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)

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 F-type mRNA of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase is found in proliferating, but not in quiescent, cells. This bifunctional enzyme catalyses the synthesis and degradation of fructose-2,6-bisphosphate, a potent stimulator of glycolysis. F-type mRNA concentration decreased upon differentiation of rat rhabdomyosarcoma cells; it increased in Rat-1 fibroblasts stimulated to proliferate by serum, by epidermal growth factor, or by the v-src oncogene product. This increase resulted, at least in part, from a stimulation of F promoter activity. The stimulation occurred at the G1/S transition of the cell cycle. It depended on a binding site for the oncogenic transcription factor E2F located in the first exon of F-type mRNA. This effect was inhibited by agents that increase cAMP concentration. The data provide the first evidence that a gene involved in the control of glycolysis can be regulated by a late-serum-response promoter in an E2F-dependent way.
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PMID:An E2F-dependent late-serum-response promoter in a gene that controls glycolysis. 747 75

BA-Han-1C rat rhabdomyosarcoma cells grow with a transformed phenotype and do not differentiate efficiently. Here, we report that these cells can be induced with pertussis toxin (PTX) to rapidly express the myogenin gene and form terminally differentiated myotubes. Potential targets for the effect mediated by PTX are G alpha i-2 and G alpha i-3 proteins, the only inhibitor GTP-binding proteins expressed in these cells. While G alpha i-2 is found at the plasma membrane, G alpha i-3 is predominantly associated with Golgi vesicles and endoplasmic reticulum, suggesting that it may regulate protein trafficking. Differentiation of BA-Han-1C cells can also be induced by suramin, heparin, and other polyanions. As these compounds bind certain peptide growth factors, we assume that differentiation of BA-Han-1C cells is blocked by pathways involving autocrine or paracrine acting growth stimulating peptides. We present evidence that bFGF and cAMP inhibit induced differentiation in BA-Han-1C cells similar to normal myogenic cell lines, suggesting that signaling pathways mediated by these compounds are unaltered.
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PMID:Differentiation of BA-HAN-1C rhabdomyosarcoma cells is controlled by a pertussis toxin sensitive signaling pathway. 829 37

Rhabdomyosarcoma is a tumor of skeletal muscle origin affecting children and young adults. Although relatively undifferentiated, cell lines derived from this tumor express myogenic regulatory factors and so may be useful models of abortive myogenic differentiation. In the present studies, we have determined the effect of increased intracellular cAMP on proliferation, morphologic differentiation, and expression of myogenic genes in the prototypic embryonal rhabdomyosarcoma cell line, RD. Whereas growth in dibutyryl cAMP (dbcAMP), forskolin, or butyrate led to morphologic differentiation, growth in dbcAMP inhibited proliferation, while growth in butyrate slowed but did not stop cell division. Expression of the genes for myogenin and myosin light chain was inhibited by dbcAMP, while butyrate decreased myogenin and increased myosin light chain transcription. MyoD and MRF4 expression was not altered under either condition and no myf5 expression was detected. We also determined the effects of dbcAMP and butyrate on total protein expression, as well as on a panel of muscle- and neural-specific proteins using functional assays, immunohistochemistry, and immunoprecipitation. The total protein levels of cells treated with either agent were double those of untreated cells. DbcAMP increased the activity of acetylcholinesterase (AChE) up to 10-fold compared to untreated cells, while butyrate had a substantially lesser effect. These increases were due to increased AChE protein synthesis and stability in dbcAMP treated cells, compared to butyrate or untreated cells. Finally, cells under all conditions expressed MAP2, a neural-specific microtubule associated protein. Together, these data suggest that intracellular cAMP levels modulate distinct subsets of the myogenic differentiation pathway in rhabdomyosarcoma cells. Moreover, they also indicate that RD cells are able to express markers of different cell lineages, which may help explain some of the paradoxical features of these tumors.
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PMID:cAMP effects on myogenic gene expression in rhabdomyosarcoma cells. 880 51

Decidual transformation of human endometrial stromal (ES) cells requires sustained activation of the protein kinase A (PKA) pathway. In a search for novel transcriptional mediators of this process, we used differential display PCR analysis of undifferentiated primary ES cells and cells stimulated with 8-bromo-cAMP (8-Br-cAMP). We now report on the role of forkhead homologue in rhabdomyosarcoma (FKHR), a recently described member of the forkhead/winged-helix transcription factor family, as a mediator of endometrial differentiation. Sustained 8-Br-cAMP stimulation resulted in the induction and nuclear accumulation of FKHR in differentiating ES cells. Immunohistochemical studies revealed that endometrial stromal expression of FKHR in vivo is confined to decidualizing cells during the late secretory phase of the cycle and coincides with the expression of CCAAT/enhancer-binding protein beta (C/EBPbeta). Reporter gene studies showed that FKHR potently enhances PKA-dependent activation of the tissue-specific decidual prolactin (dPRL) promoter, a major differentiation marker in human ES cells. Transcriptional augmentation by FKHR was effected through functional cooperation with C/EBPbeta and binding to a composite FKHR-C/EBPbeta response unit in the proximal promoter region. Furthermore, FKHR and C/EBPbeta were shown to interact directly in a glutathione S-transferase pull-down assay. These results provide the first evidence of regulated expression of FKHR and demonstrate that FKHR has an integral role in PKA-dependent endometrial differentiation through its ability to bind and functionally cooperate with C/EBPbeta.
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PMID:Cyclic AMP-induced forkhead transcription factor, FKHR, cooperates with CCAAT/enhancer-binding protein beta in differentiating human endometrial stromal cells. 1189 44

Glutamate antagonists limit the growth of human cancers in vitro. The mechanism of anticancer action of NMDA antagonists is not known, however. In this article, we report that the NMDA antagonist dizocilpine inhibits the extracellular signal-regulated kinase 1/2 pathway, an intracellular signaling cascade that is activated by growth factors and controls the proliferation of cancer cells. Dizocilpine reduces the phosphorylation of cAMP-responsive element binding protein, suppresses the expression of cyclin D1, up-regulates the cell cycle regulators and tumor suppressor proteins p21 and p53, and increases the number of lung adenocarcinoma cells in the G(2) and S phases of the cell cycle. Silencing of the tumor suppressor protein p21 abolishes antiproliferative action of dizocilpine. Consistent with inhibition of the extracellular signal-regulated kinase 1/2-signaling cascade, dizocilpine reverses the stimulation of proliferation induced by epidermal, insulin, and basic fibroblast growth factors in lung adenocarcinoma cells. Furthermore, dizocilpine prolongs the survival of mice with metastatic lung adenocarcinoma and slows the growth of neuroblastoma and rhabdomyosarcoma in mice. These findings reveal the mechanism of antiproliferative action of dizocilpine and indicate that it may be useful in the therapy of human cancers.
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PMID:NMDA antagonist inhibits the extracellular signal-regulated kinase pathway and suppresses cancer growth. 1623 Jun 11

Skeletal muscle is the major producer of lactic acid in the body, but its oxidative fibers also use lactic acid as a respiratory fuel. Monocarboxylate transporter (MCT) 1 has been suggested to play a major role in influx of L-lactic acid for oxidation. The regulation mechanism of MCT1 was characterized utilizing rhabdomyosarcoma cells as an in vitro skeletal muscle model. The uptake of L-lactic acid via MCT1 was studied in the presence of various intracellular regulatory pathways, including pathways mediated by protein kinases A, C and G (PKA, PKC and PKG), protein tyrosine kinase (PTK), and Ca2+/calmodulin modulators. The results showed that PKG-, PTK-, and Ca2+/calmodulin-mediated regulatory pathways play no role in the regulation of L-lactic acid uptake, but a role for PKC- and PKA-mediated pathways was apparent. Uptake of L-lactic acid appeared to be stimulated by phorbol 12-myristate 13-acetate (PMA, a PKC activator) via an increase in Vmax of transport processes with no alteration in Km. In parallel, PMA treatment also resulted in an increase in the level of MCT1 expression. On the other hand, exposure to 8-Br-cAMP, a cAMP analog, and to forskolin, an adenylyl cyclase activator, resulted in a significant decrease in L-lactic acid uptake. Additionally, 8-Br-cAMP reduced Vmax but not Km values. Parallel to the decrease in Vmax of L-lactic acid uptake, the level of MCT1 expression was decreased in response to incubation with 8-Br-cAMP. These results indicate the possible involvement of a PKC- and PKA-mediated pathway associated with expression of MCT1 and lactate transport.
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PMID:Regulation of monocarboxylate transporter 1 in skeletal muscle cells by intracellular signaling pathways. 2082 76

Functional genomic screening of KRAS-driven mouse sarcomas was previously employed to identify proliferation-relevant genes. Genes identified included Ubiquitin-conjugating enzyme E2 (Ube2c), Centromere Protein E (Cenpe), Hyaluronan Synthase 2 (Has2), and CAMP Responsive Element Binding Protein 3 Like 2 (Creb3l2). This study examines the expression and chemical inhibition of these candidate genes, identifying variable levels of protein expression and significant contributions to rhabdomyosarcoma (RMS) cell proliferation. Chemical treatment of human and murine RMS cell lines with bortezomib, UA62784, latrunculin A and sorafenib inhibited growth with approximate EC50 concentrations of 15-30nM for bortezomib, 25-80nM for UA62784 and 80-220nM for latrunculin A. The multi-kinase inhibitor sorafenib increased in vitro proliferation of 4 of 6 sarcoma cell lines tested. Latrunculin A was further associated with disruption of the actin cytoskeleton and reduced ERK1/2 phosphorylation. Together, this work advances opportunities for developing therapies to block progression of soft-tissue sarcomas and demonstrates that disruption of the actin cytoskeleton in sarcoma cells by latrunculin A is associated with a reduction in RMS cell growth. (167 words).
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PMID:Growth inhibition associated with disruption of the actin cytoskeleton by Latrunculin A in rhabdomyosarcoma cells. 3289 43