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)

We have used the slow myosin heavy chain (MyHC) 3 gene to study the molecular mechanisms that control atrial chamber-specific gene expression. Initially, slow MyHC 3 is uniformly expressed throughout the tubular heart of the quail embryo. As cardiac development proceeds, an anterior-posterior gradient of slow MyHC 3 expression develops, culminating in atrial chamber-restricted expression of this gene following chamberization. Two cis elements within the slow MyHC 3 gene promoter, a GATA-binding motif and a vitamin D receptor (VDR)-like binding motif, control chamber-specific expression. The GATA element of the slow MyHC 3 is sufficient for expression of a heterologous reporter gene in both atrial and ventricular cardiomyocytes, and expression of GATA-4, but not Nkx2-5 or myocyte enhancer factor 2C, activates reporter gene expression in fibroblasts. Equivalent levels of GATA-binding activity were found in extracts of atrial and ventricular cardiomyocytes from embryonic chamberized hearts. These observations suggest that GATA factors positively regulate slow MyHC 3 gene expression throughout the tubular heart and subsequently in the atria. In contrast, an inhibitory activity, operating through the VDR-like element, increased in ventricular cardiomyocytes during the transition of the heart from a tubular to a chambered structure. Overexpression of the VDR, acting via the VDR-like element, duplicates the inhibitory activity in ventricular but not in atrial cardiomyocytes. These data suggest that atrial chamber-specific expression of the slow MyHC 3 gene is achieved through the VDR-like inhibitory element in ventricular cardiomyocytes at the time distinct atrial and ventricular chambers form.
Mol Cell Biol 1998 Oct
PMID:A positive GATA element and a negative vitamin D receptor-like element control atrial chamber-specific expression of a slow myosin heavy-chain gene during cardiac morphogenesis. 974 19

The effects of three inducers of differentiation, phorbol myristate acetate (PMA), retinoic acid (RA) and interferon-gamma (IFN-gamma), on the temporal regulation of vitamin D receptor (VDR) expression in HL-60 cells were analyzed by Northern blotting and immunofluorescence assays. VDR, at the protein level, expressed by 81% of uninduced cells, was reduced to 57% after 48 h of PMA or 96 h of RA treatment, preceded by growth inhibition and cell differentiation, evaluated by CD11b expression. Sorted CD11b positive cells in G0/G1 phase exhibited 53% the VDR content of CD11b negative cells (distributed throughout the cell cycle). PMA also induced an increase in PKC beta and PKC alpha mRNA and protein. Simultaneous exposure to PMA and sphingosine blocked stimulation of CD11b and PKC expression without affecting growth arrest and VDR down regulation. Similar effects were observed during sphingosine treatment. In IFN-gamma differentiated cells, the proportion of cells in G0/G1 phase was unchanged and VDR protein was unaltered as compared to uninduced cells. Control cells in G0/G1 expressed less VDR than cells in S and G2/M phases (74% and 59% respectively). All results suggest that in HL-60 cells, reduction of VDR expression is related to growth inhibition rather than to the differentiation process.
J Steroid Biochem Mol Biol 1998 Aug
PMID:Expression of vitamin D receptor (VDR) in HL-60 cells is differentially regulated during the process of differentiation induced by phorbol ester, retinoic acid or interferon-gamma. 974 16

Calcitrol, 1,25 dihydroxyvitamin D3 (1,25-D3) has an important role in the antiproliferative and growth regulatory effects on normal and neoplastic cells (e.g. prostate cancer cells). 1,25-D3 binds to the vitamin D receptor (VDR), a member of the steroid receptor superfamily. Steroids, via intranuclear receptors, have been demonstrated to have high affinity binding to the nuclear matrix, the tissue specific scaffolding of the nucleus that is involved in the organization of DNA, replication and transcription. We hypothesized that the VDR interacts closely with the nuclear matrix in both human and rat tissues. In the studies described here, nuclear matrix proteins (NMP) were extracted from a number of rat and human tissues and immunoblot analysis performed using a rat anti-VDR antibody. The results from these studies reveal that the anti-VDR antibody detects six forms of the VDR in the NMP preparations: human testis demonstrated a protein of 57 and 52 kDa molecular weight compared with 57 and 37 kDa in the rat testis. Human prostate demonstrated proteins of 52 kDa compared to rat ventral (57 and 37 kDa) and dorsal prostate (52 and 26 kDa). Human and rat bladder NMP demonstrated a protein binding at 55 kDa and rat seminal vesicle NMP binding at 48 kDa. This is the first report of VDRs associated with the nuclear matrix. The varying molecular weight proteins reactive with the anti-VDR antibody within these tissues may represent different isoforms, proteolytic cleavage of a larger VDR or post-translational modification. The VDR-NMP interaction may be involved in the tissue specific actions of 1,25-D3 especially growth regulatory and antiproliferative effects.
J Steroid Biochem Mol Biol 1998 Aug
PMID:Association of vitamin D receptors with the nuclear matrix of human and rat genitourinary tissues. 974 21

In a previous study, we identified the element which allows the maximum response to 1,25(OH)2D3 in concert with two vitamin D-responsive elements (VDREs) in the rat 25-hydroxyvitamin D3 24-hydroxylase gene promoter, and designated it an accessory element [Ohyama, Y., Ozono, K., Uchida, M., Yoshimura, M., Shinki, T., Suda, T. and Yamamoto, O. Functional assessment of two vitamin D-responsive elements in the rat 25-hydroxyvitamin D3 24-hydroxylase gene. J. Biol. Chem., 1996, 271, 30381-30385]. The accessory element located adjacent to the proximal VDRE is not capable of binding to the vitamin D receptor (VDR), while its nucleotide sequence resembles the consensus sequence of VDREs, direct repeat 3 (DR3). To clarify the difference between the accessory element and VDREs, the function of the accessory element was compared with that of VDREs. The mutated accessory elements with a single nucleotide substitution showed the capability of binding to the VDR in vitro. However, these mutants still did not act as a VDRE when driven by the heterologous SV40 promoter. The accessory element did not enhance the function of a cAMP-responsive element. The corresponding site of the accessory element in the human 24-hydroxylase is a DR4-type element, and this element did not function as an accessory element. These results indicate that a critical nucleotide sequence is necessary for the binding to the VDR and for mediating the vitamin D effect, and suggest the different regulation between the rat and human 24-hydroxylase gene.
J Steroid Biochem Mol Biol 1998 Sep
PMID:Direct repeat 3-type element lacking the ability to bind to the vitamin D receptor enhances the function of a vitamin D-responsive element. 974 32

To characterize further the function of the intracellular vitamin D receptor (VDR), we have developed stable transfectant variants of a vitamin D-responsive cell line (U937) which express either decreased or increased numbers of VDR. In this study we have analyzed changes in gene expression associated with this variable VDR expression. Initial experiments indicated that a 50% decrease in VDR levels was associated with a 2-fold increase in cell proliferation and a similar rise in c-myc mRNA expression. Further studies were carried out using differential RNA display (DD). Sequence analysis of DD products revealed two cDNAs with identity to known gene products: the catalytic sub-unit of DNA-protein kinase (DNA-PK(CS)), and the peroxisomal enzyme 17beta-hydroxysteroid dehydrogenase type IV (17beta-HSD IV). Northern analysis confirmed that expression of both mRNAs was reduced in cells with decreased numbers of VDR. Down-regulation of 17beta-HSD IV mRNA expression was associated with enhanced estradiol inactivation by U937 cells, suggesting a link between estrogenic pathways and cell proliferation. Further Northern analyses indicated that there was no significant change in 17beta-HSD IV or DNA-PK(CS) mRNA levels following treatment with 1,25(OH)2D3, although expression of both genes varied with changes in cell proliferation. These data suggest that, in addition to its established role as a hormone-dependent trans-activator, VDR may influence gene expression by ligand-independent mechanisms.
Mol Cell Endocrinol 1998 Jul 25
PMID:Differential RNA display identifies novel genes associated with decreased vitamin D receptor expression. 978 9

The mdm2 gene is positively regulated by p53 through a p53-responsive DNA element in the first intron of the mdm2 gene. mdm2 binds p53, thereby abrogating the ability of p53 to activate the mdm2 gene, and thus forming an autoregulatory loop of mdm2 gene regulation. Although the mdm2 gene is thought to act as an oncogene by blocking the activity of p53, recent studies indicate that mdm2 can act independently of p53 and block the G1 cell cycle arrest mediated by members of the retinoblastoma gene family and can activate E2F1/DP1 and the cyclin A gene promoter. In addition, factors other than p53 have recently been shown to regulate the mdm2 gene. In this article, we report that thyroid hormone (T3) receptors (T3Rs), but not the closely related members of the nuclear thyroid hormone/retinoid receptor gene family (retinoic acid receptor, vitamin D receptor, peroxisome proliferation activation receptor, or retinoid X receptor), regulate mdm2 through the same intron sequences that are modulated by p53. Chicken ovalbumin upstream promoter transcription factor I, an orphan nuclear receptor which normally acts as a transcriptional repressor, also activates mdm2 through the same intron region of the mdm2 gene. Two T3R-responsive DNA elements were identified and further mapped to sequences within each of the p53 binding sites of the mdm2 intron. A 10-amino-acid sequence in the N-terminal region of T3Ralpha that is important for transactivation and interaction with TFIIB was also found to be important for activation of the mdm2 gene response element. T3 was found to stimulate the endogenous mdm2 gene in GH4C1 cells. These cells are known to express T3Rs, and T3 is known to stimulate replication of these cells via an effect in the G1 phase of the cell cycle. Our findings, which indicate that T3Rs can regulate the mdm2 gene independently of p53, provide an explanation for certain known effects of T3 and T3Rs on cell proliferation. In addition, these findings provide further evidence for p53-independent regulation of mdm2 which could lead to the development of tumors from cells that express low levels of p53 or that express p53 mutants defective in binding to and activating the mdm2 gene.
Mol Cell Biol 1999 Jan
PMID:Regulation of the mdm2 oncogene by thyroid hormone receptor. 985 9

The nuclear vitamin D receptor (VDR) is a member of a nuclear receptor superfamily and acts as a ligand-dependent transcription factor. A family of cotranscriptional activators (SRC-1, TIF2, and AIB-1) interacts with and activates the transactivation function of nuclear receptors in a ligand-dependent way. We examined interaction of VDR with these coactivators that was induced by several vitamin D analogs, since they exert differential subsets of the biological action of vitamin D through unknown mechanisms. Unlike other vitamin D analogs tested, OCT (22-oxa-1alpha,25-dihydroxyvitamin D3) induced interaction of VDR with TIF2 but not with SRC-1 or AIB-1. Consistent with these interactions, only TIF2 was able to potentiate the transactivation function of VDR bound to OCT. Thus, the present findings suggest that the structure of VDR is altered in a vitamin D analog-specific way, resulting in selective interactions of VDR with coactivators. Such selective interaction of coactivators with VDR may specify the array of biological actions of a vitamin D analog like OCT, possibly through activating a particular set of target gene promoters.
Mol Cell Biol 1999 Feb
PMID:Selective interaction of vitamin D receptor with transcriptional coactivators by a vitamin D analog. 989 Oct 40

1 ,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] negatively regulates expression of the avian PTH (aPTH) gene transcript, and a vitamin D response element (VDRE) near the promoter of the aPTH gene had previously been identified. The present report assessed whether the negative activity imparted by the aPTH VDRE could be converted to a positive transcriptional response through selective mutations introduced into the element. The tested sequences were derived from individual and combined mutations to 2 bp in the 3'-half of the direct repeat element, GGGTCAggaGGGTGT. Cold competition experiments using mutant and wild-type oligonucleotides in the mobility shift assay revealed minor differences in the ability of any of these sequences to compete for binding to a heterodimer complex comprised of recombinant proteins. Ethylation interference footprint analysis for each of the mutants produced unique patterns over the 3'-half-sites that were distinct from the weak, wild-type footprint. Transcriptional outcomes evaluated from a chloramphenicol acetyltransferase reporter construct utilizing the aPTH promoter found that the individual T-->A mutant produced an attenuated negative transcriptional response while the G-->C mutant resulted in a reproducibly weak positive transcriptional outcome. The double mutant, however, yielded a 4-fold increase in transcription, similar to the 7-fold increase observed from an analogous construct using the human osteocalcin VDRE. UV light crosslinking to gapped oligonucleotides assessed the polarity of heterodimer binding to the wild-type and double mutant sequences and was consistent with the vitamin D receptor preferentially binding to the 5'-half of both elements. Finally, DNA affinity chromatography was used to immobilize heterodimer complexes bound to the wild-type and double mutant sequences as bait to identify proteins that may preferentially interact with these DNA-bound heterodimers. This analysis revealed the presence of a p160 protein that specifically interacted with the heterodimer bound to the wild-type VDRE, but was absent from complexes bound to response elements associated with positive transcriptional activity. Thus, the sequence of the individual VDRE appears to play an active role in dictating transcriptional responses that may be mediated by altering the ability of a vitamin D receptor heterodimer to interact with accessory factor proteins.
Mol Endocrinol 1999 Mar
PMID:Turning a negative into a positive: vitamin D receptor interactions with the avian parathyroid hormone response element. 1007 2

Nuclear hormone receptors (NRs) regulate transcription in part by recruiting distinct transcriptional coregulatory complexes to target gene promoters. The thyroid hormone receptor (TR) was recently purified from thyroid hormone-cultured HeLa cells in association with a complex of novel nuclear proteins termed TRAPs (thyroid hormone receptor-associated proteins) ranging in size from 20 to 240 kDa. The TRAP complex markedly enhances TR-mediated transcription in vitro, suggesting a coactivator role for one or more of the TRAP components. Here we present the mouse cDNA for the 100-kDa component of the TRAP complex (mTRAP100). The mTRAP100 protein contains seven LxxLL motifs thought to be potential binding surfaces for liganded NRs, yet surprisingly fails to interact with TR and other NRs in vitro. By contrast, mTRAP100 coprecipitates in vivo with another component of the TRAP complex (TRAP220), which directly contacts TR and the vitamin D receptor in a ligand-dependent manner. Our findings thus suggest that TRAP100 is targeted to NRs in association with TRAP complexes specifically containing TRAP220. Transient overexpression of mTRAP100 in mammalian cells further enhances ligand-dependent transcription by both TR and the vitamin D receptor, revealing a functional role for mTRAP100 in NR-mediated transactivation. The presence of an intrinsic mTRAP100 transactivation function is suggested by the ability of mTRAP100 to activate transcription constitutively when tethered to the GAL4 DNA-binding domain. Collectively, these findings suggest that TRAP100, in concert with other TRAPs, plays an important functional role in mediating transactivation by specific NRs.
Mol Endocrinol 1999 Jul
PMID:Identification of mouse TRAP100: a transcriptional coregulatory factor for thyroid hormone and vitamin D receptors. 1040 64

PRL gene expression is dependent on the presence of the pituitary-specific transcription factor GHF-1/Pit-1, which is transcribed in a highly restricted manner in cells of the anterior pituitary. In pituitary GH3 cells, vitamin D increases the levels of PRL transcripts and stimulates the PRL promoter. We have analyzed the role of GHF-1 and of the vitamin D receptor (VDR) to confer vitamin D responsiveness to the PRL promoter. For this purpose we have used nonpituitary HeLa cells, which do not express GHF-1. We found that VDR activates the PRL promoter both in a ligand-dependent and -independent manner through a sequence located between positions -45/-27 in the proximal 5'-flanking region. This sequence also confers VDR and vitamin D responsiveness to a heterologous promoter. In the context of the PRL gene, VDR requires the presence of GHF-1 to activate the promoter. Truncation of the last 12 C-terminal amino acids of VDR, which contain the ligand-dependent activation function (AF2), abolishes regulation by vitamin D, suggesting that binding of coactivators to this region mediates ligand-dependent stimulation of the PRL promoter by the receptor. Indeed, expression of the coactivators, steroid hormone receptor coactivator-1 (SRC-1) and CREB-binding protein (CBP), significantly enhances the stimulatory effect of vitamin D mediated by the wild-type VDR but not by the AF2 mutant receptor. Furthermore, CBP also increases the activation of the PRL promoter by GHF-1 and the ligand-independent activation by both wild-type and mutant VDR.
Mol Endocrinol 1999 Jul
PMID:Synergistic activation of the prolactin promoter by vitamin D receptor and GHF-1: role of the coactivators, CREB-binding protein and steroid hormone receptor coactivator-1 (SRC-1). 1040 65


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