Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P51532 (transcriptional activator)
6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The transcriptional activator retinoic acid (RA) has been shown to influence the early patterning of the vertebrate eye. Models for the establishment of the retinofugal projection postulate gradients of cell-surface markers across the retinal surface that are expressed by ganglion cells and mediate the correct connection of fibers within central target fields. Spatial asymmetries of RA and RA-producing enzymes, as have been found in the eyes of mice and zebrafish, could induce the required asymmetry in gene expression. Here we exploited the large size of the retina of the embryonic chick to analyze the spatial and temporal characteristics of the RA system by HPLC in combination with a reporter cell assay. As in other embryonic vertebrates, the chick retina was found to contain different RA-generating enzymes segregated along the dorsoventral axis. The major RA isomer in both dorsal and ventral retina was all-trans RA, and no 9-cis RA could be detected. This excludes a difference in production of these two isomers as an explanation for the expression of different RA-generating enzymes. At developmental stages embryonic days (E) 4 and 5, the ventral retina contained higher all-trans RA levels than the dorsal retina. After E8, however, the difference disappeared, and in embryos at E9 and older the RA concentration was slightly higher in dorsal than ventral retina.
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PMID:Retinoic acid synthesis in the developing chick retina. 929 90

Retinoids signal biological effects through retinoic acid receptors (RAR) and retinoid X receptors (RXR) and their co-regulators. We previously reported that all-trans retinoic acid (RA) triggers terminal differentiation in the human embryonal carcinoma cell line NTERA-2 clone D1 (NT2/D1), through an RARgamma dependent pathway. RARgamma repression in NT2/D1-R1 cells accounts for RA resistance in this line. This report finds RARgamma repression is due to selective repression of RARgamma but not RARbeta transcription in NT2/D1-R1 cells. The repression is neither due to mutations in RARgamma nor its promoter containing the RA response element. Prior work was confirmed and extended by demonstrating that an RARgamma selective agonist preferentially signals differentiation of NT2/D1 cells, while RARalpha/beta, RARbeta, RXR agonists and an RAR pan-antagonist do not even when NT2/D1 cells are treated with these retinoids at 10 microM dosages. None of these examined retinoids induced differentiation of the RA resistant NT2/D1-R1 cells. In contrast, N-(4-hydroxyphenyl)retinamide (4HPR), a reported transcriptional activator of RARgamma was shown to potently induce growth inhibition and apoptosis in both NT2/D1 and NT2/D1-R1 cells. 4HPR-induced apoptosis was unaffected by co-treatment of both cell lines with equimolar RAR antagonist. Semi-quantitative reverse transcription-polymerase chain reaction (RT - PCR) assays of total RNA from 4HPR-treated NT2/D1 and NT2/D1-R1 cells did not reveal RARgamma induction. Since 4HPR signals in RA-resistant NT2/D1-R1 cells having an RARgamma transcriptional block, these results indicate that 4HPR triggers apoptosis but not differentiation through an RARgamma independent pathway. Taken together, these findings implicate a therapeutic role for 4HPR mediated apoptosis in germ cell tumors even when a maturation block is present.
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PMID:4HPR triggers apoptosis but not differentiation in retinoid sensitive and resistant human embryonal carcinoma cells through an RARgamma independent pathway. 1052 55

One allele of interferon regulatory factor-1 (IRF-1), a transcriptional activator of genes critical for growth suppression, differentiation, and apoptosis, is usually deleted in acute myeloid leukemias (AML) and myelodysplasias (MDS) with deletion of chromosome 5q31. Accelerated exon skipping of IRF-1, resulting in transcripts lacking a translation initiation site, has been hypothesized as a means of functional inactivation of IRF-1 in AML/MDS. To test this hypothesis, we developed quantitative competitive RT-PCR assays to measure levels of full length and exon-skipped IRF-1 transcripts and measured IRF-1 proteins by Western blotting in a series of 45 samples of AML (13: -5/del5(q); 11: t(15;17); 7: t(8;21); and 7: inv(16)), normal blood and marrow, and myeloid cell lines. In contrast to AMLs with inv(16) or t(8;21), two AML samples with del(5q) had accelerated exon skipping and relatively low levels of full-length transcripts, while a third sample had very low transcript levels; IRF-1 proteins were not expressed and could not be induced by interferon gamma (IFNgamma). An additional six AML cases with -5/del(5q) had moderate exon-skipping and lacked constitutive IRF-1 proteins; however IRF-1 proteins were IFNgamma-inducible. Unexpectedly, all primary acute promyelocytic leukemia (APL) samples lacked IRF-1 protein and most exhibited accelerated exon skipping; furthermore, IRF-1 could not be induced by IFNgamma or all-trans retinoic acid (ATRA) which both induce IRF-1 in the NB4 APL cell line. Thus, accelerated exon skipping results in a loss of IRF-1 expression and function that cannot be overcome by exposure to inducing agents in a subset of AML patients with -5/del(5q) and in APL.
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PMID:Lack of IRF-1 expression in acute promyelocytic leukemia and in a subset of acute myeloid leukemias with del(5)(q31). 1060 16

Brain-derived neurotrophic factor (BDNF) supports survival and regeneration of retinal ganglion cells (RGC). Since the expression of its receptor TrkB can be induced by the transcriptional activator retinoic acid (RA), we have investigated the possibility that RA promotes axonal regeneration of differentiated chick RGC synergistically with BDNF. After injection of all-trans RA onto the chorio-allantoic membrane of stage E16 chick embryos, axonal regeneration was monitored in organ cultures supplemented with BDNF. RA enhanced neurite outgrowth of retinal ganglion cells 2- to 3-fold. The dose-dependent effect was observed only after application of RA in ovo and subsequent use of the neurotrophin, not with RA alone.
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PMID:Retinoic acid increases BDNF-dependent regeneration of chick retinal ganglion cells in vitro. 1061 46

The uncoupling protein-3 (UCP-3) gene encodes for a mitochondrial protein expressed preferentially in skeletal muscle. UCP-3 mRNA is expressed in cultured muscle cells (C2C12 or L6E9) only when differentiated, at which stage UCP-3 is highly induced by all-trans retinoic acid (RA). Here we report that human UCP-3 promoter activity is dependent on MyoD and inducible by all trans-RA. The action of all trans-RA is increased by co-transfection with RA receptor (RAR). We have characterized the RA response element that controls the induction by RA in the 5' noncoding region of the UCP-3 gene. Deletion and point-mutation analysis of the hUCP-3 promoter led us to identify a direct-repeat element with one base-pair spacing (DR1) at position -71/-59 responsible for the induction by RA of the activity of the promoter. This DR1 element bound a nuclear protein complex from muscle cells that contain RAR and retinoid X receptor (RXR). In the absence of this element, the promoter became unresponsive to RA, but it was still dependent on MyoD. In conclusion, it has been established that UCP-3 gene promoter activity is dependent on MyoD, and the first regulatory pathway for UCP-3 gene promoter regulation has been recognized by identifying RA as a transcriptional activator of the gene.
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PMID:The human uncoupling protein-3 gene promoter requires MyoD and is induced by retinoic acid in muscle cells. 1102 1

After traumatic injury to the central nervous system (CNS), various cytokines orchestrate the physiological responses of injured neurons and glial cells. The control of these intercellular signals is of major interest from a medical point of view. Since the transcriptional activator retinoic acid (RA) is known to regulate gene expression of cytokines in various cell culture systems we investigated the role of RA signaling in glial cells. The transcriptional activity of RA-induced genes is largely determined by the distribution of RA, which in turn depends on the local oxidation of retinaldehyde (RAL). This is synthesized from retinol or internalized as a component of vitamin A. Using high-pressure liquid chromatography and an RA-sensitive reporter cell line, we showed that OLN-93 cells, which serve as a model system for CNS oligodendrocytes, convert all-trans-RAL to the biologically active form all-trans-RA, but neither oxidize 9-cis-RAL nor isomerize RA enzymatically. The oligodendrocyte cell line expresses a cytosolic aldehyde dehydrogenase with an apparent molecular weight of 54-57 kDa and pI of 5.3-5.7. As indicated by a zymography bioassay, this enzyme is responsible for RA synthesis. The reaction requires NAD+ as cosubstrate and can be inhibited by disulfiram and citral. No other RA-producing enzyme activities were detected. These findings are in accordance with a putative role for retinoid signaling in neuroglial interactions in the CNS.
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PMID:OLN-93 oligodendrocytes synthesize all-trans-retinoic acid in vitro. 1107 15

The transcriptional activator retinoic acid (RA) has been proposed to determine the dorsoventral polarity of the eye axis in vertebrates, thereby organizing the later developing retinotopic visual projection. We manipulated the RA distribution in the early chick eye anlage and subsequently measured gene expression with quantitative RT-PCR. Injections of all-trans RA suppressed the expression of dorsal signals Tbx5, BMP4 and to a lesser extent of ephrinB1, whereas the injection of citral, an inhibitor of RA synthesis, enhanced the expression of BMP4 and Tbx5. In contrast, the distribution of the transcription factor Pax2 in the ventral eye cup was not affected by changes in RA signaling.
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PMID:Retinoic acid-dependent regulation of BMP4 and Tbx5 in the embryonic chick retina. 1559 47

Overexpression of wild-type MN1 is a negative prognostic factor in patients with acute myeloid leukemia (AML) with normal cytogenetics. We evaluated whether MN1 plays a functional role in leukemogenesis. We demonstrate using retroviral gene transfer and bone marrow (BM) transplantation that MN1 overexpression rapidly induces lethal AML in mice. Insertional mutagenesis and chromosomal instability were ruled out as secondary aberrations. MN1 increased resistance to all-trans retinoic acid (ATRA)-induced cell-cycle arrest and differentiation by more than 3000-fold in vitro. The differentiation block could be released by fusion of a transcriptional activator (VP16) to MN1 without affecting the ability to immortalize BM cells, suggesting that MN1 blocks differentiation by transcriptional repression. We then evaluated whether MN1 expression levels in patients with AML (excluding M3-AML) correlated with resistance to ATRA treatment in elderly patients uniformly treated within treatment protocol AMLHD98-B. Strikingly, patients with low MN1 expression who received ATRA had a significantly prolonged event-free (P = .008) and overall (P = .04) survival compared with patients with either low MN1 expression and no ATRA, or high MN1 expression with or without ATRA. MN1 is a unique oncogene in hematopoiesis that both promotes proliferation/self-renewal and blocks differentiation, and may become useful as a predictive marker in AML treatment.
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PMID:MN1 overexpression induces acute myeloid leukemia in mice and predicts ATRA resistance in patients with AML. 1749 59

Treatment of HepG2 with all-trans retinoic acid (RA) induces expression of fatty acid synthase (FAS) mRNA and protein. Transfections show that the FAS promoter positively responds to retinoid X receptor (RXR) but not to RA receptor (RAR) agonists. Since RXR alone is capable of mediating the RA response of FAS, the existence of a classical RA-responsive element in the FAS promoter may be ruled out. Binding sites for NF-Y and SREBP-1 proved to be essential for the RA response. Exposure to all-trans RA increased mRNA and protein levels of SREBP-1, a transcriptional activator for FAS. Overexpression of a dominant-negative form of SREBP-1c diminished the RA-dependent increase in promoter activity. These data demonstrate that RXR ligands can stimulate the expression of a lipogenic gene solely by inducing transcription and cleavage of membrane-bound SREBP-1c.
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PMID:SREBP-1c mediates the retinoid-dependent increase in fatty acid synthase promoter activity in HepG2. 1753 80

The production of chemokines by astrocytes constitutes an important component of neuroinflammatory processes in the brain. As the transcriptional activator retinoic acid (RA), used for chemotherapy and dermatological applications, exerts anti-inflammatory effects on monocytes and lymphocytes, we have tested whether the physiologically occurring isomer, all-trans RA, affects chemokine expression by astrocytes. Under control conditions, primary cultures of murine cortical astrocytes expressed no or very low levels of CCL and CXCL chemokines. After treatment with bacterial lipopolysaccharides to simulate inflammation in vitro, we detected a strong increase in the release of CCL2 (to > 4 ng/mL in cell culture supernatant), CCL3 (> 20 ng/mL), CCL5 (> 25 ng/mL), CXCL1 (> 30 ng/mL) and CXCL2 (> 20 ng/mL). Although simultaneous exposure to RA did not significantly affect this response, 12 h pre-treatment with 0.1 microM all-trans RA strongly suppressed mRNA expression and protein release of all chemokines. The anti-inflammatory activity of RA engaged RA and retinoid X receptors and correlated with a decreased expression of the lipopolysaccharides co-receptor CD14. A minor reduction of nuclear NF-kappaB was observed but not significant, activation of Jun amino-terminal kinase, p38 and signal transducer and activator of transcription 3 were not altered by RA. The results suggest that retinoids should be further investigated as candidates for the treatment of neuroinflammation.
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PMID:Inflammatory chemokine release of astrocytes in vitro is reduced by all-trans retinoic acid. 2055 28


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