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 effects of two vitamin D analogues, EB1089 and CB1093, on insulin-like growth factor binding protein (IGFBP) expression have been examined in MCF-7 and Hs578T human breast cancer cell lines. Both vitamin D analogues inhibited IGF-1 stimulated growth of MCF-7 cells and enhanced the production of IGFBP-3 as determined by Western-ligand blotting. Recombinant human IGFBP-3 inhibited the growth of MCF-7 cells over the concentration range 1-235 ng/ml. Hs578T cells were unresponsive to the mitogenic effects of IGF-1 but growth was inhibited by the two vitamin D analogues. Treatment of Hs578T cells with EB1089 and CB1093 (10 nM) as well as 100 nM 9-cis retinoic acid (9-cis RA) or all-trans retinoic acid (ATRA) was associated with increased accumulation of IGFBP-3 in conditioned medium. Furthermore, cotreatment of Hs578T cells with EB1089 and 9-cis RA led to augmented effects on both inhibition of cell growth and IGFBP-3 accumulation in conditioned medium as assessed by Western ligand blotting and radioimmunoassay. These findings suggest a role for IGFBP-3 in the growth inhibitory effects of vitamin D analogues.
J Mol Endocrinol 1998 Feb
PMID:Growth inhibition of both MCF-7 and Hs578T human breast cancer cell lines by vitamin D analogues is associated with increased expression of insulin-like growth factor binding protein-3. 951 92

By way of differential screening of testis cDNA libraries from vitamin A-deficient (VAD) rats before and after administration of all-trans retinoic acid (ATRA), genes, the transcription of which was influenced by ATRA, were isolated. Most clones with an increased transcription encoded different subunits of the same mitochondrial protein complex, cytochrome c oxidase (COX). The mRNA expression of COX increased by a factor 3.9 +/- 1.5 (mean +/- SD, n = 4). This increased expression seems to reflect an increased energy demand in the ATRA-supplemented VAD testis. Also, one gene was isolated, the transcription of which was reduced to about 70% by ATRA. This gene, sulfated glycoprotein 2 (Sgp-2), is a major secretion product of Sertoli cells, the function of which is still unknown. The effect of ATRA on Sgp-2 expression may be direct, since the promoter of Sgp-2 contains a putative ATRA-responsive element (RARE).
Mol Reprod Dev 1998 May
PMID:Isolation and characterization of all-trans-retinoic acid-responsive genes in the rat testis. 954 4

Retinoid X receptors (RXRs) are recently characterized transcription factors that are members of the nuclear hormone receptor superfamily. However, it is not known whether the endogenous RXR complex requires its ligand for access to its hormone response element (HRE) of a target gene in vivo. Hence, dimethyl sulfate-based genomic footprinting was carried out to examine occupancy of HREs in the retinoic acid (RA) receptor beta2 (RARbeta2) gene promoter in the murine melanoma cell line S91 cultured in the absence or presence of T3, all-trans-RA (atRA), or CD2624, an RXR-selective retinoid. No footprint was observed at the RA-response element (betaRARE) in the absence of ligands. However, a footprint was detected at the betaRARE and other cis-acting elements after a 6 h incubation with CD2624 and atRA. Interestingly, only the betaRARE was footprinted after 60 min incubation with CD2624. These results suggest that the endogenous RXR complex can interact with an HRE of a target gene in the presence of ligand, and subsequently may initiate additional interactions between DNA and other transcription factors.
Mol Cell Endocrinol 1998 Jan 15
PMID:Ligand-inducible retinoid X receptor-mediated protein: DNA interactions in the retinoic acid receptor beta2 gene promoter in vivo. 954 14

Malignant rhabdoid tumors (MRT) are characterized by unique neoplastic cells demonstrating phenotypic diversity. By using the reverse transcriptase-polymerase chain reaction, we have detected expression of various genes before and after differentiation induction with four different agents in four established MRT cell lines (TM87-16, STM91-01, TTC642, and TTC549). The agents used in this study were all-trans retinoic acid (RA), 12-O-tetradecanoylphorbol-13-acetate (TPA), interleukin-3, or interferon-gamma. Before and after induction, c-myc, IGF-II, IGF-I receptor, and IGF-II receptor were constitutively expressed by all four cell lines. The neurofilament medium-size (NF-M) was constitutively expressed by the TM87-16 and TTC642, and the S100 protein alpha subunit was expressed by TM87-16, TTC642, and TTC549. Chromogranin A was expressed by TM87-16 only after treatment with either TPA or RA. MyoD, N-myc, tyrosine hydroxylase, N-CAM, trkA, and the S100 protein beta subunit were not expressed by any cell line before or after induction with these agents. All the MRT cell lines in this study except TM87-16 were highly resistant to differentiation induction. The proliferating cells in TM87-16 and TTC642 expressed mRNA profiles characteristic of neuroectoderm.
Diagn Mol Pathol 1997 Dec
PMID:Gene expression of malignant rhabdoid tumor cell lines by reverse transcriptase-polymerase chain reaction. 955 92

The crystal structure of unliganded mutant R111M of human cellular retinoic acid-binding protein type II (apo-CRABPII (R111M)) has been determined at 2.3 A and refined to a crystallographic R-factor of 0. 18. Although the mutant protein has lower affinity for all-trans-retinoic acid (RA) than the wild-type, it is properly folded, and its conformation is very similar to the wild-type. apo-CRABPII (R111M) crystallizes in space group P1 with two molecules in the unit cell. The two molecules have high structural similarity except that their alpha2 helices differ strikingly. Analyses of the molecular conformation and crystal packing environment suggest that one of the two molecules assumes a conformation compatible with RA entry. Three structural elements encompassing the opening of the binding pocket exhibit large conformational changes, when compared with holo-CRABPII, which include the alpha2 helix and the betaC-betaD and betaE-betaF hairpin loops. The alpha2 helix is unwound at its N terminus, which appears to be essential for the opening of the RA-binding pocket. Three arginine side-chains (29, 59, and 132) are found with their guanidino groups pointing into the RA-binding pocket. A three-step mechanism of RA entry has been proposed, addressing the opening of the RA entrance, the electrostatic potential that directs entry of RA into the binding pocket, and the intramolecular interactions that stabilize the RA.CRABPII complex via locking the three flexible structural elements when RA is bound.
J Mol Biol 1998 May 08
PMID:Crystal structure of apo-cellular retinoic acid-binding protein type II (R111M) suggests a mechanism of ligand entry. 960 Aug 45

The expression of acute-phase protein genes is controlled by many factors, such as IL-1, IL-6, glucocorticoids, thyroid hormone (T3), and retinoic acids. We studied the interaction of T3, glucocorticoids, all-trans retinoic acid (RA), and 9-cis retinoic acid (9cRA) on the expression of the rat alpha 1-acid glycoprotein (AGP) gene in vitro. Dexamethasone (Dex) activated AGP gene expression in a rat liver derived cell line, RLN-10. Although T3, RA, and 9cRA by themselves had no effect on AGP production, they reduced the response to Dex of the AGP gene.
Biochem Mol Biol Int 1998 Jun
PMID:Thyroid hormone, all-trans retinoic acid, and 9-cis retinoic acid functioned as negative modulators of the effect of glucocorticoid on induction of alpha 1-acid glycoprotein mRNA in RLN-10 cells. 963 25

We report the cloning and analysis of ecdysteroid receptor (bpEcR) and retinoid-X receptor (UpRXR) cDNA homologs from the fiddler crab Uca pugilator. The deduced amino acid sequence of this crustacean EcR most closely resembles the insect EcRs within the DNA binding and ligand binding domains (LBDs). For UpRXR, the DNA binding domain (DBD) shares greatest identity to the insect USPs. The ligand binding domain, however, is closer to vertebrate RXRs but may have a nonfunctional AF-2 domain. Probes derived from these clones were used to examine transcript levels in blastemas during early limb regeneration. Both UpEcR and UpRXR transcripts were detected in low amounts 1 day after limb loss, but increased during the next 4 days. Immersion of crabs in sea water containing all-trans retinoic acid increased the steady state concentrations of UpRXR transcript and altered the pattern of circulating ecdysteroids. These effects correlate with the disruptive effects of retinoic acid on blastemal differentiation observed in earlier studies.
Mol Cell Endocrinol 1998 Apr 30
PMID:Cloning of crustacean ecdysteroid receptor and retinoid-X receptor gene homologs and elevation of retinoid-X receptor mRNA by retinoic acid. 970 89

Physiological responses due to steroid hormones and retinoids are regulated by their cognate receptors and dehydrogenases. The origins of either regulatory mechanism are not fully understood. Here we examine the origins of the human 11beta-hydroxysteroid dehydrogenase-type 2, which regulates access of glucocorticoids to cells, and 17beta-hydroxysteroid dehydrogenase-type 2, which regulates access of androgens and estrogens to cells. Sequence comparisons trace their ancestry to homologs in Caenorhabditis elegans. These C. elegans proteins most closely resemble mammalian all-trans and 11-cis-retinol dehydrogenases. The similarity is sufficient -37% to 43% identity to suggest that one or more of the C. elegans homologs metabolizes a retinoid. Receptors for retinoids, but not for androgens, estrogens or glucocorticoids have been identified in C. elegans, suggesting that retinoid-mediated gene transcription is more ancient than that for adrenal and sex steroids. We propose that the hydroxysteroid dehydrogenase-type 2 mechanism for regulating the androgen, estrogen and glucocorticoid concentrations in mammals descended from that for regulating retinoid concentrations. Interestingly, E. coli contains a protein with strong sequence similarity to mammalian retinol dehydrogenases. Sequence comparisons and phylogenetic analysis indicate that the E. coli protein may be an example of horizontal transfer from a eukaryote ancestor.
J Steroid Biochem Mol Biol 1998 Sep
PMID:Evolution of mammalian 11beta- and 17beta-hydroxysteroid dehydrogenases-type 2 and retinol dehydrogenases from ancestors in Caenorhabditis elegans and evidence for horizontal transfer of a eukaryote dehydrogenase to E. coli. 974 41

Interferons (IFNs) and retinoids are potent biological response modifiers. By using JAK-STAT pathways, IFNs regulate the expression of genes involved in antiviral, antitumor, and immunomodulatory actions. Retinoids exert their cell growth-regulatory effects via nuclear receptors, which also function as transcription factors. Although these ligands act through distinct mechanisms, several studies have shown that the combination of IFNs and retinoids synergistically inhibits cell growth. We have previously reported that IFN-beta-all-trans-retinoic acid (RA) combination is a more potent growth suppressor of human tumor xenografts in vivo than either agent alone. Furthermore, the IFN-RA combination causes cell death in several tumor cell lines in vitro. However, the molecular basis for these growth-suppressive actions is unknown. It has been suggested that certain gene products, which mediate the antiviral actions of IFNs, are also responsible for the antitumor actions of the IFN-RA combination. However, we did not find a correlation between their activities and cell death. Therefore, we have used an antisense knockout approach to directly identify the gene products that mediate cell death and have isolated several genes associated with retinoid-IFN-induced mortality (GRIM). In this investigation, we characterized one of the GRIM cDNAs, GRIM-12. Sequence analysis suggests that the GRIM-12 product is identical to human thioredoxin reductase (TR). TR is posttranscriptionally induced by the IFN-RA combination in human breast carcinoma cells. Overexpression of GRIM-12 causes a small amount of cell death and further enhances the susceptibility of cells to IFN-RA-induced death. Dominant negative inhibitors directed against TR inhibit its cell death-inducing functions. Interference with TR enzymatic activity led to growth promotion in the presence of the IFN-RA combination. Thus, these studies identify a novel function for TR in cell growth regulation.
Mol Cell Biol 1998 Nov
PMID:Thioredoxin reductase mediates cell death effects of the combination of beta interferon and retinoic acid. 977 65

An analysis has been performed on the first example of a non-proline cis- peptide bond found within a complementarity determining region (CDR) of an antibody. The bond is located in CDR 3 of the heavy chain (H3) and makes substantial interactions to a peptide from a breast tumour-associated antigen. The antibody-peptide complex is compared, both in H3 length (six residues) and peptide conformation, to a number of other such complexes in the Brookhaven Data Bank (PDB). There is only one other H3 loop of the same length. Analysis of loop searches of the PDB, taken over the H3 framework of SM3, suggest that there is a limited repertoire of conformations for loops of length 6 compared to loops of length 5 and 7. It is argued that the cis-peptide bond is present because of the limited number of loop conformations of length 6, plus, the requirement of the H3 loop to contact the bound peptide. Modelling suggests that an all-trans-peptide loop conformation can replace the H3 loop and this raises the question of whether there is a trans- to cis-peptide bond isomerization upon peptide binding.
J Mol Biol 1998 Dec 04
PMID:Conformational analysis of the first observed non-proline cis-peptide bond occurring within the complementarity determining region (CDR) of an antibody. 982 97


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