A specific chromosomal abnormality in rhabdomyosarcoma

Douglass, Edwin C.; Valentine, Mark C.; Etcubanas, Erlinda; Parham, David M.; Webber, Bruce L.; Houghton, Peter J.; Green, A. A.

doi:10.1159/000132446

Cited by 291 publications

(135 citation statements)

References 11 publications

Supporting

Mentioning

132

Contrasting

Order By: Relevance

“…Human RMS cell lines, RH4 and RH5, were provided by D Shapiro (Department of Experimental Oncology, St. Jude Children's Research Hospital). The other human RMS cell lines, RH30 and CTR, were generously supplied by PJ Houghton and CP Reynolds respectively, which have been previously described (Douglass et al, 1987;Crouch et al, 1993). Cells were grown in either DMEM or RPMI-1640 medium supplemented with 10% or 15% fetal bovine serum (FBS, Gibco ± BRL, Gaithersburg, MD, USA), 2 mM glutamine, 50 units/ml penicillin and 50 mg/ml streptomycin at 378C and 5% CO 2 in a humidi®ed incubator.…”

Section: Cdna Clonesmentioning

confidence: 99%

AP-2 may contribute to IGF-II overexpression in rhabdomyosarcoma

et al. 1998

View full text Add to dashboard Cite

The human insulin-like growth factor II gene is regulated in a development-dependent manner and is not expressed in most adult tissues. However, high levels of insulin-like growth factor II mRNA are detected in many human tumors including rhabdomyosarcoma, an embryonal tumor of skeletal muscle origin. In this study, we demonstrate that the developmentally regulated transcription factor AP-2 is expressed at higher levels in human fetal skeletal muscle and rhabdomyosarcoma cells compared to human adult skeletal muscle. Endogenous insulin-like growth factor II mRNA derived from the P3 as well as transfected P3 promoter activity were modestly and consistently increased to the same extent following treatment of the rhabdomyosarcoma cell line RD with forskolin, a compound implicated in AP-2 transactivation. This e ect of AP-2 on increased transcriptional activity was con®rmed by nuclear run-on assays. Expression of AP-2B, a dominant-negative inhibitor of AP-2, suppressed the P3 promoter activity in AP-2 expressing RD cells. Furthermore, ®ve AP-2 protected regions corresponding to six AP-2 speci®c binding sites were detected in the insulin-like growth factor II P3 promoter. These data together suggest that AP-2 may contribute to the high expression of IGF-II in rhabdomyosarcoma cells.

show abstract

Section: Cdna Clonesmentioning

confidence: 99%

AP-2 may contribute to IGF-II overexpression in rhabdomyosarcoma

et al. 1998

View full text Add to dashboard Cite

show abstract

“…The alveolar subtype (aRMS) is the most aggressive with the poorest prognostic outcome. Over 85% of patients with aRMS carries a unique chromosomal translocation that produces a fusion protein known as PAX3-FKHR (Turc-Carel et al, 1986;Douglass et al, 1987;WangWuu et al, 1988). The chimeric transcription factor PAX3-FKHR contains intact N-terminal PAX3 DNAbinding domains (DBDs; the paired-box domain PD and the paired-type homeodomain HD) fused to the C-terminal region of FKHR containing truncated winged helix DBD and the activation domain (AD) of FKHR separated by a 330-amino acid linker region (Barr et al, 1993(Barr et al, , 1997Shapiro et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Identification of a new class of PAX3-FKHR target promoters: a role of the Pax3 paired box DNA binding domain

Zhang

Wang

2006

Oncogene

View full text Add to dashboard Cite

Alveolar rhabdomyosarcoma (aRMS), an aggressive skeletal muscle cancer, carries a unique t(2;13) chromosomal translocation resulting in the formation of a chimeric transcription factor PAX3-FKHR. This fusion protein contains the intact DNA-binding domains (PD: paired box binding domain; HD: paired-type homeodomain) of Pax3 fused to the activation domain of FKHR. Cells expressing Pax3 and PAX3-FKHR show vastly different gene expression patterns, despite that they share the same DNA-binding domains. We present evidence of a gain of function mechanism that allows the fusion protein to recognize and transcriptionally activate response elements containing a PD-specific binding site. This DNA recognition specificity is in contrast to the requirement for Pax3-specific target sequences that must contain a composite of PD-and HD-binding sites. Domain swapping studies suggest that an increased structural flexibility could account for the relaxed DNA targeting specificity in PAX3-FKHR. Here, we identify myogenin gene as a direct target of PD-dependent PAX3-FKHR activation pathway in vitro and in vivo. We demonstrate that PAX3-FKHR could induce myogenin expression in undifferentiated myoblasts by a MyoD independent pathway, and that PAX3-FKHR is directly involved in myogenin expression in aRMS cells.

show abstract

“…The majority of alveolar rhabdomyosarcomas are characterized by a speci®c chromosome translocation ± t(2;13)(q35;q14) (Douglass et al, 1987). This translocation has been shown to cause the fusion of 5' DNA-binding domains of the PAX3 gene to 3' regions of the FKHR gene, resulting in the expression of a chimeric protein product Galili et al, 1993).…”

Section: Introductionmentioning

confidence: 99%