#647 Upregulation of MET but not NCAM expression by the PAX3-FKHR fusion protein in alveolar rhabdomyosarcoma

Ginsberg, Jill P.; Davis, R. J.; Bennicelli, Jeannette L.; Nauta, Lauren E.; Barr, Frederic G.

doi:10.1097/00043426-199807000-00084

Cited by 71 publications

(88 citation statements)

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“…The data presented here support the notion that the majority of RMS cells will become dependent on PAX3 expression through its ability to maintain cell survival, mediated, at least in part, via direct regulation of BCL-XL. An oncogenic role of PAX3 is further supported by two additional observations: First, the oncogenic tyrosine kinase reporter c-met has been identi®ed as a common target gene for PAX3 and its fusion protein in myoblasts as well as RMS cells Ginsberg et al, 1998). Second, expression of either PAX3 and/or PAX7 is a common event in RMS (Frascella et al, 1998;SchaÈ fer et al, 1994) and possibly other tumors (FA Scholl, unpublished observation).…”

Section: Discussionmentioning

confidence: 89%

Transcriptional modulation of the anti-apoptotic protein BCL-XL by the paired box transcription factors PAX3 and PAX3/FKHR

et al. 2000

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The aberrant expression of the transcription factors PAX3 and PAX3/FKHR associated with rhabdomyosarcoma (RMS), solid tumors displaying muscle cell features, suggests that these proteins play an important role in the pathogenesis of RMS. We could previously demonstrate that one of the oncogenic functions of PAX3 and PAX3/FKHR in RMS is protection from apoptosis. BCL-XL is a prominent anti-apoptotic protein present in normal skeletal muscle and RMS cells. In the present study, we establish that BCL-XL is transcriptionally modulated by PAX3 and PAX3/FKHR, since enhanced expression of both PAX proteins stimulates transcription of endogenous BCL-XL mRNA in a cell type speci®c manner. Further, we present evidence that both PAX3 and PAX3/FKHR can transcriptionally activate the Bcl-x gene promoter in cotransfection assays. Using electrophoretic mobility shift assays, an ATTA binding site for PAX3 and PAX3/FKHR could be localized in the upstream promoter region (position 742 to 739). Finally, ectopic overexpression of either PAX3, PAX3/FKHR or BCL-XL can rescue tumor cells from apoptosis induced by antisense treatment. These results suggest that at least part of the anti-apoptotic e ect of PAX3 and PAX3/FKHR is mediated through direct transcriptional modulation of the prominent antiapoptotic protein BCL-XL.

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Section: Discussionmentioning

confidence: 89%

Transcriptional modulation of the anti-apoptotic protein BCL-XL by the paired box transcription factors PAX3 and PAX3/FKHR

et al. 2000

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“…Moreover, the c-met promoter contains putative Pax3 binding sites (Epstein et al, 1996;Phelan and Loeken, 1998). c-MET has been shown to be upregulated in human alveolar RMS expressing the PAX3-FKHR fusion protein (Epstein et al, 1996;Ferracini et al, 1996;Ginsberg et al, 1998); however, c-MET expression can reach comparable levels in a smaller fraction of human embryonal RMS lacking the t(2;13)(q35;q14) translocation as well (Ferracini et al, 1996;Ginsberg et al, 1998). These ®ndings implicate c-MET in human rhabdomyosarcomagenesis.…”

Section: The Patched/pax/met Connectionmentioning

confidence: 99%

Rhabdomyosarcoma – working out the pathways

1999

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Rhabdomyosarcomas constitute a collection of childhood malignancies thought to arise as a consequence of regulatory disruption of skeletal muscle progenitor cell growth and di erentiation. Our understanding of the pathogenesis of this neoplasm has recently bene®ted from the study of normal and malignant myogenic cells in vitro, facilitating the identi®cation of diagnostic cytogenetic markers and the elucidation of mechanisms by which myogenesis is regulated. It is now appreciated that the delicate balance between proliferation and di erentiation, mutually exclusive yet intimately associated processes, is normally controlled in large part through the action of a multitude of growth factors, whose signals are interpreted by members of the MyoD family of helix ± loop ± helix proteins, and key regulatory cell cycle factors. The latter have proven to be frequent targets of mutational events that subvert myogenesis and promote the development of rhabdomyosarcoma. Although signi®cant progress has been made in the treatment of rhabdomyosarcoma, patients presenting with metastatic disease or certain high risk features are still faced with a dismal prognosis. Only now are genetically engineered mouse models becoming available that are certain to provide fresh insights into the molecular/genetic pathways by which rhabdomyosarcomas arise and progress, and to suggest novel avenues of therapeutic opportunity.

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“…Furthermore, most of these studies used clones stably expressing the fusion protein, which precludes discrimination of direct from indirect regulatory events. Nevertheless, a number of potential target genes have been suggested by studies performed in heterologous systems such as c-met (Epstein et al, 1996;Ginsberg et al, 1998), MYCN (Khan et al, 1998), bcl-xl (Margue et al, 2000), CNR1 and BMP4 (Begum et al, 2005) or CXCR4 (Tomescu et al, 2004). However, the pathophysiological role of these target genes regarding aRMS development or maintenance remains largely unclear.…”

Section: Introductionmentioning

confidence: 99%

Comparative expression profiling identifies an in vivo target gene signature with TFAP2B as a mediator of the survival function of PAX3/FKHR

et al. 2007

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#647 Upregulation of MET but not NCAM expression by the PAX3-FKHR fusion protein in alveolar rhabdomyosarcoma

Cited by 71 publications

References 0 publications

Transcriptional modulation of the anti-apoptotic protein BCL-XL by the paired box transcription factors PAX3 and PAX3/FKHR

Transcriptional modulation of the anti-apoptotic protein BCL-XL by the paired box transcription factors PAX3 and PAX3/FKHR

Rhabdomyosarcoma – working out the pathways

Comparative expression profiling identifies an in vivo target gene signature with TFAP2B as a mediator of the survival function of PAX3/FKHR

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