Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Most rhabdomyosarcomas are poorly differentiated malignant tumors. Dimethyl sulfoxide has been shown to modulate cell differentiation in cultured human cells. We induced differentiation in human rhabdomyosarcoma cell lines A-673, RD and A-204 with 1.25% dimethyl sulfoxide, and used desmin, the protein most frequently used as a marker of muscle cell differentiation, to trace this process. As alternative markers of the degree of differentiation, we quantified the expression of the proteins actin, tropomyosin and alpha-actinin in these cell lines, and followed the changes in expression of these proteins after induction for 8, 12, 24, 48 and 72 hrs. In the process of differentiation, protein expression in both the cytoplasm and cytoskeleton was significantly increased by treatments lasting 12 hrs. (alpha-actinin) and 24 hrs. (actin). On the basis of our results, alpha-actinin can be considered as an earlier marker of differentiation than actin in human rhabdomyosarcoma cell lines. However, the earliest indication of differentiation was a modification in desmin expression (8 hrs.). Because changes in tropomyosin expression were less marked, we consider this protein as a poor marker of rhabdomyosarcoma cell differentiation.
Cell Mol Biol (Noisy-le-grand) 1993 Jul
PMID:Actin, tropomyosin and alpha-actinin as markers of differentiation in human rhabdomyosarcoma cell lines induced with dimethyl sulfoxide. 837 4

The FKHR gene, which contains a forkhead DNA-binding motif, is fused to either PAX3 or PAX7 by the t(2;13) or t(1;13) translocation in alveolar rhabdomyosarcoma,respectively. These tumors express chimeric transcripts encoding the N-terminal portion of either PAX protein fused to the C-terminal portion of FKHR. To understand the structural basis and functional consequences of these translocations, we characterized the wild-type FKHR gene and its rearrangement in alveolar rhabdomyosarcomas. By isolating and analyzing phage, cosmid and YAC clones, we determined that FKHR consists of three exons spanning 140 kb and that several highly similar loci are present in other genomic regions. Exon 1 encodes the N-terminus of the forkhead domain and is embedded within demethylated CpG island. RNA analyses reveal FKHR transcripts initiate from a TATA-less promoter within this island. Exon 2 encodes the C-terminus of the forkhead domain and a transcription activation domain, whereas exon 3 encodes a large 3' untranslated region. The intron 1-exon 2 boundary precisely matches the FHKR fusion point in the chimeric transcripts found in alveolar rhabdomyosarcomas. Using pulsed-field and fluorescence in situ hybridization analyses, we demonstrate that the 130kb FKHR intron 1 is rearranged in t(2;13)-containing alveolar rhabdomyosarcomas. Our findings indicate that FKHR intron 1 provides a large target for DNA rearrangemnt. Rearrangement of this intron with PAX3 produces two important functional consequences: in-frame fusion of N-terminal PAX3 sequences to the FKHR transcriptional activation domain and disruption of the FKHR DNA binding domain.
Hum Mol Genet 1995 Dec
PMID:Structural characterization of the FKHR gene and its rearrangement in alveolar rhabdomyosarcoma. 863 10

Application of a "formamide free" and thus "material preserving" in situ hybridization technique using the cDNA of the myf3 gene revealed the following results: Human rhabdomyosarcoma cells, characterized by a high expression of myf3 show intensive hybridization signals in their interphase. RNase treatment prior to hybridization considerably reduces the size of this signals. In comparison, isolated nuclei of human lymphocytes in which no need for the expression of this gene exists, show barely hybridization signals. Correspondingly, RNase treatment had no effect on hybridization pattern at all. In conclusion an increased transcription efficiency of a cell type specific gene is accompanied by a higher hybridization accessibility in the corresponding cell nuclei.
Cell Mol Biol (Noisy-le-grand) 1995 Dec
PMID:Transcription specific differences visualized by fluorescence in situ hybridization pattern on interphase nuclei of different cell types. 874 83

Parathyroid hormone-related peptide (PTHrP) is thought to be responsible for hypercalcemia in some patients with malignant tumors. The PTHrP gene has seven exons, giving rise to three types of PTHrP isoform through alternative splicing. We studied the expression of mRNAs in 14 human cell lines using the reverse transcription-PCR method, to examine tissue-specific expression. All the cell lines expressed at least two types of PTHrP transcript. Most cell lines expressed all four types of PTHrP mRNA isoform. However, a rhabdomyosarcoma cell line, RD, and a bladder carcinoma cell line, T24, expressed only two types. These results may suggest that PTHrP mRNA is expressed in the majority of tumor and normal tissues and that it shows less tissue- or tumor-specificity.
J Mol Endocrinol 1995 Dec
PMID:Multiple alternative splice isoforms of parathyroid hormone-related peptide mRNA in human cell lines. 874 30

One obvious phenotype of tumor cells is the lack of terminal differentiation. We previously classified rhabdomyosarcoma cell lines as having either a recessive or a dominant nondifferentiating phenotype. To study the genetic basis of the dominant nondifferentiating phenotype, we utilized microcell fusion to transfer chromosomes from rhabdomyosarcoma cells into C2C12 myoblasts. Transfer of a derivative chromosome 14 inhibits differentiation. The derivative chromosome 14 contains a DNA amplification. MDM2 is amplified and overexpressed in these nondifferentiating hybrids and in the parental rhabdomyosarcoma. Forced expression of MDM2 inhibits MyoD-dependent transcription. Expression of antisense MDM2 restores MyoD-dependent transcriptional activity. We conclude that amplification and overexpression of MDM2 inhibit MyoD function, resulting in a dominant nondifferentiating phenotype.
Mol Cell Biol 1996 Sep
PMID:Amplification of MDM2 inhibits MyoD-mediated myogenesis. 875 63

Cancer malignancy is directly related to invasiveness and metastasis and inversely related to the degree of tumor differentiation. The relation between the stage of cell differentiation and the types of invasion leading to metastasis is not entirely clear. Intramuscularly transplanted rat rhabdomyosarcomas are good models to study cell differentiation, invasion, and metastasis. Rat rhabdomyosarcoma cell lines (SMF-Ai, SMF-Da, and RMS-B and its clones) with defined invasive and metastatic potentials have been established. The stage of myogenic differentiation was evaluated morphologically and by immunohistochemistry. Invasiveness was evaluated according to the infiltration of muscle fibers and basal lamina. The SMF-Ai line is highly invasive and metastatic. It is composed of premyoblasts that were involved in intercellular, translaminar, and transcellular invasion of muscle fibers. The SMF-Da line is noninvasive and nonmetastatic. It is composed of myoblasts. The RMS-B line and its clones were at different stages of differentiation and they differed in their invasiveness and metastatic potentials. In highly invasive and metastatic clones (RMS-Bg and RMS-Bc), premyoblasts were involved in translaminar invasion. Clones composed of myoblasts, rhabdomyoblasts, and myotubes only showing intercellular invasion did not present hematogenous metastasis. Our results demonstrate a correlation between premyoblastic stage of differentiation and translaminar invasion. The presence of translaminar invasion is directly related to hematogenous metastatic ability of rat rhabdomyosarcomas.
Exp Mol Pathol 1995 Aug
PMID:Correlation between cell differentiation stage, types of invasion, and hematogenous metastasis in experimental rhabdomyosarcomas. 875 49

p57KIP2 is a potent tight-binding inhibitor of several G1 cyclin complexes, and is a negative regulator of cell proliferation. The gene encoding human p57KIP2 is located on chromosome 11p15.5, a region implicated in both sporadic cancers and Beckwith-Wiedemann syndrome (BWS), a cancer syndrome, making it a tumor suppressor candidate. Several types of childhood tumors including Wilms' tumor, adrenocortical carcinoma and rhabdomyosarcoma display a specific loss of maternal 11p15 alleles, suggesting that genomic imprinting plays an important part. Genetic analysis of the familial BWS has indicated maternal carriers and suggested a role in genomic imprinting. Previously, we demonstrated that p57KIP2 is imprinted in the mouse. Here we describe the genomic imprinting of human p57KIP2 and the reduction of its expression in Wilms' tumors. High resolution mapping locates p57KIP2 in the region responsible for both tumor suppressivity and BWS.
Hum Mol Genet 1996 Jun
PMID:Genomic imprinting of human p57KIP2 and its reduced expression in Wilms' tumors. 877 93

In the pediatric cancer alveolar rhabdomyosarcoma, characteristic t(2;13)(q35;q14) or variant t(1;13)(p36;q14) chromosomal translocations generate PAX3-FKHR or PAX7-FKHR fusion genes. Using fluorescence in situ hybridization, reverse transcriptase-polymerase chain reaction and quantitative Southern blot analyses, we demonstrate that these fusion genes are amplified in 20% of fusion-positive tumors. In particular, we found in vivo amplification of these fusions in one of 22 PAX3-FKHR-positive cases and five of seven PAX7-FKHR-positive cases. These findings indicate that translocation and amplification can occur sequentially in a cancer to alter both the structure and copy number of a gene and thereby activate oncogenic activity by complementary mechanisms.
Hum Mol Genet 1996 Jan
PMID:In vivo amplification of the PAX3-FKHR and PAX7-FKHR fusion genes in alveolar rhabdomyosarcoma. 878 35

Gene transfection has been accomplished with a variety of techniques such as DEAE dextran, calcium phosphate coprecipitation, protoplast fusion, liposomes, microinjection and recombinant bacteriophages. However, transfection by electroporation, consisting of the reversible permeabilization of cell membranes after exposure to a pulsed electric field, has been shown to be the most rapid, simple and efficient method for the stable incorporation of genes in different cell lines. We studied rhabdomyosarcoma cells subjected to electroporation in two different vol. [400 microliters (group 1) and 150 microliters (group 2] of 140 mM NaCl/15 mM Hepes buffer, pH 7.2) and evaluated the effects of electroporation volume on growth and differentiation. Low sample volumes induced a terminal process of morphological and ultrastructural myogenic differentiation in rhabdomyosarcoma cells, which concluded with cell death. Our results suggest that in electroporation low sample vol. of rhabdomyosarcoma cells induced morphological and phenotypic differentiation, with increased expression of desmin, alpha-actinin and tropomyosin.
Cell Mol Biol (Noisy-le-grand) 1996 Dec
PMID:Low sample volume causes differentiation in human rhabdomyosarcoma cell line RD subjected to electroporation. 899 25

Alveolar rhabdomyosarcoma is a pediatric soft-tissue tumor that is often difficult to distinguish from other small round-cell tumors. The PAX3-FKHR and PAX7-FKHR gene fusions that result from chromosomal translocations in this tumor provide potential molecular diagnostic markers. To apply these molecular markers to commonly available archival material, we used reverse transcriptase-polymerase chain reaction and oligonucleotide hybridization methodology to develop an assay capable of identifying PAX3-FKHR and PAX7-FKHR fusion transcripts in formalin-fixed, paraffin-embedded tissue. Use of a control assay for wild-type FKHR mRNA indicated that RNA was successfully isolated, reverse-transcribed, and amplified in 15 of 16 archival cases. Comparison of assay results for the PAX3-FKHR and PAX7-FKHR fusions with standard molecular assays of paired frozen material revealed that all eight cases of known fusion-positive rhabdomyosarcoma were correctly identified and distinguished as PAX3-FKHR or PAX7-FKHR. The seven cases of known fusion-negative rhabdomyosarcoma showed no evidence of either product. These results indicate that we have developed a molecular assay that accurately identifies the fusion transcripts characteristic of alveolar rhabdomyosarcoma in archival samples. This assay will be useful for diagnosis and for retrospective clinicopathologic correlative studies.
Diagn Mol Pathol 1997 Apr
PMID:Detection of gene fusions in rhabdomyosarcoma by reverse transcriptase-polymerase chain reaction assay of archival samples. 909 47


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