The molecular basis of the undulated/Pax-1 mutation

Chalepakis, Georges; Fritsch, R.; Fickenscher, Helmut; Deutsch, Urban; Goulding, Martyn; Gruß, Peter

doi:10.1016/0092-8674(91)90434-z

Cited by 261 publications

(178 citation statements)

References 50 publications

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“…Although weaker, PAX3-FKHR formed a complex with probe 5 (Figure 2e, lane 2) that was similarly blocked (lane 3) and competed (lanes 5 and 7). Competition was also seen with unlabeled PRS9 oligonucleotide (lane 9), a variant of the e5 sequence that contains PD-and HD-binding sites (Chalepakis et al, 1991). Equivalent results were seen with PAX7-FKHR (Figure 2f).…”

Section: Pax3 and Pax-fkhr Bind The Myod Core Enhancermentioning

confidence: 83%

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PAX-FKHR function as pangenes by simultaneously inducing and inhibiting myogenesis

et al. 2007

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Alveolar rhabdomyosarcomas (ARMS) escape terminal differentiation despite exhibiting a skeletal muscle phenotype. To understand the role of the ARMS-specific PAX-FKHR proteins in myogenesis, we characterized their regulation of MyoD expression and function. Reporter assays show that PAX-FKHR transactivate MyoD expression through its 258 bp core enhancer. Gel-shift assays confirm that PAX-FKHR bind to core enhancer sequences showing similarity to consensus PAX3/PAX-FKHRbinding sites. We show that while PAX3-FKHR activates the expression of endogenous MyoD and myogenin proteins in transduced NIH3T3 fibroblasts, it inhibits them from terminally differentiating as shown by low myogenin and myosin heavy chain expression, and lack of myotube formation. Attenuation of MyoD transcriptional activity via phosphorylation coupled to the lack of cell cycle arrest is the underlying mechanism for the differentiation block. Lastly, we show that fibroblast growth factor receptor signaling likely mediates the inhibition of differentiation by PAX3-FKHR. In a single experimental system we demonstrate that PAX3-FKHR can simultaneously induce myogenesis while preventing its completion. We propose a model whereby PAX-FKHR commit a yet undefined precursor cell to the myogenic lineage while at the same time inhibit terminal differentiation, thereby contributing to ARMS formation.

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Section: Pax3 and Pax-fkhr Bind The Myod Core Enhancermentioning

confidence: 83%

“…Gel-shift assays were carried out essentially as described (Chalepakis et al, 1991). A complete description is found in the Supplementary Information.…”

Section: Emsa and Chromatin Immunoprecipitationmentioning

confidence: 99%

PAX-FKHR function as pangenes by simultaneously inducing and inhibiting myogenesis

et al. 2007

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“…The bipartite paired domain, which is composed of two distinct HTH-based subdomains joined by a short linker (8), is a well conserved DNA-binding structure present in a family of transcription factors controlling diverse developmental processes in a wide variety of vertebrate and invertebrate species (1). The two helical subdomains and the extended linker region allow a single paired domain to interact with up to 20 base pairs of DNA, and together provide a large number of base-specific major groove and minor groove contacts that contribute to the recognition of specific DNA sequences as potential targets for regulation (6,8,14). However, with nine distinct Pax genes in mammals and seven in Drosophila, understanding how individual paired domains achieve distinct target specificities is an important step toward identifying the downstream targets of these transcription factors during development.…”

Section: Discussionmentioning

confidence: 99%

The C-terminal Subdomain Makes an Important Contribution to the DNA Binding Activity of the Pax-3 Paired Domain

Vogan¹,

Gros

1997

Journal of Biological Chemistry

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The recognition of DNA targets by Pax-3 is achieved through the coordinate use of two distinct helix-turnhelix-based DNA-binding modules: a paired domain, composed of two structurally independent subdomains joined by a short linker, and a paired-type homeodomain. In mouse, the activity of the Pax-3 paired domain is modulated by an alternative splicing event in the paired domain linker region that generates isoforms (Q ؉ and Q ؊ ) with distinct C-terminal subdomain-mediated DNA-binding properties. In this study, we have used derivatives of a classical high affinity paired domain binding site (CD19-2/A) to derive an improved consensus recognition sequence for the Pax-3 C-terminal subdomain. This new consensus differs at six out of eight positions from the C-terminal subdomain recognition motif present in the parent CD19-2/A sequence, and includes a 5 -TT-3 dinucleotide at base pairs 15 and 16 that promotes high affinity binding by both Pax-3 isoforms. However, with a less favorable guanine at position 15, only the Q ؊ isoform retains high affinity binding to this sequence, suggesting that this alternative splicing event might serve to stabilize binding to suboptimal recognition sequences. Finally, mutagenic analysis of the linker demonstrates that both the sequence and the spacing in this region contribute to the enhanced DNAbinding properties of the Pax-3/Q ؊ isoform. Altogether, our studies establish a clear role for the Pax-3 C-terminal subdomain in DNA recognition and, thus, provide insights into an important mechanism by which Pax proteins achieve distinct target specificities.

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“…We elected to use 21 attributes (corresponding to 21 nucleotide positions) in the DNA sequence targeted by the paired domain. The specific nucleotide positions used in each case were obtained by making alignments of the DNA sequences using a few early publications as primary guidelines (mainly [21,23,30,31]). We thereafter assumed that the corresponding nucleotide positions were comparable as far as amino acid -nucleotide interactions were concerned.…”

Section: Binding Datamentioning

confidence: 99%

“…158 DNA-sites were aligned with ClustalW [58], adjusted by eye, and trimmed down to 21 nucleotides. The sites were adjusted using a range of sites tested ( [23] as a guide, using their nucleotides 4-24, as well as [21,30,31]). No gaps were allowed in the nucleotide alignment.…”

Section: Binding Datamentioning

confidence: 99%

Prediction of transcription factor binding to DNA using rule induction methods

Huss

Nordström

2006

Journal of Integrative Bioinformatics

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Abbreviations: early growth response (EGR), Rule Discovery System (RDS), transcription factor (TF), transcription factor binding site (TFBS)Supplementary information: The paired domain dataset used in this article can be downloaded, in tab-separated text format, from http://www.nada.kth.se/~hussm/pax/paxdata.txt. The dataset in RDS format is available on request to hussm@nada.kth.se. 2 Abstract Background

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The molecular basis of the undulated/Pax-1 mutation

Cited by 261 publications

References 50 publications

PAX-FKHR function as pangenes by simultaneously inducing and inhibiting myogenesis

PAX-FKHR function as pangenes by simultaneously inducing and inhibiting myogenesis

The C-terminal Subdomain Makes an Important Contribution to the DNA Binding Activity of the Pax-3 Paired Domain

Prediction of transcription factor binding to DNA using rule induction methods

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