Pax-3 contains domains for transcription activation and transcription inhibition.

Chalepakis, Georges; Jones, Frederick S.; Edelman, Gerald M.; Gruß, Peter

doi:10.1073/pnas.91.26.12745

Cited by 124 publications

(107 citation statements)

References 27 publications

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“…In cotransfection assays, PAX3 was able to activate this promoter up to 4.7-fold in mouse ®broblasts and up to 13.7-fold in mouse myoblasts. This activation was dosage-dependent in that higher levels of PAX protein resulted in loss of activity as reported earlier (Bennicelli et al, 1996;Chalepakis et al, 1994). Interestingly, transcriptional activity of the PAX3/FKHR fusion protein increased the basal promoter activity up to 11.4 times in mouse myoblasts, in contrast to ®broblasts where the fusion protein behaved similarly to native Pax3.…”

Section: Discussionsupporting

confidence: 74%

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: Discussionsupporting

confidence: 74%

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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“…In these assays, PAX3 activated transcription from MITF, TYRP1 and RET binding sites, whereas PAX3 repressed transcription from the NCAM element (Chalepakis et al, 1994b;Galibert et al, 1999;Lang et al, 2000;Watanabe et al, 1998). In the case of the PDGFRA site, the ®nding of activation by PAX3 ± FKHR but not PAX3 supports the gain of transcriptional function model described previously (Epstein et al, 1998).…”

Section: Transcriptional Targets Of Wild-type and Chimeric Pax Proteinssupporting

confidence: 63%

“…Deletion analysis localized the inhibitory activity to two N-terminal domains, the homeodomain and the N-terminus including the ®rst half of the paired box (Bennicelli et al, 1996 (Figure 3). These same two regions were also shown to have independent transcriptional repression activity when fused to the GAL4 DNA binding domain (Chalepakis et al, 1994b). Protein interaction studies subsequently determined that the putative co-repressors DAXX, RB1, and HIRA bind to PAX3, and for DAXX and HIRA, interactions with PAX7 were also noted Magnaghi et al, 1998;Wiggan et al, 1998).…”

Section: Transcriptional Properties Of Wild-type and Chimeric Pax Promentioning

confidence: 98%

“…These putative binding sites contain sequences resembling a paired box binding motif (NF1, MET and RET), a homeobox binding motif (PDGFRA and BCL ± XL), or both motifs (MITF, TYRP1 and NRCAM). In one other study, a fragment from the NCAM promoter was shown to bind to cellular extracts expressing the paired box but not extracts expressing the entire PAX3 protein and thus the signi®cance of this binding site is unclear (Chalepakis et al, 1994b).…”

Section: Transcriptional Targets Of Wild-type and Chimeric Pax Proteinsmentioning

confidence: 99%

“…To investigate the di ering transcriptional potencies of the wild-type and fusion proteins, initial studies focused on the activities of the C-terminal PAX3, PAX7, and FKHR regions Chalepakis et al, 1994b;Sublett et al, 1995). These C-terminal regions were examined independent of the respective DNA binding domains by generating fusions with the GAL4 DNA binding domain.…”

Section: Transcriptional Properties Of Wild-type and Chimeric Pax Promentioning

confidence: 99%

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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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Neurulation abnormalities secondary to altered gene expression in neural tube defect susceptible splotch embryos

Bennett

Craig

et al. 1998

Teratology

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Pax-3 contains domains for transcription activation and transcription inhibition.

Cited by 124 publications

References 27 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

Gene fusions involving PAX and FOX family members in alveolar rhabdomyosarcoma

Neurulation abnormalities secondary to altered gene expression in neural tube defect susceptible splotch embryos

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