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Query: UNIPROT:P06889 (Mol)
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Vitamin A and other fat-soluble hormones and vitamins have important roles as modulators of essential biological processes such as homeostasis, development, differentiation, and oncogenesis and also as regulators of the immune system. The active form of vitamin A, retinoic acid, as well as vitamin D3 and thyroid hormones exert their actions by binding to specific nuclear receptors that represent one subfamily of the steroid/thyroid hormone receptor superfamily. To identify new members of the retinoid/thyroid hormone receptor subfamily that could play a role in the immune system, a screening of a T cell cDNA library was performed using a retinoid X receptor probe. A clone was isolated encoding a novel nuclear receptor expressed mainly in the thymus and T cell lines. This new receptor, TOR (thymus orphan receptor), is most closely related in both its DNA-binding domain and ligand-binding domain, 90% and 53%, respectively, to ROR alpha/RZR alpha and clusters with these two receptors and RZR beta in a phylogenetic tree, when both the DNA-binding domain and the ligand-binding domain sequences of nuclear receptors are compared. Thus, TOR is part of a subgroup of receptors, one of which has recently been reported to be activated by melatonin. TOR binds specifically to a direct repeat of the half-site sequence 5'-AGGTCA-3' with a four- or five-nucleotide spacer, DNA sequences that also serve as binding sites for thyroid hormone (TR), and retinoic acid receptors (RAR). In transient transfection experiments TOR does not activate a reporter gene carrying these sequences in the absence or the presence of any known nuclear receptor ligands. TOR, however, is able to repress TR and RAR activity on DR-4-TREs or DR-5-RAREs, respectively. Therefore, our data suggest that TOR, similar to COUP-TF, can negatively regulate retinoic acid and thyroid hormone signals. However, the response elements recognized by TOR and COUP-TF differ as do the expression patterns of these receptors. Thus, one important role of TOR could be to modulate retinoid and thyroid hormone signals in the thymus.
Mol Endocrinol 1995 Dec
PMID:TOR: a new orphan receptor expressed in the thymus that can modulate retinoid and thyroid hormone signals. 861 4

Interactions between vitamin A and vitamin E in suppressing lipid peroxidation were observed in bovine retinal membrane preparations submitted to peroxidative injury by the water soluble azo initiator 2,2'-azobis(2-amidino-propane) hydrochloride (AAPH). Incorporation of 0.75 nmol mg prot(-1) all-trans retinol, an amount comparable with that of the endogenous alpha-tocopherol, significantly elongated the induction time preceding the release of TBA-reactive lipid peroxidation products, and reduced the consumption rate of the endogenous alpha-tocopherol. On the other hand, all-trans retinol was not able to induce any delay to the onset of lipid peroxidation when incorporated in membranes deprived of endogenous alpha-tocopherol by exposure to UV light, although TBARS produced within 60 min decreased slightly. Consumption of all-trans retinol during peroxidation was more rapid when all-trans retinol was incorporated in membranes deprived of alpha-tocopherol than in native membranes. These data suggest that reciprocal protective effects between vitamin A and vitamin E may strongly contribute to the defence of membranes against oxidative stress.
Biochem Mol Biol Int 1995 Sep
PMID:Reciprocal protective effects of all-trans retinol and alpha-tocopherol during lipid peroxidation in retinal membranes. 865 70

In the present study it was investigated if Vitamin A supplementation could protect rat kidney microsomes and mitochondria from in vitro lipoperoxidation. After incubation of rat kidney microsomes and mitochondria in an ascorbate-Fe+2 system, at 37 degrees C during 60 min, it was observed that the total cpm/mg protein originated from light emission (chemiluminescence) was lower in those organelles obtained from the control group when compared with the vitamin A supplemented group. The fatty acid composition of microsomes and mitochondria from control group was profoundly modified when subjected to non-enzymatic lipoperoxidation with a considerable decrease of arachidonic acid, C20:4 (n-6) and docosapentaenoic acid, C22:5 (n-3) in mitochondria and docosahexaenoic acid C22:6 (n-3) in microsomes. As a consequence the peroxidizability index, a parameter based on the maximal rate of oxidation of specific fatty acids was higher in the supplemented animals than in those used as control. These results indicate that Vitamin A may act as antioxidant protecting rat kidney microsomes and mitochondria from deleterious effect.
Mol Cell Biochem 1996 Dec 20
PMID:Vitamin A inhibits lipoperoxidation ascorbate-Fe++ dependent of rat kidney microsomes and mitochondria. 897 60

Several retinoids, both natural and synthetic, were evaluated for their ability to modulate NADH oxidase activity of plasma membranes of cultured HeLa cells and the growth of HeLa cells in culture. Both NADH oxidase activity and the growth of cells were inhibited by the naturally-occurring retinoids all trans-retinoic acid (tretinoin) and retinol as well as by the synthetic retinoids, trans-acitretin, 13-cis-acitretin, etretinate and arotonoid ethylester (Ro 13-6298). For all retinoids tested, inhibition of NADH oxidase activity and inhibition of growth were correlated closely. With tretinoin, etretinate and arotonoid ethylester, NADH oxidase activity and cell growth were inhibited in parallel in proportion to the logarithm of retinoid concentration over the range of concentrations 10(-8) to 10(-5) M. Approximately 70% inhibition of both NADH oxidase activity and growth was reached at 10 microM. With retinol, trans-acitretin and 13-cis-acitretin, inhibition of NADH oxidase activity and growth also were correlated but maximum inhibition of both was about 40% at 10 microM. The possibility is suggested that inhibition of the plasma membrane NADH oxidase activity by retinoids may be related to their mechanism of inhibition of growth of HeLa cells in culture.
Mol Cell Biochem 1997 Jan
PMID:Inhibition of plasma membrane NADH oxidase activity and growth of HeLa cells by natural and synthetic retinoids. 904 26

Molecular mechanisms of lipid synthesis and their controls in hepatic stellate cells are not known. We have previously proposed that, in contrast to other fat storing cells, hepatic stellate cells are not involved in energy storage, but they represent a particular cell population specialized in storage of lipid-soluble substances, the major one being probably retinol. In agreement with this hypothesis, induction of the lipocyte phenotype in stellate cells is not under the control of insulin, but responds to retinoids and other molecules that modify the gene expression program in these cells. In the present study we have monitored the activity of the two major enzymes involved in lipid synthesis during the induction of the lipocyte phenotype in hepatic stellate cells: glycerol-3-phosphate dehydrogenase (GPDH) that mediates the de novo lipid synthesis, and lipoprotein lipase that mediates incorporation of plasma lipids. In early stages of lipocyte induction, both pathways of lipid synthesis are activated. When lipocytes have already constituted the lipid droplets, lipoprotein lipase pathway is downregulated, while GPDH activity remains high. Adult liver has been reported to lack lipoprotein lipase, but under stress, lipase activity was detected around and at the surface of the intrahepatic vasculature. We have now shown that the lipase activity can be induced in the hepatic stellate cells, located in the Disse's space. The high lipoprotein lipase activity under acute induction of lipocyte phenotype, followed by the low activity under conditions of metabolic equilibrium, are in compass with the increased activity of this enzyme under stress, and its low activity in adult liver parenchyma under normal conditions.
Mol Cell Biochem 1997 Mar
PMID:Lipid metabolism during in vitro induction of the lipocyte phenotype in hepatic stellate cells. 906 91

Concentrations of vitamins A1 (retinol), A2 (3,4-didehydroretinol) and E (alpha-tocopherol) in the liver and blubber of ringed seals from Lake Saimaa (Phoca hispida saimensis), Lake Ladoga (P. h. ladogensis), the Baltic Sea (P. h. botnica) and Spitsbergen (P. h. hispida) were determined by high-performance liquid chromatography. The freshwater seals had much lower levels of vitamin A1 but higher levels of vitamin A2 than the marine seals. The concentrations of vitamin E in the livers of the subspecies studied were high compared with earlier reports of seals, but the ranges were large. The livers of the marine seals contained more vitamin E than the livers of the freshwater seals, but the levels in the blubber were uniform in all populations, except in old specimens from the Baltic. The differences between the freshwater and marine seals are suggested to be due mainly to diet. The ratios of A1 to A2 in the liver and blubber and in the fish diet were similar for the marine seals and for the freshwater seals (but differed in the marine and freshwater populations), which suggests no great differences in the absorption, transport and metabolism of the two analogues. Blubber was an important storage site for the vitamins studied, and age-dependent increases were detected, especially for vitamin E. In the 2-month to 2-year-old ringed seals of Lake Saimaa, however, the vitamin E concentration in the blubber was not affected by age.
Comp Biochem Physiol B Biochem Mol Biol 1997 Jan
PMID:Vitamins A1 (retinol), A2 (3,4-didehydroretinol) and E (alpha-tocopherol) in the liver and blubber of lacustrine and marine ringed seals (Phoca hispida sp.). 908 Jun 60

Retinol binding protein prepared from human urine was fractionated by chromatofocusing into four isoforms: two retinol-containing (holo-) and two retinol-free (apo-) species. The pl values of the isoforms ascertained by isoelectrofocusing with an immobiline pH gradient were: holo(I) 4.79-4.77; apo(II) 4.61-4.56; holo(III) 4.63 and apo(IV) 4.46-4.41. In vitro aging experiments with apo(II) under conditions favoring deamidation (37 degrees C, pH 7-10, 3-28 days) resulted in formation of the more acidic apo(IV)-isoform. The aging rate was consistent with pH increase. It appears that the urinary RBP mixture is composed of two apo-holo pairs: a native form with genuine protein structure and an acidic form generated upon aging.
Biochem Mol Biol Int 1997 Apr
PMID:Isolation and characterization of isoforms of retinol binding protein by isoelectrofocusing. 913 38

Retinoids play fundamental roles in CNS development, but their distribution, metabolism, and function within the mature human CNS are unknown. In these studies, extracts of autopsy tissues recovered from histopathologically confirmed control and Alzheimer diseased brains were tested for their ability to synthesize retinoic acid. Retinaldehyde dehydrogenase (RLDH), the enzyme that forms retinoic acid from retinaldehyde, was present in hippocampus, frontal cortex, and parietal cortex. The RLDH activity of hippocampus and parietal cortex from Alzheimer diseased brains was 1.5- to 2-fold higher (p < 0.05) compared to the controls. In contrast, the RLDH activity of frontal cortex was the same for both Alzheimer diseased and control groups. A cultured human glioblastoma (U251) and neuroblastoma (LA-N-5) cell line synthesized retinoic acid from retinaldehyde or retinol, suggesting that a variety of neural cell types possess this activity. LA-N-5 cells grown in vitamin A-depleted medium had higher (p < 0.05) RLDH activity (0.35 +/- 0.04 nmol/mg/h) than LA-N-5 cells grown in vitamin A-replete media (0.15 +/- 0.02 nmol/mg/h). This difference was lost when retinol was added back to the medium, confirming that a reduction in vitamin A supply can induce RLDH activity in neural cells. However, this feedback mechanism does not appear to explain the higher RLDH activity of Alzheimer diseased hippocampus and parietal cortex, because the overall vitamin A status as indicated by serum retinol and carotenoid levels and by hippocampal retinoid content was similar for the Alzheimer diseased and control groups. These studies establish the presence of retinoids and RLDH activity in human brain tissues, and indicate that retinoic acid synthesis is modulated in some regions of Alzheimer diseased brain.
Mol Chem Neuropathol 1997 Apr
PMID:Retinoic acid synthesis in normal and Alzheimer diseased brain and human neural cells. 916 89

In order to understand the mechanisms of retinol action on the testis, testicular retinoic acid receptor alpha, beta(RAR alpha and beta), androgen receptor (AR) and inhibin alpha-subunit were studied in normal, vitamin A-deficient (VAD) and vitamin A-supplemented rats by immunohistochemistry and immunoblotting. Compared to the normal testis, expression of 110 K AR was up-regulated by vitamin A withdrawal, whereas 51 K RAR alpha remained unchanged. An additional 55 K RAR alpha signal was observed. Readministration of retinol caused a marked decrease of AR in the VAD testis. By 24 h, AR declined to below the normal level. Although the 51 K RAR alpha signal remained unchanged, the 55 K band was slightly up-regulated at 6 h after retinol administration. A 51 K RAR beta protein was seen in the VAD but in not the normal testis. The intensity of the 51 K RAR beta band remained constant before and after the administration of retinol, but it had a slight up-shift at 6 h after retinol injection, suggesting post-translational modification of the receptor. The inhibin alpha-subunit of 18 K protein was undetectable in the VAD testis and increased to above normal level at 24 h after retinol administration. Immunohistochemically, nuclear AR immunostaining was more intense in the VAD testis than in the normal testis. The intensity of immunostaining declined in all AR-positive cells after the injection of retinol, but the decrease was more evident in Sertoli than in other cells. At 24 h after retinol the immunostaining was undetectable in most Sertoli cells. The regulation of the inhibin alpha-subunit by retinol in the cytoplasm of Sertoli cells detected by immunohistochemistry was correlated to the results in immunoblotting. These results suggest a possible interplay between retinoids, androgen and inhibin signalling systems in Sertoli cells in the regulation of spermatogenesis during retinol action.
J Steroid Biochem Mol Biol 1997 Jan
PMID:Spermatogenesis in the vitamin A-deficient rat: possible interplay between retinoic acid receptors, androgen receptor and inhibin alpha-subunit. 918 60

The retinoic acid (RA) signaling pathway was investigated by transient transfection of a chloramphenicol acetyltransferase (CAT) reporter gene construct containing the RA response element (RARE) of the murine (m) RARbeta2 gene into murine primary epidermal keratinocytes (PEK), papilloma-derived SP1 cells, and carcinoma-derived 3P2 cells. Murine PEK transfected in a low-Ca2+ medium (0.05 mM Ca2+) exhibited a strong transactivation of the CATgene after exposure of the cells to 0.1 microM RA. Transactivation of the CATgene could, however, also be achieved by shifting RAREbeta2-transfected low-Ca2+ PEK to high-Ca2+ conditions (0.15-1.2 mM Ca2+). Concomitantly, the Ca2+ raise also led to the induction of both cellular retinol (ROL)-binding protein I (CRBPI) and cellular RA-binding protein II (CRABPII), whereas expression of cellular RA-binding protein I (CRABPI) was not observed. Moreover, induction of in vitro differentiation also activated the ROL-->RA converting enzyme system in PEK. These findings suggest the following sequence of events involved in the high Ca2+-mediated activation of RAREbeta2. First, high Ca2+ induces the synthesis of mCRBPI, which binds ROL released from retinyl ester stores and makes it accessible to the ROL-RA converting enzyme system. Enzymatically generated RA is taken over by mCRABPII and transported to the nucleus, where it acts as ligand for nuclear receptors, which complex with RAREbeta2 to activate the reporter gene. This hypothetical cascade of RA signaling was supported by our findings that inhibition of the ROL-->RA converting enzyme system by citral abolished the Ca2+-mediated transactivation of the CAT gene in a nontoxic manner. Studies in transformed murine cell lines revealed that Ca2+-induced activation of RAREbeta2 was essentially maintained in papilloma-derived SP1 cells, although all parameters of the Ca2+-dependent RAREbeta2 activation cascade were induced to a much lower extent. In contrast, strong RAREbeta2 activity was already observed in low-Ca2+ carcinoma-derived 3P2 cells. Low-Ca2+ 3P2 cells also expressed high levels of both mCRBPI and mCRABPII and possessed a highly active ROL-->RA converting enzyme system. Again, inhibition of the enzyme by citral abolished RAREbeta2 activity in low-Ca2+ 3P2 cells. Our data show that Ca2+-induced differentiation in cultured murine PEK entails a series of events that ultimately lead to the activation of RARE-containing genes. These properties are maintained in transformed epidermal keratinocytes. However, with increasing malignant potential of the cells, the respective signaling pathway becomes independent from a differentiation stimulus and leads to constitutive activation of RARE-controlled genes.
Mol Carcinog 1997 Sep
PMID:Retinoic acid signaling cascade in differentiating murine epidermal keratinocytes: alterations in papilloma- and carcinoma-derived cell lines. 932 36


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