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

Retinoic acid receptor-alpha mRNAs were found in both Sertoli and germ cells of the testis. A 2.7-kilobase (kb) mRNA was expressed solely in Sertoli cells, whereas a 3.4-kb mRNA was distributed in both Sertoli and germ cells. In addition, we report two new, but minor, germ cell-specific mRNAs detected primarily in the pachytene spermatocytes. By contrast, only one transcript for retinoic acid receptor-beta was found in the testis, exclusively in Sertoli cells. These results suggest that each mRNA may have specific functions in mediating the effects of retinoids during spermatogenesis. The expression of retinoic acid receptor-alpha mRNAs was regulated during the spermatogenic cycle, showing a 7-fold increase in the level of 3.4-kb mRNA at stages VIII-IX. Since stage VIII is where the development of germ cells is arrested at the prophase of meiosis in the vitamin A-deficient testis, this result suggests that alpha mRNA transcription may be necessary before more advanced germ cells than preleptotene spermatocytes would be observed in the testis. The most striking finding was that the treatment of vitamin A-deficient rats with retinol led to a rapid increase in the retinoic acid receptor-alpha mRNA levels. The level of mRNAs was increased 3-fold at its peak, but diminished by 12 h. This precise regulation of receptor by retinol suggests that its synthesis is required before it can be used to modulate the transcription of retinoid-inducible genes. In contrast, the regulation of retinoic acid receptor-beta mRNA was different from the alpha mRNAs, in that its level remained unchanged for 48 h after the injection of retinol.
Mol Endocrinol 1990 Nov
PMID:The regulation of retinoic acid receptor mRNA levels during spermatogenesis. 217 39

We have recently described in genital skin fibroblasts (GSF) a relatively abundant 56 kDa protein with androgen-binding activity. This protein is missing in GSF of most patients with complete androgen insensitivity syndrome (CAI). The protein has many characteristics compatible with the androgen receptor; it has in fact been tentatively considered as a precursor or degradation form of the prototypic (approximately 100 kDa) human androgen receptor. We have prepared an antiserum to this protein, which allowed us to detect it as a direct product by in vitro translation of mRNA from GSF. It is thus very unlikely to be a degradation product of a larger precursor. Furthermore, covalent photolytic labeling of this protein with the androgen analogue [3H]mibolerone revealed a much lower affinity for this protein than is known for the androgen receptor. Finally, the GSF of two exceptional patients with complete androgen insensitivity syndrome due to negligible androgen receptor-binding activity express this protein normally, as determined on two-dimensional gels by Western blot analysis with the antiserum and by photolytic covalent labeling with androgen analogues. These data indicate that the protein is not a precursor or a degradation product of the receptor; nor is it androgen-induced. They are more compatible with the idea that the protein is another member of the steroid/thyroid/retinoic acid receptor supergene family, perhaps as an unorthodox product of the human androgen receptor gene.
Mol Cell Endocrinol 1990 Jan 22
PMID:The 56 kDa androgen-binding protein in human genital skin fibroblasts: its relation to the human androgen receptor. 231 25

A cDNA encoding a novel member of the thyroid/steroid hormone receptor superfamily, called Rev-ErbA alpha, has been isolated from a rat GH3 cell library. Rev-ErbA alpha is an approximately 56-kilodalton protein most similar in structure to the thyroid hormone receptor (c-erbA) and the retinoic acid receptor, but it does not bind either thyroid hormone or retinoic acid. The mRNA encoding Rev-ErbA alpha is present in many tissues and is particularly abundant in skeletal muscle and brown fat. A genomic DNA fragment containing the entire Rev-ErbA alpha cDNA sequence was isolated and characterized. Remarkably, this DNA fragment also contained a portion of the c-erbA alpha gene. r-erbA alpha-1 and r-erbA alpha-2 are alternative splice products of the c-erbA alpha gene and are members of the receptor superfamily. The genes encoding Rev-ErbA alpha and r-erbA alpha-2 overlap, with their coding strands oriented opposite one another. A 269-base-pair segment of the bidirectionally transcribed region is exonic in both the Rev-ErbA alpha and r-erbA alpha-2 genes, resulting in complementary mRNAs. Thus, through alternative splicing and opposite-strand transcription, a single genomic locus codes for three different members of the thyroid/steroid hormone receptor superfamily. Potential implications of this unusual genomic arrangement are discussed.
Mol Cell Biol 1989 Mar
PMID:A novel member of the thyroid/steroid hormone receptor family is encoded by the opposite strand of the rat c-erbA alpha transcriptional unit. 254 65

The human promyelocytic leukemia cell line HL-60 can be induced to differentiate into granulocytes upon exposure to retinoids. Previously we have shown that extracts of undifferentiated HL-60 cells possess a specific retinoid-binding activity (RSBP-1) corresponding to an approximate 95 kilodalton (kDa) protein as determined by size-exclusion chromatography. We now extend these observations to reveal a second approximate 95 kDa retinoic acid-binding component (RSBP-2), which is separable from RSBP-1 using anion exchange chromatography. We further show that the chromatographic properties of RSBP-1 and RSBP-2 are identical to those found for the retinoid-binding activities present in extracts of HeLa cells transfected with the human retinoic acid receptor (RAR) expression vectors RAR-beta phi and RAR-alpha phi, respectively. Moreover, an antiserum preparation directed against RAR-beta selectively immunoprecipitated both the retinoid-binding activity in extracts of HeLa cells transfected with RAR-beta phi and that corresponding to RSBP-1 in HL-60 cell extracts. Similarly, an antiserum preparation directed against RAR-alpha immunoprecipitated the retinoid-binding activity in extracts from RAR-alpha phi transfected HeLa cell as well as that corresponding to RSBP-2 in HL-60 cell extracts. Using these antisera, Western blot analyses of extracts from HL-60 cells, and from HeLa cells transfected with either RAR-alpha phi or RAR-beta phi, confirmed that RSBP-2 and RSBP-1 are identical to RAR-alpha and RAR-beta, respectively. However, RAR-alpha, RAR-beta, RSBP-1, and RSBP-2 appeared as an approximate 51 kDa species in sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis in contrast with an apparent approximate 95 k mol wt as estimated from size-exclusion chromatography in the presence of 0.6 M KCl.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Endocrinol 1989 Jul
PMID:The retinoic acid receptors alpha and beta are expressed in the human promyelocytic leukemia cell line HL-60. 255 97

Thyroid hormone receptor acts as a hormone-dependent transcriptional transactivator and as a transcriptional repressor in the absence of thyroid hormone. Specifically, thyroid hormone receptor can repress retinoic acid-induced gene expression through interactions with retinoic acid receptor. (Retinoic acid is a potent teratogen in the frog Xenopus laevis, acting at early embryonic stages to interfere with the formation of anterior structures. Endogenous retinoic acid is thought to act in normal anterior-posterior axis formation.) We have previously shown that thyroid hormone receptor RNA (alpha isotype) is expressed and polysome-associated during Xenopus embryogenesis preceding thyroid gland maturation and endogenous thyroid hormone production (D. E. Banker, J. Bigler, and R. N. Eisenman, Mol. Cell. Biol. 11:5079-5089, 1991). To determine whether thyroid hormone receptor might influence the effects of retinoic acid in early frog development, we have examined the results of ectopic thyroid hormone receptor expression on retinoic acid teratogenesis. We demonstrate that microinjections of full-length thyroid hormone receptor RNA protect injected embryos from retinoic acid teratogenesis. DNA binding is apparently essential to this protective function, as truncated thyroid hormone receptors, lacking DNA-binding domains but including hormone-binding and dimerization domains, do not protect from retinoic acid. We have shown that microinjections of these dominant-interfering thyroid hormone receptors, as well as anti-thyroid hormone receptor antibodies, increase retinoic acid teratogenesis in injected embryos, presumably by inactivating endogenous thyroid hormone receptor. This finding suggests that endogenous thyroid hormone receptors may act to limit retinoic acid sensitivity. On the other hand, after thyroid hormone treatment, ectopic thyroid hormone receptor mediates teratogenesis that is indistinguishable from the dorsoanterior deficiencies produced in retinoic acid teratogenesis. The previously characterized retinoic acid-responsive gene, Xhox.lab2, can be induced by thyroid hormone in embryos ectopically expressing thyroid hormone receptor and is less responsive to retinoic acid in such embryos. The fact that both thyroid hormone and retinoic acid can affect overlapping gene expression pathways to produce abnormal embryonic axes and can regulate the same early-expressed gene suggests a model in which thyroid hormone receptor blocks retinoic acid receptor-mediated teratogenesis by directly repressing retinoic acid-responsive genes.
Mol Cell Biol 1993 Dec
PMID:Thyroid hormone receptor can modulate retinoic acid-mediated axis formation in frog embryogenesis. 750 77

All-trans-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid (designated "acyclic retinoid") induced upregulation of the albumin gene expression at its transcriptional level, whereas all-trans-retinoic acid (RA) induced downregulation of the expression in both PLC/PRF/5 and HuH7 human hepatoma cell lines. These up- and down regulations of the albumin gene expression coordinated with high and low levels of mRNA for hepatocyte nuclear factor-1 (HNF-1), which is one of the most potent transcription factors for the albumin gene, implying that retinoids may regulate albumin gene expression through HNF-1 expression in opposite ways. The PLC/PRF/5 and HuH7 hepatoma cell lines expressed retinoid X receptor-alpha (RXR alpha) mRNA, whose expression was constitutive. Acyclic retinoid and all-trans-RA both induced upregulation of retinoic acid receptor-beta (RAR beta), and both suppressed cell proliferation-related phenotypic expressions by the alpha-fetoprotein gene and the c-myc oncogene. 9-cis-RA, whose receptor is known to be RXR alpha, also induced upregulation of albumin and HNF-1 expression. These results suggest that acyclic retinoid may act through both RXR alpha and RAR beta, whereas all-trans-RA conveys only RAR beta-mediated functions, at least in these two hepatoma cell lines.
Mol Carcinog 1994 Jul
PMID:Positive and negative regulations of albumin gene expression by retinoids in human hepatoma cell lines. 751 16

Nuclear retinoic acid receptors (RARs) function as ligand-activated trans-acting transcription factors and mediate the effects of retinoids on gene expression, cell growth, and differentiation. Determination of the receptors' expression in premalignant and malignant lesions may provide prognostic value and direct the selection of receptor-specific retinoids in cancer prevention or treatment. We describe a sensitive and practical in situ hybridization method for the analysis of RARs in tissue sections of fixed and embedded surgical specimens. Digoxigenin-labeled antisense and sense RNA probes were prepared for nuclear RAR-alpha, RAR-beta, and RAR-gamma. The specificity of the probes for their respective receptor mRNAs was demonstrated by Northern blot hybridization to total RNA extracted from murine and human cells. Optimal conditions for in situ localization of the RAR mRNA were established using cultured tumor cells, and these conditions were then used for the detection of RAR mRNA in formalin-fixed, paraffin-embedded sections of surgical specimens from human tumors. The hybridization stain was detected in the cytoplasm (where it was expected to be localized) and not seen in the cell nucleus. This method provides a rapid detection procedure with good resolution that allows one to clearly distinguish strongly and weakly stained cells. A comparison of receptor expression in head and neck squamous carcinoma specimens and in adjacent normal tissues revealed a significant decrease in the level of RAR-beta mRNA in the tumor cells.
Diagn Mol Pathol 1994 Jun
PMID:Detection of nuclear retinoic acid receptor mRNA in histological tissue sections using nonradioactive in situ hybridization histochemistry. 752 Mar 32

Calreticulin is a ubiquitous calcium binding/storage protein found primarily in the endoplasmic reticulum. Calreticulin has been shown to inhibit DNA binding and transcriptional activation by glucocorticoid and androgen hormone receptors by binding to the conserved sequence KXFF(K/R)R, present in the DNA-binding domains of all known members of the steroid/nuclear hormone receptor superfamily. To determine whether calreticulin might be a general regulator of hormone-responsive pathways, we examined its effect on DNA binding in vitro and transcriptional activation in vivo by heterodimers of the peroxisome proliferator-activated receptor (PPAR) and the 9-cis retinoic acid receptor (RXR alpha). We show here that purified calreticulin inhibits the binding of PPAR/RXR alpha heterodimers and of other nuclear hormone receptors, to peroxisome proliferator-responsive DNA elements in vitro. However, overexpression of calreticulin in transiently transfected cultured cells had little or no effect on transactivation mediated by PPAR/RXR alpha. Therefore, while calreticulin inhibits the binding of both nuclear and steroid hormone receptors to cognate response elements in vitro, our findings suggest that calreticulin does not necessarily play an important role in the regulation of all classes of hormone receptors in vivo.
Mol Cell Endocrinol 1995 Jun
PMID:Calreticulin modulates the in vitro DNA binding but not the in vivo transcriptional activation by peroxisome proliferator-activated receptor/retinoid X receptor heterodimers. 755 79

T-cell hybridomas, thymocytes, and T cells can be induced to undergo apoptotic cell death by activation through the T-cell receptor. This process requires macromolecular synthesis and thus gene expression, and it has been shown to be influenced by factors regulating transcription. Recently, activation, T-cell hybridomas rapidly express the Fas/CD95 receptor and its ligand, Fas ligand (FasL), which interact to transduce the death signal in the activated cell. Retinoids, the active metabolites of vitamin A, modulate expression of specific target genes by binding to two classes of intracellular receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs). They are potent modulators of apoptosis in a number of experimental models, and they have been shown to inhibit activation-induced apoptosis in T-cell hybridomas and thymocytes. Particularly effective is the prototypic pan-agonist 9-cis retinoic acid (9-cis RA), which has high affinity for both RARs and RXRs. We report here that 9-cis RA inhibits T-cell receptor-mediated apoptosis in T-cell hybridomas by blocking the expression of Fas ligand following activation. This inhibition appears to be at the level of FasL mRNA, with the subsequent failure to express cell surface FasL. RAR-selective (TTNPB) or RXR-selective (LG100268) ligands alone were considerably less potent than RAR-RXR pan-agonists. However, the addition of both RAR- and RXR-selective ligands was as effective as the addition of 9-cis RA alone. The demonstrates that the inhibitory effect requires the ligand-mediated activation of both retinoid receptor signaling pathways.
Mol Cell Biol 1995 Oct
PMID:9-cis retinoic acid inhibition of activation-induced apoptosis is mediated via regulation of fas ligand and requires retinoic acid receptor and retinoid X receptor activation. 756 9

Transcription regulation by DNA-bound activators is thought to be mediated by a direct interaction between these proteins and TATA-binding protein (TBP), TFIIB, or TBP-associated factors, although occasionally cofactors or adapters are required. For ligand-induced activation by the retinoic acid receptor-retinoid X receptor (RAR-RXR) heterodimer, the RAR beta 2 promoter is dependent on the presence of E1A or E1A-like activity, since this promoter is activated by retinoic acid only in cells expressing such proteins. The mechanism underlying this E1A requirement is largely unknown. We now show that direct interaction between RAR and E1A is a requirement for retinoic acid-induced RAR beta 2 activation. The activity of the hormone-dependent activation function 2 (AF-2) of RAR beta is upregulated by E1A, and an interaction between this region and E1A was observed, but not with AF-1 or AF-2 of RXR alpha. This interaction is dependent on conserved region III (CRIII), the 13S mRNA-specific region of E1A. Deletion analysis within this region indicated that the complete CRIII is needed for activation. The putative zinc finger region is crucial, probably as a consequence of interaction with TBP. Furthermore, the region surrounding amino acid 178, partially overlapping with the TBP binding region, is involved in both binding to and activation by AF-2. We propose that E1A functions as a cofactor by interacting with both TBP and RAR, thereby stabilizing the preinitiation complex.
Mol Cell Biol 1995 Nov
PMID:Adenovirus E1A functions as a cofactor for retinoic acid receptor beta (RAR beta) through direct interaction with RAR beta. 756 39


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>