Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Extracts prepared from several lines of transformed cells were examined for the presence of cellular binding proteins specific for retinoids. Extracts of human retinoblastoma cell line WERI-Rb1 contained a cellular binding protein specific for retinoic acid, whereas extracts of human retinoblastoma cell line Y-79 contained cellular binding proteins for both retinol and retinoic acid. Upon purification, the latter two binding proteins proved to have properties similar to those of the corresponding proteins obtained from bovine retina. Smaller amounts of these binding proteins were detected in extracts of undifferentiated and differentiated neuroblastoma and McCoy cells. HeLa and rat glioma cells had no detectable amount of binding proteins. The 11-cis-retinal-binding protein, present in extracts of human, rat, and bovine retina, was not found in any of the cell lines examined.
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PMID:Cellular retinol- and retinoic acid-binding proteins in transformed mammalian cells. 56 21

A method for saturation analysis of cellular retinoic acid and retinol binding proteins, CRABP and CRBP, respectively, in cultured cells and human tumor samples, and its application to a retinoic acid resistant subline of the human neuroblastoma LA-N-5 cell line is described. Assessment of retinoid binding was accomplished by incubation of cytosols with increasing concentrations of [3H]retinoid (28-43 Ci/mmol; 1 Ci = 37 GBq) for 24 h. Bound retinoid was separated from free retinoid by adsorption with dextran-coated charcoal. Nonspecific binding was quantitated in parallel incubations which had been treated with p-chloromercuribenzene sulfonate (PCMBS), resulting in selective elimination of sulfhydryl-dependent ligand binding to both CRABP and CRBP. Quantitation was accomplished by Scatchard analysis of specific (PCMBS sensitive) binding. Employing this technique, specific retinoid binding was attributed to the presence of 2S macromolecules which displayed the known properties of CRABP and CRBP, namely ligand specificity, saturability, high ligand affinity, and PCMBS sensitivity. The apparent dissociation constants (Kd) for retinoic acid binding in cytosols prepared from murine 3T6 fibroblasts, rat testes, and a human ovarian tumor were 7, 11, and 35 nM, respectively. These preparations also bound retinol with high affinity, exhibiting Kds of 12, 26, and 48 nM, respectively. A retinoic acid resistant subline of LA-N-5 cells designated LA-N-5-R9 was established by long-term culture in the presence of 10(-6) M retinoic acid. This subline is resistant to the effects of retinoic acid in that it requires a 10-fold higher concentration of retinoic acid for 50% inhibition of growth than the parent line and displays no retinoic acid induced morphologic differentiation. Saturation analysis of CRABP in the parent and resistant subline reveal no significant alteration in either CRABP content or affinity. These results indicate that resistance to retinoic acid induced differentiation in LA-N-5-R9 occurs distal to CRABP binding or that CRABP does not mediate this response to retinoic acid.
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PMID:Saturation analysis of cellular retinoid binding proteins: application to retinoic acid resistant human neuroblastoma cells and to human tumors. 303 Mar 71

Although the mechanism whereby vitamin A mediates normal cell differentiation and inhibits tumor cell proliferation is unknown, intracellular receptor-like proteins for retinol and retinoic acid have been implicated in the molecular action of vitamin A. We have assayed these two binding proteins, cellular retinol binding protein (protein R) and cellular retinoic acid binding protein (protein RA), in the cytosolic fraction of various normal and tumor cells via sucrose density gradient centrifugation and saturation analysis. Employing charcoal separation of bound and free tritiated retinoid, the saturation analysis yields an approximate Kd for ligand binding and an estimate of the number of protein R and protein RA molecules per cell. Unique protein R and protein RA macromolecules sedimenting at 2 S with Kd values of 7-42 nM are detected in murine cells (1 degree epidermal, 3T6 fibroblasts and melanoma) and human neuroblastoma cells. Concentrations of the intracellular binding proteins range from 55 000 to 3 000 000 copies per cell. When one cell line (C-127 mouse mammary) is transformed by bovine papilloma virus, protein RA levels increase from undetectable to 193 000 copies per cell. Assessment of growth inhibition by 10(-6) M retinol or retinoic acid in the culture medium reveals that there exists a partial, but not absolute, correlation between the presence of protein R or protein RA and the antiproliferative effect of the particular retinoid in the tested cell lines. We conclude that the 2 S intracellular binding proteins for the retinoids are present in most vitamin A responsive cells, but may not be essential for biologic actions of the vitamin such as growth inhibition in monolayer culture.
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PMID:Identification and quantitation of intracellular retinol and retinoic acid binding proteins in cultured cells. 632 Sep 9

The antineoplastic effects of a novel retinoid derivative E5166 on cultured human neuroblastoma, GOTO cells, were investigated. E5166, as well as retinoic acid and retinol, suppressed the proliferation of GOTO cells and the synthesis of DNA, RNA and protein; the inhibitory potency of E5166 was not stronger than that of the natural vitamin A derivatives. E5166 also inhibited amino acid transport, but was found to stimulate sugar transport in the neuroblastoma cells.
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PMID:Effect of polyprenoic acid (E5166) on a human neuroblastoma cell line in culture. 649 54

Competition of all-trans-retinol and all-trans-retinaldehyde with 3H-labeled all-trans-retinoic acid (RA) for binding to retinoic acid receptors (RARs) was examined in human neuroblastoma cell nuclear extracts. All-trans-retinol was 35-fold less potent than all-trans-RA, whereas all-trans-retinaldehyde was 500-fold less active in binding to the nuclear receptors. To confirm that all-trans-retinol binds to RARs, experiments were carried out with RARs alpha, beta, and gamma expressed as bacterial fusion proteins. All-trans-retinol was only 4- to 7-fold less potent than all-trans-RA in binding to all three RAR subtypes. The all-trans-retinol binding observed was not the result of metabolism of retinol to RA or some other active compound during the binding experiment. Retinyl acetate was virtually inactive in competition binding experiments, while very slight activity was observed with 13-cis-RA and all-trans-retinaldehyde. Significant competition occurred with 4-hydroxy-RA and 4-keto-RA, which were 15- to 40-fold less potent than all-trans-RA. The 9-cis isomer of RA was equipotent with all-trans-retinol in these studies. These results suggest that all-trans-retinol cannot be excluded as a physiologically significant ligand for RAR-mediated gene expression.
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PMID:All-trans-retinol is a ligand for the retinoic acid receptors. 839 16

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.
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PMID:Retinoic acid synthesis in normal and Alzheimer diseased brain and human neural cells. 916 89

Vitamin A and its derivatives (retinoids) have profound effects on the proliferation and differentiation of many cell types and are involved in a diverse array of developmental and physiological regulatory processes, including those responsible for the development of the mature nervous system. Retinoid signals are mediated by retinoic acid (RA) receptors (RARs) and retinoid X receptors (RXRs), which show distinct spatio-temporal patterns of expression during development and in adult tissues. We have used SK-N-BE2(c) neuroblastoma cells to study the effects of reciprocal regulation of expression of various RARs. We show that in these cells RARgamma1 acts as a repressor of RARbeta2 transcription in the absence of an agonist. In the presence of RA, the expression of RARgamma1 is reduced and that of RARbeta2 is induced. Overexpression of RARgamma1 neutralizes the effects of RA on RARbeta induction. Expression of an RARgamma1-specific antisense construct leads to the constitutive expression of RARbeta2. Although both overexpression of RARgamma1 and its reduction of expression can result in inhibition of cell proliferation, they induce different morphological changes. Reduction of RARgamma1 (and induction of RARbeta) leads to increased apoptosis, whereas RARgamma1 overexpression leads to differentiation in the absence of apoptosis. Thus, RARgamma1 appears to control a differentiation-apoptosis switch in SK-N-BE2(c) neuroblastoma cells.
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PMID:Retinoic acid receptor gamma1 (RARgamma1) levels control RARbeta2 expression in SK-N-BE2(c) neuroblastoma cells and regulate a differentiation-apoptosis switch. 977 64

The mechanism of the fetal embryopathology resulting from ethanol ingestion during pregnancy is not established. This review summarizes recent research on the interaction of ethanol and vitamin A in models that explore if an interaction between these two compounds might potentially be the mechanism for fetal alcohol syndrome. The rationale for this hypothesis includes the known facts that: (1) in adults, ethanol ingestion alters vitamin A metabolism and tissue distribution; (2) there are many phenotypic similarities between fetal alcohol syndrome and malformations of both vitamin A toxicity and deficiency; and (3) the vitamin A metabolite, retinoic acid (RA), is a potent mediator in embryogenesis and differentiation. One interaction that could possibly alter fetal development is that the synthesis of RA from retinol, catalyzed by alcohol dehydrogenase, might be competitively inhibited by ethanol leading to RA deficiency. Controversy over this hypothesis continues. Another model demonstrates in vivo effects of pregnant rat mother's ethanol consumption on retinol, retinyl ester, RA content, RA receptor (RAR) binding, and the levels of RAR expression in developing fetal organs. The variable responses in this model still need clarification, and specific defects resulting from specific RAR changes have not yet been identified. In a quail embryo model, ethanol treatment mimics vitamin A deficiency, and RA appears to prevent the adverse effects of ethanol. Finally, RA and ethanol reverse or block each other's effects in studies on isolated neuroblastoma cells. Taken together, these experiments show definite interactions between ethanol and vitamin A. Further studies are needed to determine if any of these mechanisms significantly contribute to prenatal ethanol consumption embryopathy; but, clearly this hypothesis is gaining experimental support.
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PMID:The interaction of ethanol and vitamin A as a potential mechanism for the pathogenesis of Fetal Alcohol syndrome. 980 41

Vitamin A, its physiologic metabolites, and synthetic derivatives (retinoids) have been shown to have protective effects against the development of certain types of cancer. In addition, pharmacologic amounts of retinoids have been used with some success in the treatment of a few human tumors. The chemoprevention effect of retinoids is most likely exerted at the tumor-promotion phase of carcinogenesis. Retinoids block tumor promotion by inhibiting proliferation, inducing apoptosis, inducing differentiation, or a combination of these actions. Clinically, isotretinoin (13-cis-retinoic acid) significantly decreases the incidence of second primary tumors in patients with head-and-neck cancer and reduces appearance of non-melanoma skin cancer in patients with xeroderma pigmentosum. Retinoic acid has proved to be an effective treatment for promyelocytic leukemia. However, retinoid resistance limits its use as a single agent. Clinical trials are in progress to determine the efficacy of retinoids in treating other types of cancer such as neuroblastoma and breast carcinoma. The development of receptor-selective retinoids and selective inhibitors of retinoid metabolism may lead to further use of retinoids in both chemoprevention and treatment of cancer.
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PMID:Recent advances in the use of vitamin A (retinoids) in the prevention and treatment of cancer. 1111 36

Fetal ethanol exposure has many detrimental effects on neural development, which possibly occurs through ethanol-induced disruption of the function of vitamin A. In LAN-5 neuroblastoma cells, retinol (10(-6) M) and retinoic acid (RA; 10(-5)-10(-6) M) increased RAR beta mRNA expression. Ethanol downregulated RAR beta levels, even in the presence of retinol. RAR beta mRNA expression was decreased by ethanol in the presence of 10(-6) M RA, but not 10(-5) M RA. With cycloheximide (CX), RA still stimulated RAR beta mRNA, but the effect of ethanol was abolished. The mRNA expression of GAP-43, an important factor in neural development, increased with 10(-6) M retinol and 10(-5)-10(-9) M RA. Ethanol decreased GAP-43 mRNA expression in the presence or absence of retinol. Ethanol was without effect on GAP-43 mRNA at 10(-5) M RA, but did lower the levels at 10(-6) and 10(-7) M RA. CX prevented the effects of both RA and ethanol on GAP-43 mRNA. These studies provide support for the hypothesis that retinoid function is altered by ethanol.
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PMID:Interaction of ethanol with retinol and retinoic acid in RAR beta and GAP-43 expression. 1112 Mar 88


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