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 receptor (TR) and retinoic acid receptor (RAR) isoforms interact with the nuclear corepressors [NCoR (nuclear corepressor protein) and SMRT (silencing mediator for retinoid and thyroid hormone receptors)] in the absence of ligand to silence transcription. NCoR and SMRT contain C-terminal nuclear hormone receptor (NHR) interacting domains that each contain variations of the consensus sequence I/L-x-x-I/V-I (CoRNR box). We have previously demonstrated that TRbeta1 preferentially interacts with NCoR, whereas RARalpha prefers SMRT. Here, we demonstrate that this is due, in part, to the presence of a novel NCoR interacting domain, termed N3, upstream of the previously described domains. An analogous domain is not present in SMRT. This domain is specific for TR and interacts poorly with RAR. Our data suggest that the presence of two corepressor interacting domains are necessary for full interactions with nuclear receptors in cells. Interestingly, mutation of N3 alone specifically decreases binding of NCoR to TR in cells but does not decrease NCoR-RAR interactions. In addition, while the exact CoRNR box sequence of a SMRT interacting domain is critical for recruitment of SMRT by RAR, the CoRNR box sequences themselves do not explain the strong interaction of the N2 domain with TRbeta1. Additional regions distal to the CoRNR box sequence are needed for optimal binding. Thus, through sequence differences in known interacting domains and the presence of a newly identified interacting domain, NCoR is able to preferentially bind TRbeta1. These preferences are likely to be important in corepressor action in vivo.
Mol Endocrinol 2001 Jul
PMID:The specificity of interactions between nuclear hormone receptors and corepressors is mediated by distinct amino acid sequences within the interacting domains. 1143 7

CtBP (carboxyl-terminal binding protein) participates in regulating cellular development and differentiation by associating with a diverse array of transcriptional repressors. Most of these interactions occur through a consensus CtBP-binding motif, PXDLS, in the repressor proteins. We previously showed that the CtBP-binding motif in E1A is flanked by a Lys residue and suggested that acetylation of this residue by the p300/CBP-associated factor P/CAF disrupts the CtBP interaction. In this study, we show that the interaction between CtBP and the nuclear hormone receptor corepressor RIP140 is regulated similarly, in this case by p300/CBP itself. CtBP was shown to interact with RIP140 in vitro and in vivo through a sequence, PIDLSCK, in the amino-terminal third of the RIP140 protein. Acetylation of the Lys residue in this motif, demonstrated in vivo by using an acetylated RIP140-specific antibody, dramatically reduced CtBP binding. Mutation of the Lys residue to Gln resulted in a decrease in CtBP binding in vivo and a loss of transcriptional repression. We suggest that p300/CBP-mediated acetylation disrupts the RIP140-CtBP complex and derepresses nuclear hormone receptor-regulated genes. Disruption of repressor-CtBP interactions by acetylation may be a general mode of gene activation.
Mol Cell Biol 2001 Sep
PMID:Acetylation of nuclear hormone receptor-interacting protein RIP140 regulates binding of the transcriptional corepressor CtBP. 1150 61

Patients with TSH-secreting pituitary tumors (TSHomas) have high serum TSH levels despite elevated thyroid hormone levels. The mechanism for this defect in the negative regulation of TSH secretion is not known. We performed RT-PCR to detect mutations in TRbeta from a surgically resected TSHoma. Analyses of the RT-PCR products revealed a 135-bp deletion within the sixth exon that encodes the ligand-binding domain of TRbeta2. This deletion was caused by alternative splicing of TRbeta2 mRNA, as near-consensus splice sequences were found at the junction site and no deletion or mutations were detected in the tumoral genomic DNA. This TRbeta variant (TRbeta2spl) lacked thyroid hormone binding and had impaired T3-dependent negative regulation of both TSHbeta and glycoprotein hormone alpha-subunit genes in cotransfection studies. Furthermore, TRbeta2spl showed dominant negative activity against the wild-type TRbeta2. These findings strongly suggest that aberrant alternative splicing of TRbeta2 mRNA generated an abnormal TR protein that accounted for the defective negative regulation of TSH in the TSHoma. This is the first example of aberrant alternative splicing of a nuclear hormone receptor causing hormonal dysregulation. This novel posttranscriptional mechanism for generating abnormal receptors may occur in other hormone-resistant states or tumors in which no receptor mutation is detected in genomic DNA.
Mol Endocrinol 2001 Sep
PMID:Aberrant alternative splicing of thyroid hormone receptor in a TSH-secreting pituitary tumor is a mechanism for hormone resistance. 1151 2

The farnesoid X-activated receptor (FXR; NR1H4), a member of the nuclear hormone receptor superfamily, induces gene expression in response to several bile acids, including chenodeoxycholic acid. Here we used suppression subtractive hybridization to identify apolipoprotein C-II (apoC-II) as an FXR target gene. Retroviral expression of FXR in HepG2 cells results in induction of the mRNA encoding apoC-II in response to several FXR ligands. EMSAs demonstrate that recombinant FXR and RXR bind to two FXR response elements that are contained within two important distal enhancer elements (hepatic control regions) that lie 11 kb and 22 kb upstream of the transcription start site of the apoC-II gene. A luciferase reporter gene containing the hepatic control region or two copies of the wild-type FXR response element was activated when FXR-containing cells were treated with FXR ligands. In addition, we report that hepatic expression of both apoC-II and phospholipid transfer protein mRNAs increases when mice are fed diets supplemented with cholic acid, an FXR ligand, and this induction is attenuated in FXR null mice. Finally, we observed decreased plasma triglyceride levels in mice fed cholic acid- containing diets. These results identify a mechanism whereby FXR and its ligands lower plasma triglyceride levels. These findings may have important implications in the clinical management of hyperlipidemias.
Mol Endocrinol 2001 Oct
PMID:Farnesoid X-activated receptor induces apolipoprotein C-II transcription: a molecular mechanism linking plasma triglyceride levels to bile acids. 1157 4

The SMRT corepressor complex participates in transcriptional repression by a diverse array of vertebrate transcription factors. The ability to recruit SMRT appears to play a crucial role in leukemogenesis by the PML-retinoic acid receptor alpha (RARalpha) oncoprotein, an aberrant nuclear hormone receptor implicated in human acute promyelocytic leukemia (APL). Arsenite induces clinical remission of APL through a incompletely understood mechanism. We report here that arsenite is a potent inhibitor of the interaction of SMRT with its transcription factor partners, including PML-RARalpha. Arsenite operates, in part, through a mitogen-activated protein (MAP) kinase cascade culminating in phosphorylation of the SMRT protein, dissociation of SMRT from its nuclear receptor partners, and a relocalization of SMRT out of the nucleus into the cytoplasm of the cell. Conversely, inhibition of this MAP kinase cascade attenuates the effects of arsenite on APL cells. Our results implicate SMRT as an important biological target for the actions of arsenite in both normal and neoplastic cells.
Mol Cell Biol 2001 Nov
PMID:Arsenic trioxide is a potent inhibitor of the interaction of SMRT corepressor with Its transcription factor partners, including the PML-retinoic acid receptor alpha oncoprotein found in human acute promyelocytic leukemia. 1158

Chicken ovalbumin upstream promoter-transcription factor (COUP-TF), DAX-1, and steroidogenic factor-1 (SF-1) are orphan members of the nuclear hormone receptor superfamily. COUP-TF and DAX-1 have been shown to negatively regulate the transcriptional activity of SF-1, a steroidogenic cell-specific activator of various steroidogenic cytochrome P450 genes. We therefore examined the expression levels and immunolocalization of COUP-TF, DAX-1, and SF-1 in human adrenal gland (NL) and adrenocortical adenomas, and compared the results with CYP17 expression levels and its enzyme activities to study their potential correlation with adrenocortical steroidogenesis. In NL (n = 10), expressions of COUP-TF, DAX-1, and SF-1 were detected in the nuclei of adrenocortical cells, but not in the medulla. In cortisol-producing adenomas causing Cushing syndrome (CS, n = 20), CYP17 expression was upregulated (298 +/- 2% vs NL 98 +/- 4%), whereas expression levels of both COUP-TFs (COUP-TFI, 52 +/- 5% vs NL 98 +/- 4%; COUP-TFII, 18 +/- 4% vs NL 98 +/- 4%) and DAX-1 (42 +/- 4% vs NL 100 +/- 4%) were reduced. In deoxycorticosterone-producing adenomas (DOC, n = 2), on the other hand, CYP17 expression was extremely reduced (8 and 12% vs NL 98 +/- 4%), whereas DAX-1 expression increased markedly (350 and 360% vs NL 100 +/- 4%). Expression levels of SF-1 did not differ between NL (100 +/- 8%) and CS (106 +/- 10%), but its expression appeared to be decreased in DOC (25 and 20%). These results showed CYP17 expression to be upregulated and downregulated in CS and DOC, respectively, in a manner reciprocal to that of its repressors, COUP-TF and/or DAX-1. In summary, the results indicate that co-localization of COUP-TF, DAX-1, and SF-1 in NL was lost in adrenocortical tumors and that these orphan receptors play an important role in the regulation of steroidogenesis in human adrenals.
Mol Genet Metab
PMID:Expression profiles of COUP-TF, DAX-1, and SF-1 in the human adrenal gland and adrenocortical tumors: possible implications in steroidogenesis. 1159 17

Like other nuclear receptors, the AR exerts its transcriptional function by binding to cis elements upstream of promoters and interacting with other transcriptional factors (e.g. activators, repressors, and modulators). Among them, histone acetyltransferases (HATs) and histone deacetylases (HDACs) play critical roles in altering the acetylation state of core histones, thereby regulating nuclear hormone receptor-mediated transcription. The nuclear receptor corepressor can repress the TR and RAR in the absence of ligand through either a Sin3A-dependent or -independent manner by recruiting HDACs. AR and some other steroid hormone receptors cannot silence transcription through a similar mechanism in that they are located in the cytoplasm as complexes with heat-shock proteins before exposure to ligand. It has been shown that AR can bind to p160/SRC, cAMP response element-binding protein-binding protein (CBP)/P300 and other coactivators to increase the AR-mediated transcription. However, the molecular mechanism for turning AR from transcriptionally active into silent states is unknown. In this study, we demonstrated that the transcription repressor, 5'TG3' interacting factor (TGIF), selectively represses AR-mediated transcription from several AR-responsive promoters. The repression is mediated through binding of TGIF to the DNA binding domain of AR and is trichostatin sensitive. We also identified a direct protein-protein interaction between TGIF and a transcription corepressor, Sin3A, which suggests a novel pathway for TGIF recruiting HDAC1 to the repression complex. These results provide fresh insight into understanding the mechanism for repressing AR-, and perhaps other steroid hormone receptor-, mediated transcriptions.
Mol Endocrinol 2001 Nov
PMID:5'TG3' interacting factor interacts with Sin3A and represses AR-mediated transcription. 1168 23

It was previously shown that CYP3A4 is induced in the human intestinal Caco-2 cell model by treatment with 1alpha,25-dihydroxy vitamin D3 (1,25-D3). We demonstrate the vitamin D analog, 19-nor-1alpha,25-dihydroxy vitamin D2, is also an effective inducer of CYP3A4 in Caco-2 cells, but with half the potency of 1,25-D3. We report that treatment of LS180 cells, a human intestinal cell line, with 1 to 10 nM 1,25-D3 dose dependently increased CYP3A4 protein and CYP3A4 mRNA expression. CYP3A4- and CYP3A23-promoter-Luciferase reporter constructs transiently transfected into LS180 cells were transcriptionally activated in a dose-dependent manner by 1,25-D3, whereas mutation of the nuclear hormone receptor binding motif (ER6) in the CYP3A4 promoter abrogated 1,25-D3 activation of CYP3A4. Although the CYP3A4 ER6 promoter element has been shown to bind the pregnane X receptor (PXR), this receptor does not mediate 1,25-D3 induction of CYP3A4 because a) PXR is not expressed in Caco-2 cells; b) PXR mRNA expression is not induced by 1,25-D3 treatment of LS180 cells; and c) the ligand binding domain of human PXR was not activated by 1,25-D3. 1,25-D3 uses the vitamin D receptor to induce CYP3A4 because a) the vitamin D receptor (VDR)-retinoid X receptor (RXR) heterodimer binds specifically to the CYP3A4 ER6; b) selective mutation of the CYP3A4 ER6 disrupted the binding of VDR-RXR; and c) reporter constructs containing only three copies of the CYP3A4 ER6 linked to a TK-CAT reporter were activated by 1,25-D3 only in cells cotransfected with a human VDR expression plasmid. These data support the hypothesis that 1,25-D3 and VDR induce expression of intestinal CYP3A by binding of the activated VDR-RXR heterodimer to the CYP3A PXR response element and promoting gene transcription.
Mol Pharmacol 2001 Dec
PMID:Transcriptional control of intestinal cytochrome P-4503A by 1alpha,25-dihydroxy vitamin D3. 1172 48

Dax-1, a member of the nuclear hormone receptor superfamily of transcription factors, is known to be involved in gonadal development in mammals. To date, Dax-1 has only been isolated in reptiles, birds and mammals. The expression of Dax-1 is down-regulated in the developing testis, but persists in the ovary of mice (Swain et al., Nat. Genet. 12 (1996) 404) and chicken (Smith et al., J. Mol. Endocrinol. 24 (2000) 23). Curiously, there is no sex difference in the expression patterns of Dax-1 in the American alligator (Western et al., Gene 241 (2000) 223). To understand its role(s) in gonadal development in vertebrates, molecular cloning of Dax-1 in amphibians is required. In this study, we cloned an amphibian Dax-1 homologue of the frog Rana rugosa and examined its expression profile during gonadal development. Cloned Dax-1 cDNA encoded a protein of 287 amino acids. Unlike mammalians that possess the three and one half repeat elements representing the putative DNA binding domain in the predicted sequence of Dax-1 protein, the frog had a single poorly conserved copy of the repeat unit. By RT-PCR analysis, the Dax-1 mRNA was detected in the liver and pancreas, but not in the testis and ovary of adult frogs. However, Dax-1 expression was seen first in the embryo at stage 12 and became stronger in tadpoles until stage X. The Dax-1 was transcribed in the testis stronger than in the ovary of frogs at stage XXV (just after completion of metamorphosis). In the gonad of frogs 2 months after metamorphosis (at this stage postmeiotic cells can be seen in the seminiferous tubules), the Dax-1 was expressed only in males. In addition, the Dax-1 transcription declined gradually as ovarian development proceeded, but its expression was down-regulated and then up-regulated rapidly when female-to-male sex reversal was caused by administration of testosterone into female tadpoles. Taken together, the results suggest that the Dax-1 may be closely involved in testicular development of amphibians.
 ...
PMID:Expression of Dax-1 during gonadal development of the frog. 1173 19

Sex steroids, including testosterone, play a major role in determining peak bone mass in mammals and the subsequent loss of total bone mass with advancing age. Testosterone, and its active metabolite dihydrotestosterone (DHT), bind with high affinity to the androgen receptor (AR), a member of the nuclear hormone receptor superfamily. These receptors function as transcription factors, binding together with accessory proteins to specific DNA response elements in the promoters of androgen responsive genes. To further characterize AR function in a model species of relevance to bone and pharmaceutical research, we cloned a partial canine AR from a canine kidney cDNA library and then cloned the remaining 5' segment by PCR from canine ventral prostate cDNA. The complete sequence obtained was 3577 bp. This sequence contained a single open reading frame of 2721 bp, potentially encoding a protein of 907 amino acids with a predicted molecular weight of 98.7 kD. Sequence analysis of the protein encoded by this open reading frame reveals that the modular domains providing the DNA binding and ligand binding functions are identical to those reported for eight other mammalian ARs. Northern analysis of poly-A+ RNA from ventral prostate revealed three very low abundance transcripts of approximately 9 kb and RT-PCR analysis showed relatively high expression of AR in canine ventral prostate, testis, and kidney, with lower levels detectable in spleen, skeletal muscle, heart, and liver. Competition binding studies using 3H-DHT as ligand demonstrated specific displacement by DHT, testosterone, and the anabolic steroid stanozolol, with IC50 values of 1.3, 2.5 and 3.8 nM, respectively. Binding of DHT also resulted in the stimulation of an androgen responsive-luciferase reporter following cotransfection with the canine AR into 293 cells. Immunohistochemistry using an antibody directed to the C-terminal 19 amino acids of the human AR showed strong staining of the secretory epithelial cells in canine ventral prostate. Together, these data indicate that we have cloned the canine AR and that its functional DNA binding and ligand binding domains are absolutely conserved with those reported for eight other species.
Mol Cell Biochem 2001 Oct
PMID:Molecular cloning and functional characterization of the canine androgen receptor. 1176 33


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