Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The vitamin A derivative retinoic acid plays a critical role during the differentiation of myeloid progenitors towards the neutrophil lineage. This role is primarily mediated by binding of retinoic acid to retinoic acid receptor alpha (RARalpha), a nuclear receptor that modulates the expression of multiple downstream targets via retinoic acid response elements. The importance of this signalling pathway in myelopoiesis is evidenced by the recurrent disruption of the RARalpha gene by chromosomal rearrangements in all cases of acute promyelocytic leukemia (APL). Biochemical evidence suggests RARalpha performs two opposing functions, one as a repressor of gene expression in the absence of ligand, the second as a transcriptional activator in the presence of ligand, each controlled by multimeric complexes of transcription corepressors and coactivators, respectively. Here the molecular mechanisms activated by retinoic acid during myelopoiesis in the context of neutrophil development will be reviewed, together with some of the more recently identified targets of the retinoic signalling pathway.
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PMID:Retinoids in myelopoiesis. 1275 21

Beyond their classical nutritional roles, nutrients modify gene expression and function in target cells and, by so doing, affect many fundamental biological processes. An emerging example, which is the focus of this review, is the involvement of vitamin A in the regulation of the level and functioning of body fat reserves. Retinoic acid, the carboxylic acid form of vitamin A, is a transcriptional activator of the genes encoding uncoupling proteins, and results in animals indicate that whole body thermogenic capacity is related to the vitamin A status. Retinoic acid also influences adipocyte differentiation and survival, with high doses inhibiting and low doses promoting adipogenesis of preadipose cells in culture. Moreover, vitamin A status can influence the development and function of adipose tissues in whole animals, with a low vitamin A status favouring increased fat deposition.
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PMID:Vitamin A and the regulation of fat reserves. 1294 20

In mammalian peripheral nerves a crush lesion causes interactions between injured neurons, Schwann cells and haematogenous macrophages that can lead to successful axonal regeneration. We suggest that the transcriptional activator retinoic acid (RA), takes part in gene regulation after peripheral nerve injury and that RA signalling is activated via the cellular retinoic acid binding protein (CRABP)-II and cellular retinol binding protein (CRBP)-I. With RT-PCR and immunoblotting all necessary components of the RA signalling pathway were detected in the sciatic nerve of adult rats. These are retinoic acid receptors, retinoid X receptors, the retinoic acid synthesizing enzymes RALDH-1, RALDH-2, and RALDH-3, in addition, the cellular retinoid binding proteins CRBP-I, CRABP-I and CRABP-II. Enzyme activity of RALDH-2 was detectable in the nerve, and using a transgenic reporter mouse we found local activation of RA responsive elements in the regenerating nerve. Sciatic nerve crush as well as transection resulted in a more than 10-fold up-regulation of CRBP-I, which is thought to facilitate the synthesis of RA. Both kinds of injury also caused a 15-fold increase in transcript and protein concentration of CRABP-II, a possible mediator of RA transfer to its nuclear receptors.
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PMID:Activation of retinoic acid signalling after sciatic nerve injury: up-regulation of cellular retinoid binding proteins. 1295 3

Tfap2a is a transcriptional activator expressed in many different cell types, including neurons, neural crest derivatives and epidermis. We show that mutations at the zebrafish locus previously called mont blanc (mob) or lockjaw (low) encode tfap2a. The mutant phenotype reveals that tfap2a is essential for the development of hindbrain noradrenergic (NA) neurons of the locus coeruleus, medulla and area postrema, as well as for sympathetic NA neurons, epibranchial placode derived visceral sensory ganglia, and craniofacial and trunk crest derivatives. We focus our analysis on the role of tfap2a NA differentiation in the CNS. In the locus coeruleus, Phox2a and Tfap2a are co-expressed and are both required for NA development. By contrast, in the medulla Phox2a and Tfap2a are expressed in adjacent overlapping domains, but only tfap2a activity is required for NA differentiation, as NA neurons develop normally in soulless/phox2a mutant medulla. phox2a and tfap2a do not appear to affect each others expression. Our studies show that two distinct inductive mechanisms control NA development in the zebrafish hindbrain. For the posterior hindbrain, we identify retinoic acid as an important signal to induce NA differentiation in the medulla oblongata and area postrema, where it expands the tfap2a expression domain and thus acts upstream of tfap2a. By contrast, previous work revealed Fgf8 to be involved in specification of NA neurons in the locus coeruleus. Thus, although the inductive signals may be distinct, hindbrain NA neurons of the locus coeruleus and the posterior groups both require Tfap2a to establish their noradrenergic identity.
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PMID:Noradrenergic neurons in the zebrafish hindbrain are induced by retinoic acid and require tfap2a for expression of the neurotransmitter phenotype. 1453 39

PML-RAR is an oncogenic transcription factor forming in acute promyelocytic leukemias (APL) because of a chromosomal translocation. Without its ligand, retinoic acid (RA), PML-RAR functions as a constitutive transcriptional repressor, abnormally associating with the corepressor-histone deacetylase complex and blocking hematopoietic differentiation. In the presence of pharmacological concentrations of RA, PML-RAR activates transcription and stimulates differentiation. Even though it has been suggested that chromatin alteration is important for APL onset, the PML-RAR effect on chromatin of target promoters has not been investigated. Taking advantage of the Xenopus oocyte system, we compared the wild-type transcription factor RARalpha with PML-RAR as both transcriptional regulators and chromatin structure modifiers. Without RA, we found that PML-RAR is a more potent transcriptional repressor that does not require the cofactor RXR and produces a closed chromatin configuration. Surprisingly, repression by PML-RAR occurs through a further pathway that is independent of nucleosome deposition and histone deacetylation. In the presence of RA, PML-RAR is a less efficient transcriptional activator that is unable to modify the DNA nucleoprotein structure. We propose that PML-RAR, aside from its ability to recruit aberrant quantities of histone deacetylase complexes, has acquired additional repressive mechanisms and lost important activating functions; the comprehension of these mechanisms might reveal novel targets for antileukemic intervention.
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PMID:Retinoic acid receptor alpha fusion to PML affects its transcriptional and chromatin-remodeling properties. 1461 19

The majority of the functions of vitamin A are carried out by its metabolite, retinoic acid (RA), a potent transcriptional activator acting through members of the nuclear receptor family of transcription factors. In the CNS, RA was first recognized to be essential for the control of patterning and differentiation in the developing embryo. It has recently come to light, however, that many of the same functions that RA directs in the embryo are involved in the regulation of plasticity and regeneration in the adult brain. The same intricate metabolic control system of synthetic and catabolic enzymes, combined with cytoplasmic binding proteins, is used in both embryo and adult to create regions of high and low RA to modulate gene transcription. This review summarizes some of the discoveries in the new field of retinoid neurobiology including its functions in neural plasticity and LTP in the hippocampus; its possible role in motor disorders such as Parkinson's disease, motoneuron disease, and Huntington's disease; its role in regeneration after sciatic nerve and spinal cord injury; and its possible involvement in psychiatric diseases such as depression.
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PMID:Retinoic acid signaling in the nervous system of adult vertebrates. 1535 8

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

Cartilage-derived retinoic acid-sensitive protein (CD-RAP) is a small secreted matrix protein expressed in developing and adult cartilage and by chondrocytes in culture. We have previously shown that the expression of Cd-rap, like many other cartilage matrix proteins, is repressed by interleukin 1beta and that the transcription factor CCAAT/enhancer-binding protein (C/EBP) beta plays an important role in the interleukin 1beta-induced repression (Okazaki, K., Li, J., Yu, H., Fukui, N., and Sandell, L. J. (2002) J. Biol. Chem. 277, 31526-31533). The co-activators CREB-binding protein (CBP) and p300 are transcriptional co-regulators that participate in the activities of many different transcription factors including C/EBP. Here we show that CBP/p300 can reverse the inhibitory effect of C/EBP and moreover can stimulate expression of Cd-rap. The mechanism of this effect is shown to involve a unique synergy whereby CBP/p300 stimulate Cd-rap gene expression by at least two mechanisms. First, binding of CBP/p300 to C/EBPbeta leads to sequestration of C/EBP eliminating DNA binding and subsequent repression; second, binding of CBP/p300 to the transcriptional activator Sox9 increases Sox9 DNA binding to the Cd-rap promoter leading to further stimulation of gene transcription. This is an example of a complementary transcriptional network whereby two very different mechanisms act together to confer a functional increase in transcription. This new paradigm is likely generally applicable to cartilage genes as Col2a1 cartilage collagen gene responds similarly.
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PMID:Transcriptional Co-activators CREB-binding protein/p300 increase chondrocyte Cd-rap gene expression by multiple mechanisms including sequestration of the repressor CCAAT/enhancer-binding protein. 1572 56

Tracking stem cell localization, survival, differentiation, and proliferation after transplantation in living subjects is essential for understanding stem cell biology and physiology. In this study, we investigated the long-term stability of reporter gene expression in an embryonic rat cardiomyoblast cell line and the role of epigenetic modulation on reversing reporter gene silencing. Cells were stably transfected with plasmids carrying cytomegalovirus promoter driving firefly luciferase reporter gene (CMV-Fluc) and passaged repeatedly for 3-8 months. Within the highest expressor clone, the firefly luciferase activity decreased progressively from passage 1 (843+/-28) to passage 20 (250+/-10) to passage 40 (44+/-3) to passage 60 (3+/-1 RLU/microg; P<0.05 vs. passage 1). Firefly luciferase activity was maximally rescued by treatment with 5-azacytidine (DNA methyltransferase inhibitor) compared with trichostatin A (histone deacetylase inhibitor) and retinoic acid (transcriptional activator; P<0.05). Increasing dosages of 5-azacytidine treatment led to higher levels of firefly luciferase mRNA (RT-PCR) and protein (Western blots) and inversely lower levels of methylation in the CMV promoter (DNA nucleotide sequence). These in vitro results were extended to in vivo bioluminescence imaging (BLI) of cell transplant in living animals. Cells treated with 5-azacytidine were monitored for 2 wk compared with 1 wk for untreated cells (P<0.05). These findings should have important implications for reporter gene-based imaging of stem cell transplantation.
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PMID:Effects of epigenetic modulation on reporter gene expression: implications for stem cell imaging. 1624 67

The molecular mechanisms involved in neuronal/astroglial cell fate decisions during the development of the mammalian central nervous system are poorly understood. Here, we report that PRP19beta, a splice variant of mouse PRP19alpha corresponding to the yeast PRP19 protein, can function as a neuron-astroglial switch during the retinoic acid-primed neural differentiation of P19 cells. The beta-variant possesses an additional 19 amino acid residues in-frame in the N-terminal region of the alpha-variant. The forced expression of the alpha-variant RNA caused the down-regulation of oct-3/4 and nanog mRNA expression during the 12-48 h of the late-early stages of neural differentiation and was sufficient to convert P19 cells into neurons (but not glial cells) when the cells were cultured in aggregated form without retinoic acid. In contrast, the forced expression of the beta-variant RNA suppressed neuronal differentiation and conversely stimulated astroglial cell differentiation in retinoic acid-primed P19 cells. Based on yeast two-hybrid screening, cyclophilin A was identified as a specific binding partner of the beta-variant. Luciferase reporter assay mediated by the oct-3/4 promoter revealed that cyclophilin A could act as a transcriptional activator and that its activity was suppressed by the beta-variant, suggesting that cyclophilin A takes part in the induction of oct-3/4 gene expression, which might lead to neuroectodermal otx2 expression within 12 h of the immediate-early stages of retinoic acid-primed neural differentiation. These results show that the alpha-variant gene plays a pivotal role in neural differentiation and that the beta-variant participates in neuronal/astroglial cell fate decisions.
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PMID:Involvement of the mouse Prp19 gene in neuronal/astroglial cell fate decisions. 1635 98


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