Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The characteristics of 7 human melanoma cell lines were compared with those of the xenografts from which they were established. The ultrastructure, melanin content, isozyme pattern and chromosome numbers of the cell lines were closely similar to those of the corresponding xenografts. The different cell lines gave rise to colonies in soft agar of size and morphology similar to the parent xenografts, and the plating efficiencies were clearly correlated. However, no correlation was found between the growth rates in vivo and either the doubling times and saturation densities in monolayer cultures or the plating efficiencies in soft agar. Moreover, one of the cell lines lost its tumorigenic ability upon establishment in culture. Thus, although the properties of the cell lines by and large reflected those of the parent xenografts, important inconsistencies were seen. The data emphasize that extrapolations from continuous cell lines in vitro to tumour cells in vivo are not necessarily valid. A high content of cellular fibronectin was correlated with a compact colony morphology in soft agar and rapid attachment and spreading on plastic. The growth rates and cellular morphology of the cell lines were strongly influenced by TPA, DMSO, retinoic acid and theophylline, but not by alpha-melanocyte-stimulating hormone. A murine cell line established from one of the xenografts grew in soft agar and produced sarcoma in mice. The malignant murine cells had arisen by transformation of murine stromal cells during the first subcultures in vitro, possibly caused by a factor produced by the human melanoma cells.
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PMID:Do cell lines in vitro reflect the properties of the tumours of origin? A study of lines derived from human melanoma xenografts. 732 90

MTS1 is a metastasis-associated gene highly expressed in high-metastasis tumors. Here we show that the expression of the suppressor gene p53 protein correlates with mts1 expression. In murine melanoma B16-F1 cells, alpha-melanocyte-stimulating hormone up-regulated mts1 and increased p53 positivity in immunohistochemical tests. In B16-ML8 cells, retinoic acid reduced mts1 expression together with a reduction of p53 positivity. The variation of p53 in association with mts1 gene expression suggests that the mts1 product might interact with and stabilize p53. Taxol-induced aneuploidy increased the proportion of G0G1 phase cells, increased p53 positivity, and down-regulated mts1. This suggests that mts1 transcription may have been negatively regulated, possibly on account of the stabilization of microtubules by taxol. We postulate that the control of G1-S transition by p53 could be due to p53 sequestration by mts1, leading to microtubule depolymerization and signaling entry, into the S phase. Thus, a coordinated function of mts1 and p53 may be involved not only in uncontrolled growth but also in cytoskeletal depolymerization that could lead to cancer invasion.
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PMID:Metastasis-associated mts1 gene expression correlates with increased p53 detection in the B16 murine melanoma. 791 76

Topical all-trans retinoic acid (RA) modulates growth and differentiation of skin and is used in the treatment of various dermatological disorders. RA is metabolized to 4-hydroxy RA, 4-oxo RA and 5,6-epoxy RA, which are believed to be markedly less active than RA. 3,4-didehydroretinoic acid (ddRA) is a metabolite of 3,4-didehydroretinol which is present in skin. ddRA is biologically active and acts as a morphogen. We have determined the relative biological activity of ddRA, 4-hydroxy RA, 4-oxo RA and 5,6-epoxy RA as assessed by three retinoid responsive systems relevant to skin. RA, ddRA, 4-hydroxy RA, 4-oxo RA and 5,6-epoxy RA (10-100 nM) reduced epidermal transglutaminase activity in human keratinocytes to similar extents, and inhibited alpha-melanocyte-stimulating hormone-isobutylmethylxanthine-inducible tyrosinase activity in Cloudman S-91 mouse melanoma cells by 67, 39, 48, 51 and 19%, respectively, at 100 nM. Daily topical application of the retinoids to hairless mouse skin for 4 days resulted in dose-dependent changes in epidermal thickness and global histological score. The relative potencies of RA, ddRA, 4-hydroxy RA, 4-oxo RA and 5,6-epoxy RA, as calculated by parallel line assay, were 1.0, 0.60, 0.34, 0.29 and 0.18, respectively, for epidermal hyperplasia and 1.0, 0.78, 0.23, 0.14 and 0.08, respectively, for global histological score. Interestingly, the compounds exhibited a similar rank order of potency with respect to induction of cellular retinoic acid binding protein-II mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Retinoic acid metabolites exhibit biological activity in human keratinocytes, mouse melanoma cells and hairless mouse skin in vivo. 810 99

Specific high-affinity receptors for alpha-melanocyte-stimulating hormone (alpha-MSH) are found in variable abundance on many melanoma cell lines. We have examined melanocortin peptides and other factors for their ability to regulate the number of MSH receptors in eleven human and two mouse melanoma cell lines. MSH induced up-regulation of its own receptors in three human cell lines and down-regulation in six human and two mouse melanoma cell lines. No regulation was observed in two human lines. Scatchard analysis revealed modulation of the number of receptors per cell without any change in affinity. The concentrations inducing half-maximal response for up- and down-regulation were 1.6 nM and 0.23 nM, respectively. ACTH1-17 and [Nle4,D-Phe7]-alpha-MSH were more potent, whereas ACTH1-24, desacetyl-alpha-MSH, and [Nle4]-alpha-MSH were less potent in receptor up-regulation as compared to alpha-MSH. Down-regulation but not up-regulation could be fully mimicked by Gs-protein activation and partially by elevation of cellular cAMP. Combination of different agents which increase cAMP was found to be counterregulatory. TPA and retinoic acid generally down-regulated MSH receptors but had no effect on HBL cells. Several protein kinase inhibitors increased MSH binding in B16 cells. MSH-induced receptor down-regulation and melanin synthesis were most effectively antagonized by selective inhibitors of cAMP-dependent protein kinase in these cells. Taken together, MSH receptors on melanoma cells are both positively and negatively regulated. Whereas cAMP-dependent protein kinase activation seems to be involved in down-regulation, the mechanism responsible for up-regulation remains to be elucidated.
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PMID:Homologous and heterologous regulation of alpha-melanocyte-stimulating hormone receptors in human and mouse melanoma cell lines. 816 86

Neuroblastoma cell lines have been reported to contain two proopiomelanocortin (POMC) mRNA transcripts. We have now shown by immunocytochemistry and radioimmunoassay (RIA) that a number of neuroectodermally derived cell lines contain immunoreactive beta-endorphin although cell concentrations were not characteristic of any tumour type. To explore further the functional significance of beta-endorphin expression, we analysed neuroblastoma cell lines having intermediate (I), substrate adherent (S) and neuronal (N) phenotypes. No differences in cell beta-endorphin content were detected. However, the expression of POMC mRNA and of immunoreactive beta-endorphin was reduced within a few hours of treatment of these cell lines with retinoic acid. Culture of the cell lines in the presence of beta-endorphin resulted in small but significant increases in growth. Although the POMC gene is in the same chromosomal segment as N-myc, which is normally amplified in neuroblastoma, no corresponding amplification of POMC could be demonstrated. The data suggest that POMC gene products may contribute to the autocrine/paracrine growth of neuroectodermal tumours.
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PMID:Modulation of POMC expression in human neuroectodermal cells. 828 Jan 57

PO-B was originally characterized as a transcriptional regulatory factor of the pro-opiomelanocortin (POMC) gene; however, it has become increasingly clear that this protein may be active in tissues outside the pituitary, since it is present in diverse cell types, including differentiated HL-60 promyelocytic leukemia cells. We previously showed that PO-B DNA-binding is progressively induced during differentiation of promyelomonocytic leukemic HL-60 cells to the macrophage-like lineage (with phorbol esters). We now report that PO-B DNA-binding in HL-60 cells is similarly induced during differentiation to the granulocytic lineage (with either retinoic acid or dimethylsulfoxide). Either a genetic or pharmacologic blockade of HL-60 differentiation prohibited these inductive effects. These studies have prompted our interest in the dynamics of other transcription factor changes during HL-60 differentiation. Of these, we observed that another transcription factor (AP-1) is also robustly induced at the DNA-binding level during macrophage-like HL-60 differentiation, but not during granulocytic differentiation. Conversely, the DNA-binding of the transcription factor AP-2 was slightly reduced by TPA-induced HL-60 differentiation but unchanged during granulocyte differentiation. From these data, we conclude that the induction of PO-B DNA binding is a general marker of HL-60 myelomonocytic differentiation, but that qualitative aspects of the induction of additional distinct transcription factors, such as AP-1, may contribute to lineage-specific determinants of cell fate.
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PMID:Effects of TPA, bryostatin 1, and retinoic acid on PO-B, AP-1, and AP-2 DNA binding during HL-60 differentiation. 913 88

Retinoid X receptors (RXRs) are transcriptional factors that belong to the steroid/thyroid hormone receptor superfamily. There are 3 RXR isoforms-alpha, beta, gamma-known to bind 9-cis-retinoic acid as their ligand. The expression of RXRs in human pituitary glands and pituitary adenomas has not been extensively investigated. To determine whether specific RXR isoforms may play roles in the state of differentiation of pituitary adenomas, we have investigated the immunohistochemical expression of RXR alpha and RXR gamma in 6 nontumorous pituitaries and in 60 different pituitary adenomas using isoform-specific antibodies. In the nontumorous pituitaries. RXR alpha was expressed in the nuclei of almost all cells, while RXR gamma was only expressed in thyrotropin (TSH) cells and in some cells positive for growth hormone (GH) and glycoprotein alpha-subunit (alpha SU) but not in luteinizing hormone (LH) beta-subunit, follicle-stimulating hormone (FSH) beta-subunit, prolactin (PRL) or adrenocorticotropin (ACTH) cells by double immunostaining. All 60 adenomas were RXR alpha positive, and 39 of 60 adenomas (65%) were positive for RXR gamma. The incidence of RXR gamma immunoreactivity in the different adenoma types was: 13 of 16 GH-producing adenomas (81.3%), 9 of 14 PRL-secreting adenomas (64.3%), 6 of 6 TSH-secreting adenomas (100%), 2 of 5 ACTH-secreting adenomas (40%) and 9 of 19 nonfunctioning adenomas (47.4%) including immunohistochemically gonadotropin-subunit-positive adenomas. The colocalization of RXR gamma with the TSH beta subunit, GH and alpha SU in the same adenoma cells was frequently observed, and sometimes RXR gamma was colocalized with PRL, ACTH, FSH beta or LH beta as shown by double immunostaining. We conclude that RXR alpha is expressed in both human pituitaries and pituitary adenomas. In contrast, RXR gamma is expressed more broadly in pituitary adenomas than in normal pituitaries and thus may play a role in the differentiation-specific cell types in the human pituitary both under physiological and pathological conditions.
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PMID:Immunohistochemical expression of retinoid X receptor isoforms in human pituitaries and pituitary adenomas. 914 2

Cushing syndrome is caused by an excess of adrenocorticotropic hormone (ACTH) production by neuroendocrine tumors, which subsequently results in chronic glucocorticoid excess. We found that retinoic acid inhibits the transcriptional activity of AP-1 and the orphan receptors Nur77 and Nurr1 in ACTH-secreting tumor cells. Retinoic acid treatment resulted in reduced pro-opiomelanocortin transcription and ACTH production. ACTH inhibition was also observed in human pituitary ACTH-secreting tumor cells and a small-cell lung cancer cell line, but not in normal cells. This correlated with the expression of the orphan receptor COUP-TFI, which was found in normal corticotrophs but not in pituitary Cushing tumors. COUP-TFI expression in ACTH-secreting tumor cells blocked retinoic acid action. Retinoic acid also inhibited cell proliferation and, after prolonged treatment, increased caspase-3 activity and induced cell death in ACTH-secreting cells. In adrenal cortex cells, retinoic acid inhibited corticosterone production and cell proliferation. The antiproliferative action and the inhibition of ACTH and corticosterone produced by retinoic acid were confirmed in vivo in experimental ACTH-secreting tumors in nude mice. Thus, we conclude that the effects of retinoic acid combine in vivo to reverse the endocrine alterations and symptoms observed in experimental Cushing syndrome.
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PMID:Retinoic acid prevents experimental Cushing syndrome. 1160 19

Neuroblastoma is predominantly a paediatric neoplasm of the sympathetic nervous system. Despite the aggressive nature of the disease, spontaneous regression is frequently observed in infants diagnosed under the age of 12 months; especially with a specific stage referred to as stage 4s. Discovering the conditions, the elements, the mechanism and the indices behind this regression phenomenon could have therapeutic potential for prevention and cure. A review of the literature has implicated adrenocorticotropin hormone in both the aetiology and spontaneous regression of neuroblastoma. Manipulation of adrenocorticotropin hormone may offer hope for prevention and cure. Ingestible products such as retinoic acid, glycyrrhizic acid, salsolinol and ketoconazole acting in concert, could represent instrumental tools in a therapeutic manipulation process.
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PMID:Adrenocorticotropic hormone in the aetiology and regression of neuroblastoma. 1220 96

The successful treatment of Cushing syndrome depends on specific therapy directed against the etiology of hypercortisolism. In addition to surgical procedures, various drugs have been employed in the management of this difficult disease. Compounds with neuromodulatory properties have been effective in only a limited number of cases of hypothalamic-pituitary-dependent Cushing disease, the most common form of Cushing syndrome. These agents include serotonin antagonists (cyproheptadine, ketanserin, ritanserin), dopamine agonists (bromocriptine, cabergoline), GABA agonists (valproic acid [sodium valproate]), and somatostatin analogs (octreotide). Interesting new avenues at the pituitary level involve the potential use of thiazolidinedione compounds, such as rosiglitazone, and of retinoic acid, which are ligands of different nuclear hormone receptors involved in hypothalamic-pituitary regulation. The most exciting news, however, in the pharmacologic approach to Cushing syndrome refers to the adrenal corticotropin (adrenocorticotropic hormone; ACTH)-independent forms, in which aberrant adrenal receptors, through the binding of their respective ligands, could lead to chronic cortisol overproduction. They include receptors for gastric inhibitory peptide (GIP), beta-adrenergic agonists, luteinizing hormone (LH)/human chorionic gonadotropin, serotonin (5-HT(4) receptor), vasopressin (V(1) receptor), and angiotensin II (AT(1) receptor). In GIP-dependent Cushing syndrome, the most frequent subtype of ACTH-independent macronodular adrenal hyperplasia associated with the presence of aberrant adrenocortical hormone receptors described so far, octreotide administration before each meal showed clinical efficacy only in the first few months, probably because of somatostatin receptor downregulation in GIP-secreting cells. Long-term medical treatments with propranolol and the gonadotropin-releasing hormone analog leuprorelin (leuprolide acetate) were effective in patients with catecholamine-dependent and LH-dependent Cushing syndrome, respectively. The oral vasopressin V(1) receptor antagonist OPC-21268 and the angiotensin II (AT(1)) receptor antagonist candesartan cilexetil were also able to decrease cortisol levels during the few days of administration of the drugs in patients with specific receptor abnormalities. These adrenal forms of Cushing syndrome are rare, and clinical data are scarce. Moreover, the real clinical significance of aberrant hormone receptors is still under investigation, as is the possibility of avoiding surgery by pharmacologic manipulation. Patients in whom these intriguing syndromes are suspected require detailed investigation protocols, which should be carried out in specialized centers. While awaiting further developments, the use of traditional medical treatment at the adrenal level with adrenal steroid inhibitors is still valuable in several instances.
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PMID:Pharmacologic management of Cushing syndrome : new targets for therapy. 1578 46


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