Consistent chromosomal translocation in alveolar rhabdomyosarcoma

Turc‐Carel, Claude; Lizard-Nacol, Sarab; Justrabo, E; Favrot, M.; Philip, Thierry; Tabone, Eric

doi:10.1016/0165-4608(86)90069-5

Cited by 212 publications

(73 citation statements)

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“…This tumor consists of several different subtypes, depending primarily on their characteristic histology, with alveolar (RMS-A) and embryonal (RMS-E) subtypes being the two most common forms. The genesis of RMS-A usually involves a structural rearrangement of chromosome 13 with chromosomes 2 or 1 (Turc-Carel et al, 1986). This is thought to result in the fusion of the fkhr gene (a member of the forkhead family of transcription factors) with pax3 or pax7, respectively (Galili et al, 1993;Shapiro et al, 1993;Davis et al, 1994).…”

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confidence: 99%

Myostatin inhibits rhabdomyosarcoma cell proliferation through an Rb-independent pathway

et al. 2004

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Rhabdomyosarcoma (RMS) tumors are the most common soft-tissue sarcomas in childhood. In this investigation, we show that myostatin, a skeletal muscle-specific inhibitor of growth and differentiation is expressed and translated in the cultured RMS cell line, RD. The addition of exogenous recombinant myostatin inhibits the proliferation of RD cells cultured in growth media, consistent with the role of myostatin in normal myoblast proliferation inhibition. However, unlike normal myoblasts, upregulation of p21 was not observed. Rather, myostatin signalling resulted in the specific downregulation of both Cdk2 and its cognate partner, cyclin-E. The analysis of Rb reveals that there was no change in its phosphorylation status with myostatin treatment, consistent with D-type-cyclinCdk4/6 complexes being active in the absence of p21. Moreover, the activity of Rb appeared to be unchanged between treated and nontreated RD cells, as determined by the ability of Rb to bind E2F1. The examination of NPAT, a substrate of cyclin-E-Cdk2 involved in the transcriptional activation of replication-dependent histone gene expression, revealed that it undergoes a loss of phosphorylation with myostatin treatment. Supporting this, a downregulation in H4-histone gene expression was observed. These results suggest that myostatin could potentially be used as an inhibitor of RMS proliferation and define a previously uncharacterized, Rb-independent mechanism for the inhibition of muscle precursor cell proliferation by myostatin.

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Section: Introductionmentioning

confidence: 99%

Myostatin inhibits rhabdomyosarcoma cell proliferation through an Rb-independent pathway

et al. 2004

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“…The most prevalent ®nding in ARMS is a translocation, t(2;13)(q35-37;q14), which was detected in 70% of ARMS cases (Douglass et al, 1987;Turc-Carel et al, 1986;Wang-Wuu et al, 1988) (Figure 1). In addition, a variant translocation, t(1;13)(p36;q14), was identi®ed in a smaller subset of ARMS cases (Biegel et al, 1991;Oncogene (2001) 20, 5736 ± 5746 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc *Correspondence: FG Barr; E-mail: barrfg@mail.med.upenn.edu Douglass et al, 1991).…”

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Gene fusions involving PAX and FOX family members in alveolar rhabdomyosarcoma

2001

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The chromosomal translocations t(2;13)(q35;q14) and t(1;13)(p36;q14) are characteristic of alveolar rhabdomyosarcoma, a pediatric soft tissue cancer related to the striated muscle lineage. These translocations rearrange PAX3 and PAX7, members of the paired box transcription factor family, and juxtapose these genes with FKHR, a member of the fork head transcription factor family. This juxtaposition generates PAX3 ± FKHR and PAX7 ± FKHR chimeric genes that are expressed as chimeric transcripts that encode chimeric proteins. The fusion proteins, which contain the PAX3/PAX7 DNA binding domain and the FKHR transcriptional activation domain, activate transcription from PAX-binding sites with higher potency than the corresponding wild-type PAX proteins. This increased function results from the insensitivity of the FKHR activation domain to inhibitory e ects of N-terminal PAX3/PAX7 domains. In addition to altered function, the fusion products are expressed in ARMS tumors at higher levels than the corresponding wild-type PAX products due to two distinct mechanisms. The PAX7 ± FKHR fusion is overexpressed as a result of in vivo ampli®cation while the PAX3 ± FKHR fusion is overexpressed due to a copy number-independent increase in transcriptional rate. Finally, though FKHR subcellular localization is regulated by an AKTdependent pathway, the fusion proteins are resistant to these signals and show exclusively nuclear localization. Therefore, these translocations alter biological activity at the levels of protein function, gene expression, and subcellular localization with the cumulative outcome postulated to be aberrant regulation of PAX3/PAX7 target genes. This aberrant gene expression program is then hypothesized to contribute to tumorigenic behavior by impacting on the control of growth, apoptosis, di erentiation and motility. Oncogene (2001) 20, 5736 ± 5746.

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“…These are heterogeneous groups of malignant skeletal muscle tumors with alveolar rhabdomyosarcoma (aRMS) 1 as the more malignant subtype (4 -8). Most of the alveolar tumors carry a characteristic t(2,13)(q35;q14) chromosomal translocation (9,10), and a minor group of aRMS carries a variant t(1,13)(p36;q14) chromosomal translocation (11). Both chromosomal translocations result in the same inframe fusion of Pax genes (Pax3 gene from chromosome 2 and Pax7 gene from chromosome 1) to the FKHR gene located on chromosome 13 (11)(12)(13).…”

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confidence: 99%