Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0035412 (rhabdomyosarcoma)
 6,156 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three clonal rat rhabdomyosarcoma subpopulations (A, B, C) with a block of differentiation at different levels of rhabdomyogenesis were exposed to the differentiation inducers retinoic acid (RA), N-methylformamide (NMF) and sodium butyrate (NaBut). Since an increased expression of c-raf and c-fos had recently been demonstrated for subpopulation C after exposure to RA and NMF (1), the mRNA expression of c-raf, c-fos and retinoic acid receptor (RAR) alpha, beta and gamma was compared in all three subpopulations. After exposure to RA, NMF or NaBut, subpopulation C exhibited a significant (p = 0.0001) increase in creatine kinase (CK) activity and in morphological differentiation. In subpopulation B, the response was confined to a significant (p = 0.0001) increase in creatine kinase activity, whereas subpopulation A proved to be differentiation-refractory. On the molecular level, a uniform increase in c-raf expression became evident in all three subpopulations after 6 to 12 hours, persisting at an elevated level throughout the observation period of 120 hours. In contrast, the pattern of c-fos expression observed after exposure to RA, NMF or NaBut was heterogeneous. Expression of RAR alpha and gamma was detected in all subpopulations, whereas RAR beta mRNA was not expressed. Summarizing our results, the uniform pattern of c-raf expression might suggest a participation of c-raf in differentiation signal transduction. Since the three subpopulations differ markedly in their degree of differentiation, the block of differentiation characteristic for each subpopulation supposedly becomes effective only after the action of the c-raf gene product.
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PMID:Increase in proto-oncogene raf expression precedes differentiation induction in different clonal rhabdomyosarcoma subpopulations. 131 93

Two clonal rat rhabdomyosarcoma cell lines BA-Han-1B and BA-Han-1C with different capacities for myogenic differentiation have been examined for the expression of muscle regulatory basic helix-loop-helix (bHLH) proteins of the MyoD family. Whereas cells of the BA-Han-1C subpopulation constitutively expressed MyoD1 and could be induced to differentiate with retinoic acid (RA), BA-Han-1B cells did not express any of the myogenic control factors and appeared to be largely differentiation-defective. Upon induction with RA, BA-Han-1C cells expressed also myogenin, in contrast to BA-Han-1B cells which never activated any of the genes encoding muscle bHLH factors. The onset of myogenin transcription in BA-Han-1C cells required de novo protein synthesis and DNA replication suggesting that RA probably did not act directly on the myogenin gene. Although MyoD1 was expressed in proliferating BA-Han-1C myoblasts, muscle-specific reporter genes were not activated indicating that MyoD was biologically inactive. However, transfections with plasmid expressing additional MyoD1 protein resulted in the transactivation of muscle genes even in the absence of RA. mRNA encoding the negative regulatory HLH protein Id was expressed in proliferating BA-Han-1C cells and disappeared later after RA induction which suggested that it may be involved in the regulation of MyoD1 activity. The myogenic differentiation of malignant rhabdomyosarcoma cells strictly correlated with the activation of the myogenin gene. In fact, stable transfections of BA-Han-1C cells with myogenin expressing plasmids resulted in spontaneous differentiation. Together, our results suggest that the transformed and undifferentiated phenotype of BA-Han-1C rhabdomyosarcoma cells is associated with the inactivation of the myogenic factor MyoD1 as well as lack of myogenin expression. RA alleviates the inhibition of myogenic differentiation, probably by activating MyoD protein and myogenin gene transcription. BA-Han-1B cells did not respond to RA and the differentiated phenotype could not be restored by overexpression of MyoD1 or myogenin.
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PMID:Retinoic acid induces myogenin synthesis and myogenic differentiation in the rat rhabdomyosarcoma cell line BA-Han-1C. 132 66

The control of myogenin (Myf-4), one of the muscle-specific regulatory proteins, is particularly interesting since its expression appears obligatory in myoblasts at the onset of differentiation. We isolated the human Myf-4 (myogenin) gene and determined promoter elements which direct cell type-specific expression and are subject to transactivation by the muscle transcription factors Myf-5 and MyoD1 in fibroblasts. Extrinsic signals such as serum components and purified growth factors or potential intracellular signals such as cAMP down-regulate transcription of the myogenin gene. Constitutive expression of the catalytic subunit of PKA completely suppresses transactivation of the myogenin promoter by Myf-5 or MyoD1 suggesting that cAMP may act via phosphorylation by PKA. In contrast to normal myogenic cell lines in which differentiation and myogenin expression can be induced by the removal of serum components, retinoic acid (RA) is required for differentiation in the rat rhabdomyosarcoma cell line BA-Han-1C. This model system was utilized to investigate factors which influence the balance between the transformed state and differentiation. Administration of retinoic acid to BA-Han-1C cells leads to the accumulation of myogenin mRNA approximately 48 h after the addition of RA. This late induction requires ongoing protein- and DNA-synthesis suggesting that trans- and cis-acting factors may be involved in the control. The critical involvement of myogenin in the process of terminal muscle differentiation was also demonstrated in the rat L6 muscle cell line which has been blocked for differentiation by the transforming protein E1a of Ad5 adenovirus. In cells which stably express E1a, myogenin expression is completely suppressed while Myf-5 continues to be synthesized normally. However, E1a inhibits the transactivator function of Myf-5, as demonstrated on GAL4-Myf5 chimeric proteins. A possible interpretation of this result is that Myf-5 or factors activated by Myf-5 are required for the expression of myogenin and myogenin itself is necessary for the terminal differentiation of myoblasts.
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PMID:Regulation of myogenin expression in normal and transformed myogenic cell lines. 134 Oct 49

The influence of all-trans-retinoic acid-beta-D-glucopyranosylester, all-trans-retinoic acid-beta-D-galactopyranosylester, methyl-(1-O-retinoyl-beta-D-glucopyranoside)uronate and all trans-retinyl-beta-D-glucuronide were investigated on the celle line BA-HAN-1C. This clonal cell line was derived from a dimethylbenzanthracene induced rhabdomyosarcoma in the rat. The tumor cells were incubated for 5 days with medium which was supplemented with various concentrations of the different compounds. The action of the retinoids were measured by comparing the cellular growth and the creatine kinase activity (as differentiation marker) with an supplemented cell line. The retinoids which are based on all-trans-retinoic acid (all-trans-retinoic acid-beta-D-glucopyranosylester, all-trans-retinoic acid-beta-D-galactopyranosylester, methyl-(1-O-retinoyl-beta-D-glucopyranoide)uronate and their chemical precursors) showed similar biological effects as all-trans-retinoic acid and could be used in higher concentrations than retinoic acid without the appearance of toxic effects. The all-trans-retinyl-beta-D-glucuronide derivatives did not show any influence on the cell growth and their creatinine kinase activity. With respect to the effects of the compounds two hypothesis about their function were possible: They act as a whole molecule, or: they are bound to a receptor where the really effective substance, all-trans-retinoic acid is released from the molecule by hydrolytic cleavage as required. Investigations with the carbohydrates D-glucose, D-galactose and D-uronic acid disproved the second theorie because these substances enormously support the growth of the tumor cells. The effectively of the free all-trans-retinoic acid would have been diminished by these components. However, this effect did not appear if hydrolysis is considered.
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PMID:Effects of novel retinoids on growth and differentiation of a rhabdomyosarcoma cell line. 141 77

We have been evaluating the role of all-trans-retinoic acid (RA) in the differentiation and growth of human rhabdomyosarcoma (RMS) cell lines. Treatment of both embryonal (RD) and alveolar (RH30) human RMS cell lines with all-trans-RA resulted in a dose-dependent inhibition of cell growth with a maximal inhibition of 92 and 66%, respectively, at 5 x 10(-6) M. When 13-cis-RA was used under identical experimental conditions, maximal growth inhibition was 41 and 37%, respectively. This stereo-specific growth inhibition was not associated with morphological or biochemical evidence of myogenic differentiation. Furthermore, all-trans-RA demonstrated no evidence of competition with binding of insulin-like growth factor II (IGF-II), an autocrine growth factor in RMS, to its membrane receptor as evaluated by an [125I]IGF-I-receptor-binding assay. Attempts to rescue all-trans-RA growth-inhibited RMS cells with exogenous IGF-II resulted in no increase in growth compared to cells treated with all-trans-RA alone. We conclude that RA inhibits the growth of human RMS cell lines in a dose-dependent, stereo-specific manner, is not associated with differentiation, and does not appear to be directly related to IGF-II.
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PMID:All-trans-retinoic acid inhibits the growth of human rhabdomyosarcoma cell lines. 189 78

The clonal rat rhabdomyosarcoma cell line BA-HAN-1C is composed of proliferating mononuclear cells, some of which spontaneously fuse to terminally differentiated myotube-like giant cells. Both the induction of differentiation by retinoic acid (RA) and by sodium butyrate (NaBut), as well as the inhibition of proliferation by fetal calf serum (FCS)-depleted medium uniformly resulted in the same effects. There was a significant (p less than 0.001) inhibition of proliferation and induction of cellular differentiation, as evidenced by a significant (p less than 0.05) increase in creatine kinase activity. Furthermore, after exposure to RA-supplemented or FCS-depleted medium, a significant (p less than 0.001) increase in the number of myotube-like giant cells was observed. These effects were preceded by a uniform enhancement of c-raf mRNA expression, which became evident 6 h after exposure to RA, NaBut and FCS-depleted media. C-raf mRNA expression persisted at an elevated level throughout the observation period of 5 days after exposure to RA or NaBut, whereas the increased expression of c-raf mRNA observed after FCS-depletion declined near to the basal level after only 24 h. Furthermore, a transient c-fos mRNA expression was observed 15 and 30 min after exposure to RA-supplemented and FCS-depleted medium but not after exposure to NaBut. The present results suggest a possible role of c-raf in the regulation of differentiation and proliferation of this cell line. Since all our experiments with RA, NaBut and FCS-depletion resulted in an early peak of c-raf mRNA expression, it is suggested that this early peak may be sufficient to trigger events crucial for differentiation and proliferation of BA-HAN-1C tumor cells.
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PMID:Uniform response of c-raf expression to differentiation induction and inhibition of proliferation in a rat rhabdomyosarcoma cell line. 198 May 57

In vitro cultures and clonal derivatives have been established from rat rhabdomyosarcomas induced by Moloney-Murine Sarcoma Virus (MSV) or by nickel sulfide; differentiation ability has been studied as expression of desmin, embryonic and adult myosin isoforms, alpha-actin isoforms and cellular fusion. The two rhabdomyosarcoma models showed different levels of myogenic differentiation. Multinucleated myotube-like structures were frequently observed in cultures derived from nickel-induced tumours. Desmin was present in 50-80% of cells and embryonic myosin in up to 10%. In MSV-tumour-derived cultures and in their metastases or clonal derivatives two cell types are present in different ratios: spindle-shaped cells, adherent to plastic surfaces, and rounded cells, loosely attached or floating free in the medium. These cultures showed features of myogenic differentiation (10-80% desmin-positive cells), but embryonic myosin expression and production of multinucleated myotube-like structures were very rare events. Cultures from autochthonous lymph node and lung metastatic cells showed similar patterns of differentiation. Retinoic acid increased differentiated features (myotube formation and embryonic myosin expression) only in nickel-induced rhabdomyosarcoma cells. The two models described here mimic the heterogeneity in differentiation pattern found among human rhabdomyosarcomas. Myogenic differentiation ability was retained at a good level by nickel-induced tumours, whereas it was strongly impaired in MSV-induced tumours.
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PMID:In vitro differentiation of rhabdomyosarcomas induced by nickel or by Moloney murine sarcoma virus. 203 98

BA-HAN-IC is a clonal rat rhabdomyosarcoma cell line consisting of proliferating mononuclear tumor cells, some of which spontaneously fuse to form terminally differentiated post-mitotic myotubes. Exposure of BA-HAN-IC cells to retinoic acid (RA) or N-methylformamide (NMF) resulted in a significant inhibition of proliferation (p less than 0.001) and in cellular differentiation, as evidenced by a significant increase in the creatine kinase (CK) activity (p less than 0.05) and the number of terminally differentiated post-mitotic myotubes (p less than 0.001). Furthermore, between 5% (NMF) and 30% (RA) of the mononuclear tumor cells exhibited ultrastructural features of rhabdomyogenic differentiation, not observed in their mononuclear counterparts under standard growth conditions. Although BA-HAN-IC cells responded to both inducers of differentiation, differences in time course and magnitude of both increase of differentiation and growth inhibition were observed. These effects of RA and NMF were preceded by a marked enhancement of c-raf expression which became evident 6 and 12 hr after exposure to RA and NMF, respectively, and which persisted throughout the observation period of 5 days. Furthermore, a transient expression of c-fos could be observed 15 and 30 min after exposure to RA. Our results suggest that c-raf expression might be implicated in the differentiation process of BA-HAN-IC tumor cells.
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PMID:Enhanced expression of the proto-oncogenes fos and raf in the rhabdomyosarcoma cell line BA-HAN-1C after differentiation induction with retinoic acid and N-methylformamide. 210 33

BA-HAN-1C is a clonal rat rhabdomyosarcoma cell line consisting of proliferating mononuclear tumor cells, some of which spontaneously fuse to form terminally differentiated postmitotic myotubelike giant cells. Exposure to retinoic acid resulted in an inhibition of proliferation and a marked increase in cellular differentiation. The number of myotubelike giant cells significantly increased, and about 30% of the mononuclear tumor cells exhibited morphological features of rhabdomyogenic differentiation which were not observed in the mononuclear cells of untreated cultures. Morphological differentiation was paralleled by an increase in total creatine kinase activity as a biochemical marker of differentiation. These effects of retinoic acid were preceded by an increased expression of proto-oncogene raf and transient expression of proto-oncogene fos. The maximum level of fos expression was observed at 15 min and of raf at 12 hr after exposure to retinoic acid. No expression of the proto-oncogenes src, myb, myc, ros, mos, erbA, and erbB was detected.
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PMID:Morphological, biochemical, and molecular biological characterization of a rat rhabdomyosarcoma cell line during differentiation induction in vitro. 227 13

Three clonal subpopulations (A, B, C) isolated from the same rhabdomyosarcoma of the rat were tested and compared for their susceptibility to differentiation induction using retinoic acid (RA), dimethylformamide (DMF), and N-monomethylformamide (NMF). These subpopulations differ in that a block to spontaneous differentiation is imposed at different stages which are characteristic for each subpopulation. Whereas tumor cell proliferation was significantly inhibited (P less than 0.001) in all three subpopulations, the effects of RA, DMF, and NMF on tumor cell differentiation were strikingly heterogeneous. The response was most marked in subpopulation C, as evidenced by a significant increase in the number of terminally differentiated myotube-like giant cells (P less than 0.001) and in biochemical differentiation, as indicated by the creatine kinase activity (P less than 0.05). Between 5% (DMF and NMF) and 30% (RA) of the mononuclear cells in subpopulation C exhibited thick and thin myofilaments, which were never observed in the mononuclear cells of the control. In contrast, subpopulation A and B responded to RA, DMF, and NMF quite heterogeneously with an increase in biochemical differentiation, whereas terminally differentiated myotube-like giant cells were never observed. These results demonstrate that the therapeutic potential of differentiation induction in malignant tumors may be impaired by tumor heterogeneity.
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PMID:Heterogeneous response to differentiation induction in different clonal subpopulations of a rat rhabdomyosarcoma cell line (BA-HAN-1). 258 54


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