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)

ZT3, isolated from a murine muscle cell cDNA library by a low-stringency hybridization, encodes a zinc finger domain containing factor with a transcript of 5.0 kb. A 3' 2.5 kb partial nucleotide sequence contains an ORF of 1.5 kb where 17 canonical C2H2 zinc finger domains organized in tandem were identified. It maps on mouse chromosome 11, close to two mutations which affect skeletal formation. ZT3 expression depends upon differentiation of myogenic cells in culture, since it is upregulated with myogenin and inhibited in scr-transfected C2C12 cells. ZT3 is not expressed in NIH3T3 or C3H10T1/2 fibroblasts, but is induced when fibroblasts are myogenically converted by transfection with the muscle regulatory genes (MRFs). Its expression is also upregulated in the rhabdomyosarcoma cell line RD induced to myogenic differentiation by TPA treatment. In postimplantation embryos, ZT3 is diffusely expressed but higher expression is detectable in the neural tube and encephalic vesicles, in the somites and, at a high level, in the limb buds as they form. During further development ZT3 is expressed in many tissues of neuroectodermal and mesodermal origin, but its expression decreases during fetal development and in the adult it is restricted to skeletal and cardiac muscle and to spleen. This pattern of expression suggests a possible role played by ZT3 in differentiating skeletal muscle. Its expression in other tissues is compatible with the suggestion that members of this class of DNA-binding factors play different roles during post-implantation development and in the adult life.
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PMID:Differentiation dependent expression in muscle cells of ZT3, a novel zinc finger factor differentially expressed in embryonic and adult tissues. 880 10

Terminal differentiation of myocytes involves withdrawal from the cell cycle, induction of myogenin expression, and finally formation of myotubes. To study the factors that regulate the initial phase of muscle differentiation, we analyzed the binding activities of transcription factors AP-1, Sp-1, and NF-kappa B in L6, C2C12, and rhabdomyosarcoma BA-Han-1C cells. Temporal changes in transcription factor binding activities were compared to the activation of myogenin promoter-driven CAT reporter gene and the expression level of myogenin, a master gene of myogenic differentiation. We observed a prominent decrease in the nuclear binding activities of AP-1, Sp-1, and NF-kappa B already 12 to 24 h after the transfer of cells to differentiation medium. The response was very similar in L6 and C2C12 myocytes and in BA-Han-1C rhabdomyosarcoma cells. The down-regulation clearly preceded the activation of myogenin promoter and the induction of myogenin and retinoblastoma expression, as well as the initiation of myocyte fusion. Cholera toxin and okadaic acid, established inhibitors of myogenin expression and muscle differentiation, strongly up-regulated the binding activities of AP-1, Sp-1, and NF-kappa B in differentiation medium. Myogenin expression and myocyte fusion were also inhibited. Levels of nuclear c-Fos and c-Jun proteins, components of the AP-1 complex, showed a prominent decrease already after 12 h in differentiation medium. These results show that the down-regulation of the proliferation-promoting transcription factors is a prerequisite to the initiation of myocyte differentiation.
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PMID:Down-regulation of transcription factors AP-1, Sp-1, and NF-kappa B precedes myocyte differentiation. 895 80

Rhabdomyosarcoma, a tumor of skeletal muscle origin, appears developmentally arrested at an early stage in the myogenic differentiation pathway. The proliferation of an alveolar rhabdomyosarcoma cell line Rh30 is dependent on the insulin-like growth factor (IGF) II/IGF-I receptor (IGF-IR) signaling pathway and is highly sensitive to recombinant human IFN-alpha 2a, which induces growth arrest and differentiation of these malignant myoblasts. IFN-alpha 2a-induced growth arrest of Rh30 cells was observed within 48 h, and reduction in colony formation was obtained with an IC50 of 0.81 IU/ ml for 72 h exposure. Down-regulated expression of IGF-IR was apparent by 24 h after initiation of IFN-alpha 2a treatment. Furthermore, an initial increase followed by reduced expression of MyoD, in concert with elevated expression of myogenin, increased frequency of skeletal muscle myosin-positive cells, and the formation of multinucleated cells, indicated an enhancement of differentiation of Rh30 cells in the presence of IFN-alpha 2a. To probe the role of IGF-IR in the differentiation of Rh30 cells along the myogenic lineage, the effect of antisense RNA-mediated reduction of endogenous IGF-IR on growth and expression of muscle-specific proteins was determined. Rh30 cells transfected to stably express antisense IGF-IR (clone AS [symbol: see text] 23)showed significant reduction in growth rate, decreased expression of IGF-IR protein, increased expression of MyoD, myosin heavy chain, and an increased number of multinucleated cells in comparison to the parental line. These data are consistent with overexpression of IGF-IR inhibiting differentiation. IFN-alpha 2a treatment of AS [symbol: see text] 23 cells further induced both MyoD and myogenin expression, thereby allowing cells to proceed further downstream of the differentiation pathway.
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PMID:Alpha 2a-interferon-induced differentiation of human alveolar rhabdomyosarcoma cells: correlation with down-regulation of the insulin-like growth factor type I receptor. 905 94

Characteristic chromosome aberrations and the rearranged genes resulting in chimeric fusion genes have been reported in some bone and soft tissue tumors; t(X; 18) in synovial sarcoma, t(11; 22) in Ewing's sarcoma and primitive neuroectodermal tumor, and t(2; 13) in alveolar rhabdomyosarcoma. We practically used the chromosome analysis and the reverse transcription-polymerase chain reaction (PCR) method as a tool for diagnosis and follow up. All of 10 cases of synovial sarcoma had a chimeric product of SYT/SSX gene. Eleven cases of Ewing's sarcoma and primitive neuroectodermal tumor showed 6 variants of chimeric products between EWS gene and Fli1 gene in the PCR-directed sequence analysis. Although PAX3/FKHD or PAX7/FKHD transcripts were amplified in alveolar rhabdomyosarcoma cases, MyoD1 and myogenin gene which are myogenic transcription factor were also expressed in most rhabdomyosarcomas. These findings indicate that molecular biological analysis may be a useful supplementary method for pathologic diagnosis of bone and soft tissue tumors.
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PMID:[Pathologic diagnosis on bone and soft tissue tumors by molecular biological methods]. 925 13

The blastemal component of Wilms' tumor (WT) might be indistinguishable histologically from other small, blue, round-cell tumors of childhood, including alveolar rhabdomyosarcoma (RMS), particularly in small biopsy specimens and in the setting of metastatic disease. Furthermore, there are currently no reliable blastemal markers. Deparaffinized sections of 9 formalin-fixed blastema-predominant WTs and 46 RMSs were immunostained with antibodies to desmin (D33), myogenin (F5D), MyoD1 (5.8A), and muscle-specific actins (HHF35), after heat-induced epitope retrieval. WE defined as positive those cases with more than 5% of cells immunostained (only nuclear staining was considered as positive for myogenin and MyoD1). Antibodies to desmin were positive in eight (89%) of nine cases of blastema-predominant WT; in contrast, no case was positive for any of the other muscle-associated proteins. Of the 46 cases of RMS, all were positive for desmin, 42 were positive for myogenin and MyoD1, and 43 were positive for muscle actins. Desmin immunoreactivity, of and by itself, cannot be considered specific for RMS, but when accompanied by immunoreactivity for other myogenic proteins, it is highly characteristic of RMS. Our data also suggest that desmin immunoreactivity, in the absence of other muscle-associated protein expression, might be considered a clue to the diagnosis of the blastemal WT. Particularly in the context of small biopsy specimens or in metastatic settings, the use of a panel of antibodies to desmin as well as to other myogenic proteins, such as MyoD1 or myogenin, can help to discriminate between WT and RMS. Additional studies are required to determine whether desmin immunoreactivity in the blastemal component of WT represents true desmin expression.
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PMID:Antibodies to desmin identify the blastemal component of nephroblastoma. 931 Sep 52

We examined a panel of cell lines for the expression of the myogenic proteins myoD and myogenin. High level expression of both proteins was seen in rhabdomyosarcoma (RMS). To determine whether promoter elements from these genes could direct RMS cell-specific expression, we generated reporter constructs containing one or two copies of the myoD enhancer coupled to the SV40 promoter. Transient transfection reporter assays confirmed the selective expression of beta-galactosidase (beta-gal) in 8 RMS cell lines. In contrast, very low expression from the myoD enhancer/SV40 promoter was detected in four non-RMS cell lines. To determine whether the hybrid promoter could elicit RMS-specific cytotoxicity, a mammalian expression vector containing the herpes simplex virus thymidine kinase (HSVtk) under control of the hybrid myoD enhancer/SV40 promoter was constructed. After electroporation into several cell lines, selective RMS cell kill was observed after treatment with ganciclovir. These data suggest that in vivo tumor-specific expression of HSVtk from the myoD enhancer/SV40 promoter may provide an alternative to current chemotherapy.
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PMID:Rhabdomyosarcoma-specific expression of the herpes simplex virus thymidine kinase gene confers sensitivity to ganciclovir. 969 70

Committed skeletal muscle myoblasts undergo terminal differentiation when shifted from a high-mitogen medium to a low-mitogen medium. However, expression of the myogenic regulatory factor MyoD seems to be similar in proliferating and differentiating cells, suggesting that its function is attenuated in proliferating myoblasts. To further understand the potential mechanisms that may attenuate MyoD function, we have examined the effect of posttranslational modification. By analogy with myogenin, we have examined the role of phosphorylation in regulating the function of MyoD. MyoD contains two putative protein kinase C (PKC) phosphorylation sites (Thr115 and Ser200). The former site is analogous to Thr85 within the highly conserved basic domain of myogenin that has been demonstrated to negatively regulate the myogenic differentiation functions of myogenin. To test whether hyperphosphorylation of the same PKC site in MyoD would attenuate its function, we generated a mutant MyoD with a single amino acid substitution (Thr115-Ala) that disrupts the PKC phosphorylation site (Thr115) within the conserved basic domain. Wild-type and mutant MyoD were introduced into cells using an E1, E3-deleted adenoviral vector. In mouse C3H10T1/2 fibroblasts, both wild-type and mutant MyoD induced terminal myogenic differentiation when growth factors were withdrawn from the cell culture. Consistent with these results, nuclear extracts from infected cells, but not those from uninfected cells, demonstrated complex formation with an oligonucleotide containing an E-box consensus sequence. Growth arrest was associated with the up-regulation of p21cip1, cell fusion to multinucleated myotubes, and the expression of a muscle differentiation marker (myosin heavy chain). On the other hand, when infected cells were maintained under high mitogenic conditions (in the presence of 10% fetal bovine serum), the expression of wild-type or mutant MyoD slowed cell growth and induced p21cip1. Only mutant MyoD caused cell fusion, myosin heavy chain expression, and altered mobility of the E-box oligonucleotide in gel shift assays. Furthermore, after infection, MyoD was phosphorylated, and phosphothreonine was detected in wild-type MyoD immunoprecipitated only from C3H10T1/2 cells grown under high mitogenic conditions. These results suggest that Thr115 may play an important role in the regulation of MyoD function under conditions of high mitogenesis. MyoD was also phosphorylated in malignant rhabdomyosarcoma (RMS) cells in which MyoD function was attenuated. Phosphothreonine was also detected in MyoD immunoprecipitates. Rh30 alveolar RMS cells were infected with an adenovirus expressing either wild-type or mutant MyoD. In contrast to the results in fibroblasts, when overexpressed in malignant Rh30 RMS cells, mutant MyoD arrested cell growth without inducing p21cip1 and caused cell fusion. However, no muscle differentiation markers were detected, indicating that an overexpression of mutant MyoD lacking Thr115 caused Rh30 cells to become quiescent and recapitulate at least some aspects of myogenesis (cell fusion).
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PMID:Mutation of Thr115 in MyoD positively regulates function in murine fibroblasts and human rhabdomyosarcoma cells. 975 Nov 14

We reviewed six cases of rhabdomyosarcoma as a rare second primary malignancy in children with bilateral retinoblastoma after irradiation treatment. The patients comprised four females and two males (age range 1 year 4 months-7 years 11 months). Second tumors arose in the temporal muscle inside or close to the previously irradiated fields. All the children were alive and well 24-72 months after diagnosis. Microscopic examination showed proliferation of closely packed, small round cells with scanty cytoplasm, coarse nuclear chromatin, and increased mitotic activity without a myxoid background nor obvious alveolar architecture. The most characteristic feature was the presence of rosette-like structures in four tumors. Immunoreactivity for many skeletal muscle markers was evident, including desmin (six of six), muscle-specific actin (HHF35) (six of six), sarcomeric actin (six of six), myogenin (six of six), vimentin (six of six), and myoglobin (three of six). On reverse transcriptase-polymerase chain reaction examination, three second tumors lacked specific chimeric transcripts for alveolar rhabdomyosarcoma and Ewing's sarcoma. Unexpectedly, variable reactivity for neurofilament (150 kd) was identified in six of six second tumors as well as 15 of 20 sporadic primary rhabdomyosarcomas (75%) examined as controls, the result being confirmed by Western blot analysis. In addition, staining for retinoblastoma-susceptibility gene protein was negative in all second tumors, in contrast to positivity in 14 of 17 sporadic primary tumors (82%). This finding suggests that retinoblastoma-susceptibility gene abnormalities could be associated with the development of second primary rhabdomyosarcoma. We consider that knowledge of the occurrence of rhabdomyosarcoma and appropriate immunohistochemical study are helpful for avoiding a misdiagnosis of recurrent retinoblastoma or Ewing's sarcoma when encountering patients with a history of bilateral retinoblastoma who developed second small round cell neoplasms.
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PMID:Second primary rhabdomyosarcomas in patients with bilateral retinoblastoma: a clinicopathologic and immunohistochemical study. 980 27

The diagnosis of rhabdomyosarcoma (RMS) is usually straight-forward when light microscopy and immunohistochemistry are used. However, tumors that exhibit a low degree of differentiation and small biopsies can lead to confusion. In such patients and for the detection of minimal (residual) disease, a polymerase chain reaction (PCR)-based approach would be a valuable diagnostic adjunct. This type of approach would be highly sensitive and should be free from the risk for contamination of the tumor sample with normal tissue. Because myogenin and the alpha and gamma subunit of the fetal type acetylcholine receptor (AChR) are specific immunohistochemical markers for RMS, their expression on the mRNA level in RMS, other childhood and adult tumors, and normal tissues was studied. Although the sensitivity of both approaches was 100% in embryonal and alveolar RMS, detection of myogenin mRNA was not specific for RMS but occurred in normal muscle and the majority of the other normal tissues and childhood tumors. Conversely, detection of fetal AChR mRNA as defined by an alpha/tau ratio of < 1 was encountered only in RMS and denervated muscle. The authors conclude that mRNA of the fetal type AChR but not myogenin is a highly specific and sensitive target for the PCR-based diagnosis of RMS.
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PMID:Polymerase chain reaction-based diagnosis of rhabdomyosarcomas: comparison of fetal type acetylcholine receptor subunits and myogenin. 983 66

p16INK4A (p16) tumour suppressor induces growth arrest by inhibiting function of cyclin-dependent kinase (CDK)4 and CDK6. Homozygous p16 gene deletion is frequent in primary rhabdomyosarcoma (RMS) cells as well as derived cell lines. To confirm the significance of p16 gene deletion in tumour biology of RMS, a temperature-sensitive p16 mutant (E119G) gene was retrovirally transfected into the human RMS cell line RD, which has homozygous gene deletion of p16 gene. Decrease from 40 degrees C (restrictive) to 34 degrees C (permissive) culture temperature reduced CDK6-associated kinase activity and induced G1 growth arrest. Moreover, RD-p16 cells cultured under permissive condition demonstrated differentiated morphology coupled with expressions of myogenin and myosin light chain. These suggest that deletion of p16 gene may not only facilitate growth but also inhibit the myogenic differentiation of RD RMS cells.
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PMID:Restoration of p16INK4A protein induces myogenic differentiation in RD rhabdomyosarcoma cells. 1009 32


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