3 or Dex. PTHrP and PTH/PTHrP receptor mRNA were measured by blot hybridization analysis of RNA prepared from uteri collected 2, 4 and 24 h after treatment. Uterine horns were used to measure the effect of the steroids on the ability of PTHrP(1-34) to inhibit spontaneous myometrial contraction. When E2, Vit D3 and Dex were given alone, only E2 altered PTHrP mRNA levels in the uterus, however, a 1 h pretreatment with Dex but not Vit D3 markedly diminished this effect of E2. The temporal decline in uterine PTH/PTHrP receptor mRNA levels measured 2 and 4 h after E2 treatment inversely correlated to changes in sensitivity of the tissue to PTHrP(1-34) measured at 24 h after E2 administration. In comparison to E2 alone, treatment with Vit D3 and E2 augmented the uterine responsiveness to PTHrP(1-34) while pretreatment with Dex (1 mg/kg) and E2 decreased this response. These data indicate that in the uterus, Dex opposes the positive effect of E2 on PTHrP gene activity and differentially modulates the action of PTHrP on myometrial tone. Moreover, elevations in the circulating levels of cortisol at term may serve to decrease both the uterine expression of PTHrP and the local action of PTHrP on the myometrium prior to parturition, therefore promoting myometrial contraction associated with labor.
J Steroid Biochem Mol Biol 1995 Jun
PMID:Steroid regulation of parathyroid hormone-related protein expression and action in the rat uterus. 762 65

The transporter of vitamin D and its metabolites in blood has received increasing attention in recent years, and is recognized to be a member of a gene family that includes albumin and alpha-fetoprotein. Identical to the group specific component (Gc-globulin) of serum, the protein is a single-chain polypeptide constitutively synthesized in liver that circulates in amounts in far excess of normal vitamin D metabolite concentrations in blood. It plays the major role in the egress of endogenously synthesized vitamin D, from skin and appears to restrain D-sterols from too rapid/excessive cell entry. Along with plasma gelsolin, it comprises the plasma actin-scavenger system that facilitates removal of actin, liberated from lysed cells, by depolymerization and prevention of polymerization. Recently, the protein has been shown to behave as a co-chemotaxin specific for the complement peptide C5a, and its sialic acid-free form has been reported to play a role in macrophage activation. The latter functions strongly implicate its participation in inflammation responses. A unifying hypothesis might also suggest the protein to provide focal D-sterol delivery to cells that are important to the resolution of tissue injuries.
J Steroid Biochem Mol Biol 1995 Jun
PMID:Plasma vitamin D-binding protein (Gc-globulin): multiple tasks. 762 13

The nuclear vitamin D receptor (VDR) binds the 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) hormone with high affinity and elicits its actions to stimulate gene expression in target cells by binding to the vitamin D-responsive element (VDRE). VDREs in such positively controlled genes as osteocalcin, osteopontin, beta 3 integrin and vitamin D-24-OHase are direct hexanucleotide repeats with a spacer of three nucleotides. The present studies of VDR/VDRE interaction utilized full-length human vitamin D receptor (hVDR) that was overexpressed in E. coli, purified to near homogeneity (> 95%), and its authenticity confirmed by demonstrating high affinity hormone binding and reactivity to monoclonal antibody 9A7 gamma. The expressed hVDR displays strict dependence on the family of retinoid X receptors (RXRs) for binding to the vitamin D-responsive element (VDRE) in the rat osteocalcin gene. Similar overexpression in E. coli of the DNA binding domain (delta 134), containing only residues 4-133 of hVDR, generated a receptor species that possesses intrinsic DNA binding activity. Both full-length and delta 134 hVDRs retain similar DNA binding specificities when tested with several natural hormone responsive elements, indicating that the N-terminal zinc finger region determines hVDR-DNA sequence selectivity. The C-terminal region of the molecule is required for hormone binding and confers the receptor with the property of very high affinity DNA binding, via heterodimerization between hVDR and RXR. A natural ligand for the RXR co-receptor, 9-cis retinoic acid, suppresses both VDR-RXR binding to the VDRE and 1,25(OH)2D3 stimulated transcription, indicating that 9-cis retinoic acid recruits RXR away from VDR to instead form RXR homodimers.
J Steroid Biochem Mol Biol 1995 Jun
PMID:Receptor mediated genomic action of the 1,25(OH)2D3 hormone: expression of the human vitamin D receptor in E. coli. 762 14

We have studied two proteins potentially involved in the regulation of the 25-OH-D-1-hydroxylase, which is located in the renal mitochondria and which is responsible for the production of the steroid hormone 1,25(OH)2D3. The endogenous inhibitor of cyclic AMP-dependent protein kinase, PKI, is down regulated by 1,25(OH)2D3. Having cloned and sequenced PKI cDNA, we studied its message levels and found them to be regulated by 1,25(OH)2D3 tissue specifically in the kidney and in kidney cell culture. In other experiments we over expressed the ferredoxin component of the 1-hydroxylase and found it to be physically and chemically indistinguishable from those of classic steroidogenic tissues. The mRNA encoding the ferredoxin component is up-regulated by chronic vitamin D deficiency, which at the same time leads to sustained elevation in 1-hydroxylase activity; no short term effect of 1,25(OH)2D3 on ferredoxin mRNA in kidney cell culture could be demonstrated. Finally, there was an association between decreased phosphorylation of ferredoxin and decreased 1-hydroxylase activity brought about by treatment of cultured kidney cells with TPA. Control of the renal signaling events involved in the production of 1,25(OH)2D3 remains a fruitful area of investigation in the field of the metabolism and actions of vitamin D and its metabolites.
J Steroid Biochem Mol Biol 1995 Jun
PMID:Regulation of the ferredoxin component of renal hydroxylases at transcriptional and postranslational levels and of the protein inhibitor of cyclic AMP-dependent kinase. 762 15

Vitamin D-binding protein (DBP), a multifunctional, highly polymorphic glycoprotein responsible for the transport of vitamin D and for sequestering extracellular actin, was isolated from human serum and crystallized using vapour diffusion methods. The crystals were grown from 7.5% v/v polyethylene glycol 400 and 0.1 M acetate buffer at pH 4.6. These crystals show diffraction patterns consistent with the tetragonal space groups P4(1) and P4(3) with unit cell dimensions a = b = 135.5(4) A and c = 75.9(4) A. They diffract to 2.3 A. Using polyacrylamide gel electrophoresis it was shown that according to their electrophoretic mobility the O-glycosylated isoforms, with a terminal sialic acid residue, are absent in the crystals.
J Steroid Biochem Mol Biol 1995 Jul
PMID:Crystallization and X-ray investigation of vitamin D-binding protein from human serum. Identification of the crystal content. 763 9

Intestinal Ca absorption from the diet consumed during one night was measured in male rats fed a normal (0.5%) Ca, low fiber (3% cellulose) diet by determining the decrease in 47Ca/47Sc ratio between diet and feces. One-half of the rats had been cecectomized 9 weeks previously at 14 weeks of age. Calcitriol injections, given intraperitoneally the morning of the experiment, stimulated fractional intestinal Ca absorption 2.5-fold in intact rats (16.9 +/- 2.0% to 42.2 +/- 1.8%) and 2.3-fold in cecectomized rats (20.1 +/- 1.4% to 46.8 +/- 1.2%). Similar results were obtained when the data were calculated in terms of total Ca absorption expressed as mg/day. Thus, although the cecum can absorb Ca when diets contain large amounts of digestible fiber, cecectomy does not influence the stimulation of intestinal Ca absorption induced by calcitriol in vitamin D-replete rats fed a low fiber diet.
J Steroid Biochem Mol Biol 1995 Jul
PMID:The cecum does not participate in the stimulation of intestinal calcium absorption by calcitriol. 763 18

The effects of the novel vitamin D analogue, EB1089 alone, or in combination with the retinoid, 9-cis retinoic acid (9-cis RA) on indices of apoptosis in MCF-7 breast cancer cells have been examined. EB1089 was capable of reducing bcl-2 protein, a suppressor of apoptosis, and increasing p53 protein levels in MCF-7 cell cultures following 96h treatment. In the presence of 9-cis RA, EB1089 acted to further enhance the down-regulation and up-regulation of bcl-2 and p53 respectively. Furthermore, EB1089 induces DNA fragmentation in MCF-7 cells, a key feature of apoptosis, alone and in combination with 9-cis RA in situ. The observation that EB1089 and 9-cis RA act in a cooperative manner to enhance induction of apoptosis in these cells may have therapeutic implications.
J Mol Endocrinol 1995 Jun
PMID:Vitamin D derivatives in combination with 9-cis retinoic acid promote active cell death in breast cancer cells. 766 28

Total RNA was isolated from kidneys of Sprague-Dawley rats. Oligo (dT)-primed single-stranded cDNA was obtained by the reverse transcriptase reaction from which a 285 bp cDNA probe coding for 25-hydroxyvitamin D3-24-hydroxylase [25(OH)D3-24-OHase] was generated by the polymerase chain reaction. Northern blotting performed with kidney poly (A)+ RNA isolated from rats (1) fed a standard diet, (2) depleted in D3 and hypocalcemic, and (3) fed a standard diet and injected intraperitoneally with 50,000 IU of vitamin D3 for 5 days showed that the transcript for 24-OHase was weakly expressed in control, and highly induced in vitamin D3-treated animals. No transcript could be elicited in vitamin D-depleted hypocalcemic animals in which 25(OH)D3-1 alpha-OHase was maximally induced. The data show that 24-OHase is independently regulated of 1 alpha-OHase, strongly suggestive of the enzymes being encoded by two distinct genes.
J Steroid Biochem Mol Biol 1993 Jun
PMID:Rat kidney 25-hydroxyvitamin D3 1 alpha- and 24-hydroxylases: evidence for two distinct gene products. 768 41


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