Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Retinoic acid treatment of B16 mouse melanoma cells induces a differentiated phenotype. This is accompanied by a decrease in monolayer growth rate, loss of the ability to form colonies in soft agarose, increased production of melanin and other melanocyte-specific markers. In addition, retinoic acid treatment of these cells decreases their tumorigenicity when injected subcutaneously into mice. Our laboratory has found that an early biochemical change after the addition of retinoic acid is a large increase in PKC. PKC is an enzyme whose activity is activated by diacylglycerol and calcium and has been shown to be an important mediator of substances that stimulate growth or differentiation. Since PKC is a multi-gene family, it was important for us to determine which isotype(s) was expressed in B16 cells and which type was induced by retinoic acid. We found that only PKC-alpha is expressed in these cells, and this is the form that is induced by retinoic acid. The retinoic acid-induced increased in PKC-alpha is found at both the RNA and protein level. The mechanism of induction is not yet clear since there is only a small increase in the transcription rate and no change in the stability of the mRNA for PKC-alpha in treated cells. In addition, the induction of PKC by retinoic acid can be blocked by inhibitors of protein synthesis, suggesting that the induction requires the synthesis of new protein(s). In order to determine the role of increased PKC-alpha in the retinoic acid-induced differentiation, we transfected full-length PKC-alpha cDNA in mammalian expression vectors into B16 cells. Two clones that stably overexpressed PKC-alpha to different levels were isolated. The phenotype of these clones resembled WT cells treated with retinoic acid, i.e. they had longer doubling times, decreased ability to form colonies in soft agar, increased melanin production, and decreased tumorigenicity in mice. Recent data suggest a role for the RAR-beta in mediating the effect of retinoic acid on PKC induction. B16 cells express a very low amount of RAR-beta mRNA. The level is increased drastically by retinoic acid treatment without any requirement for protein synthesis. When B16 cells were transfected with and overexpressed RAR-beta, they also expressed more PKC-alpha mRNA and protein, and the induction of PKC by retinoic acid was not blocked by protein synthesis inhibitors. In summary, these finding suggest a key role for PKC-alpha in the pathway by which retinoic acid induces B16 mouse melanoma differentiation.
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PMID:Interactions between retinoic acid and protein kinase C in induction of melanoma differentiation. 806 88

Melanoma cell invasion in vitro was tested by means of confrontation cultures of melanoma multicellular spheroids with rounded fragments of embryonic chick heart tissue. Quantitative determination of invasion was performed using a computerized image analysis program, facilitating the evaluation of the efficacy of potentially anti-invasive compounds. Retinoic acid (RA; 1 microM) [corrected] considerably impaired K1735-M2 melanoma cell invasion, as demonstrated by various measuring parameters. Parameter TUMAREA, expressing the amount of tumor tissue, indicates a growth inhibitory effect and the invasion parameter STRCSTR shows that after treatment with RA the stromal component was better preserved than in untreated controls. Besides the inhibitory effect of RA on melanoma cell invasion in confrontation cultures, RA increased the dynamics of adhesion of melanoma cells to the extracellular matrix components type I collagen and laminin, and slightly impaired melanoma cell directional migration. Fluorescence microscopy using rhodamine-labeled phalloidin showed that RA also modulated the organization of the actin cytoskeleton by inducing the formation of actin-containing stress fibers. Our data show that 1 microM RA exhibited a pronounced anti-invasive effect on highly metastatic melanoma cells in vitro. Impairment of host tissue degradation, altered adhesion abilities, changes in the actin cytoskeleton, as well as the antiproliferative effect may all account for inhibition of melanoma cell invasion.
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PMID:Inhibition of K1735-M2 melanoma cell invasion in vitro by retinoic acid. 837 16

Retinoic acid (RA) has been shown to inhibit melanogenesis in B16 mouse melanoma cells (B16 cells). On the other hand, it has been reported that RA increases protein kinase C (PKC) activity in these cells. Further investigation was carried out to identify the PKC subspecies expressed in B16 cells and to examine the changes in the level of each PKC subspecies by RA treatment. Hydroxyapatite column chromatography, immunoblot analysis, and kinetic analysis have shown that B16 cells express the alpha subspecies of PKC. Northern blot analysis has indicated that these cells normally express mRNA for the alpha, delta, epsilon, and zeta subspecies. Upon treatment of B16 cells with 1 microM RA for 48 h, both the activity of the alpha-subspecies and the level of mRNA for the alpha subspecies were increased, resulting in the decrease of melanin polymer formation and tyrosinase activity. Neither the enzyme activities nor mRNA for the beta and gamma subspecies were detected in either the RA-treated or untreated cells. The levels of mRNA for the delta, epsilon, and zeta subspecies were not altered by RA treatment. The demonstration of a selective increase of the alpha subspecies of PKC is a unique finding.
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PMID:Selective increase of the alpha subspecies of protein kinase C and inhibition of melanogenesis induced by retinoic acid in melanoma cells. 843 8

Retinoic acid (RA) is known to play a role in various aspects of skeletal development in vivo, including morphogenesis, growth plate maturation, and apoptosis. In cell culture, RA treatment of chondrocytes suppresses the differentiated phenotype characterized by production of type II collagen and aggrecan. In an effort to discover molecules involved in regulation of the chondrocyte phenotype or related to developmental processes such as chondrogenesis, mRNAs from bovine chondrocytes cultured with and without RA were amplified by reverse transcription-polymerase chain reaction (PCR) and compared by differential display. PCR products whose expression was inhibited by RA treatment were cloned. One cDNA encodes a molecule we call cartilage-derived retinoic acid-sensitive protein (CD-RAP), and its properties are described here. The full-length bovine CD-RAP mRNA was cloned after amplification by the rapid amplification of cDNA ends procedure, and a part of the rat CD-RAP mRNA was amplified by reverse transcription-PCR using sequence-specific primers. The bovine CD-RAP mRNA contains an open reading frame of 130 amino acids. CD-RAP mRNA expression, as determined by Northern blot analysis and in situ hybridization, was present only in cartilage primordia and cartilage. The inhibition of CD-RAP mRNA expression by RA in vitro was time- and dose-dependent and was tested over concentrations from 10(-8) to 10(-6) M. Southern blot analysis of genomic DNA indicated that CD-RAP was encoded by a single copy gene and that no other genes were closely related. What appears to be the human homologue of CD-RAP was recently isolated and cloned from a melanoma cell line and shown to function as a growth inhibitory protein (Blesch, A., Boberhoff, A.-K., Apfel, R., Behl, C., Hessdoerfer, B., Schmitt, A., Jachimcza, P., Lottspeich, F., Buettner, R., and Bogdahn, U. (1994) Cancer Res. 54, 5695-5701). Neither CD-RAP nor this protein showed any homology to known proteins. We speculate that, in vivo, CD-RAP functions during cartilage development and maintenance.
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PMID:Cloning of a retinoic acid-sensitive mRNA expressed in cartilage and during chondrogenesis. 862 36

Retinoic acid (RA)-induced differentiation of B16 mouse melanoma cells is accompanied by a large increase in the amount of PKCalpha protein. Overexpression of PKCalpha in these cells results in a more differentiated phenotype. To determine if these findings had general applicability to murine melanomas, we investigated the relationship between sensitivity to RA and induction of PKCalpha in three different murine melanoma cell lines. RA inhibited the anchorage-dependent growth of all three cell lines, with JB/MS being the most sensitive, S91 intermediate, and RPMI the least affected. RA also inhibited soft agar colony formation in JB/MS, but had little effect on RPMI. All cell lines expressed PKCalpha, but not beta or gamma. RA induced a large concentration-dependent increase in PKCalpha protein in JB/MS (6- to 10-fold), a smaller increase in S91 (2- to 3-fold), and very little induction of PKCalpha in RPMI. Previously we had observed that the amount of PKCalpha increased with the density of B16 cells in culture. We found that this density-dependent increase in PKCalpha occurred in three out of four melanoma cell lines examined. These results suggest that PKCalpha plays an important role in RA-induced murine melanoma cell differentiation.
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PMID:The relationship between susceptibility to retinoic acid treatment and protein kinase C alpha expression in murine melanoma cell lines. 863 92

Clinical studies of patients with melasma have shown that topical 20 percent azelaic acid is superior to 2 percent hydroquinone and as effective as 4 percent hydroquinone, without the latter's undesirable side effects. Tretinoin appears to enhance this effect of azelaic acid. Azelaic acid with tretinoin caused more skin lightening after three months than azelaic acid alone, and a higher proportion of excellent responders at the end of treatment. The effect of azelaic acid can be attributed to its ability to inhibit the energy production and/or DNA synthesis of hyperactive melanocytes, and partially to its antityrosinase activity. This may also account for the beneficial effect on postinflammatory hyperpigmentation. Destruction of malignant melanocytes by a combination of the same activities, enhanced by the greater permeability of tumoral cells to azelaic acid, may account for the clinical effects of azelaic acid observed in lentigo maligna and individual lesions of primary melanoma.
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PMID:Melanin hyperpigmentation of skin: melasma, topical treatment with azelaic acid, and other therapies. 865 29

Retinoic acid receptor (RAR) alpha and gamma mRNAs were constitutively expressed in B16 melanoma cells with or without retinoic acid (RA) treatment. RAR beta mRNA, however, was significantly expressed only after exposure to RA. Induction of RAR beta by RA occurred within 1 h and was not inhibited by cycloheximide (i.e., did not require new protein synthesis). All three RAR mRNA levels were dramatically decreased with 8-bromo-cyclic AMP treatment and could not be rescued by addition of RA. Analysis of RAR gamma revealed that this decrease occurred within 1 h of exposure to 8-bromo-cyclic AMP and was not blocked by simultaneous treatment with cycloheximide. The stability of RAR gamma mRNA was not altered by cyclic AMP treatment. Nuclear extracts from 8-bromo-cyclic AMP-treated cells showed a large decrease in protein binding to a retinoic acid response element (RARE) oligonucleotide compared to control cells. This correlated with a marked reduction of RA-stimulated RARE-reporter gene activity in transfected cells which were treated with cyclic AMP. Pretreatment of B16 cells with cyclic AMP prior to RA addition dramatically reduced induction of PKC alpha, an early marker of RA-induced cell differentiation. Thus, cyclic AMP can antagonize the action of RA most likely via its ability to inhibit RAR expression.
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PMID:Control of retinoic acid receptor expression in mouse melanoma cells by cyclic AMP. 865 95

Retinoic acid and its natural and synthetic analogs (retinoids) affect a wide array of biological processes. Retinoids are used in the treatment of many skin diseases and are promising drugs for several cancers. Most of their actions are thought to result from changes in gene expression which is caused via nuclear retinoic acid receptors and retinoid X receptors. We conducted a study to determine whether the expression of these receptors is different in malignant tumors and tumor cell lines versus normal tissue. We performed reverse transcription PCR from 29 tissue specimens of squamous cell carcinomas and one melanoma of the head and neck, as well as from 13 cell lines established from head and neck cancer. We were looking for the expression pattern of RAR alpha, beta, gamma and RXR alpha. Only RAR gamma was expressed 100% in cell lines and tissue specimens. RAR beta showed 100% expression in tissue specimens whereas 54% expression in cell lines was seen. All other receptors were diminished in their expression. In the positive controls all receptors were expressed at 100%. The expression of RAR alpha and RAR beta was partially lost in cell lines established from squamous cell carcinoma of the head and neck. The 100% expression of RAR beta in tissue samples versus 54% in cell lines can be explained by the clonal growth of malignant cells in cell lines and also possible "contamination" by normal cells in the tissue specimen. In concordance with the literature it seems that RARa and beta play a pivotal role in mediating the response to retinoids.
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PMID:Expression of retinoic acid receptors in squamous cell carcinomas and their possible implication for chemoprevention. 881 37

Retinoic acid (RA) induces differentiation of B16 mouse melanoma cells, which is accompanied by an increase in protein kinase Calpha (PKCalpha) as well as a selective enrichment of nuclear PKCalpha. We report here that RA also increases AP-1 activity in these cells. Transient transfection of B16 cells with luciferase reporter gene constructs indicated that RA induced a concentration-dependent increase in AP-1 activity. Acute treatment (2 h) of B16 cells with phorbol dibutyrate (PDB) increased AP-1 activity by 10-fold. RA treatment did not change the expression of Jun family members; however, it decreased the expression of c-Fos. In contrast acute PDB treatment induced c-Fos expression, while having little effect on c-Jun. Five DNA-protein complexes were formed with nuclear extracts from B16 cells and an oligonucleotide containing an AP-1 consensus sequence. Several complexes were decreased in cells treated with RA. Conversely, certain complexes were increased in cells acutely treated with PDB. The slowest migrating complexes were shown to contain Fos family members. Down-regulation of PKC inhibited both the acute PDB-induced and the RA-induced increase in AP-1 activity. The selective PKC enzyme inhibitor, bisindolylmaleimide, reduced PDB-stimulated AP-1 activity, but enhanced RA-induced AP-1 activity. These results together with our previous studies suggest the intriguing possibility that PKC protein, but not enzyme activity, may be required for RA-induced AP-1 activity.
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PMID:Characterization of retinoic acid-induced AP-1 activity in B16 mouse melanoma cells. 913 41

Retinoic acid (RA) induces growth inhibition, differentiation or cell death in many human neuroblastoma cell lines. Recently, the transactivation activity of nuclear retinoids receptors has been shown to be modulated through physical association with other proteins that act as co-activators or as co-repressors. We investigated the expression of the co-repressor (SMRT) and co-activator (Trip 1) for retinoid and thyroid-hormone receptors in several neuroectodermal tumour cell lines, and its modulation by all-trans-retinoic acid, as well as by synthetic agonists, for RAR alpha, RAR beta, RAR gamma and RXR. We demonstrate that (i) SMRT and Trip-1 mRNAs are expressed in many human neuroblastoma and melanoma cell lines in basal conditions, (ii) SMRT mRNA expression in human neuroblastoma cell line SK-N-BE(2) increases after 48 hours of incubation with 1 microM RA and RARs specific agonists, (iii) Trip-1 mRNA in the same cell line does not change during incubation with RA or selective synthetic agonists for RARs and RXR.
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PMID:Expression of co-factors (SMRT and Trip-1) for retinoic acid receptors in human neuroectodermal cell lines. 916 3


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