Disease relevance of PAX3

• Epistatic relationship between Waardenburg syndrome genes MITF and PAX3 [1].
• Gene expression signatures identify rhabdomyosarcoma subtypes and detect a novel t(2;2)(q35;p23) translocation fusing PAX3 to NCOA1 [2].
• In the pediatric cancer alveolar rhabdomyosarcoma (ARMS), the 2;13 chromosomal translocation juxtaposes the PAX3 and FKHR genes to generate a chimeric transcription factor [3].
• To explore molecular pathways altered by this oncoprotein, we generated an inducible form by fusing PAX3-FKHR to a modified estrogen receptor ligand-binding domain and expressed this construct in the RD embryonal rhabdomyosarcoma cell line [3].
• Genes responsible for syndromic forms of hearing loss include the COL4A5 gene in Alport syndrome and the PAX3 and MITF genes in Waardenburg syndrome [4].

Psychiatry related information on PAX3

• During early human development, PAX6 and PAX3 genes seem to be involved in the brain regionalization and establishment of dorso-ventral polarity of the spinal cord [5].
• While further studies continue, possible interpretations include involvement of a regulatory gene(s) for PAX 3 and other genes at the other breakpoints related causally to the spina bifida and mental retardation [6].

High impact information on PAX3

• Two recent papers provide compelling evidence that hair graying is due to incomplete melanocyte stem cell maintenance and identify Pax3 and Mitf as key molecules that help regulate the balance between melanocyte stem cell maintenance and differentiation [7].
• We further show that PAX3 proteins associated with WS1 in either the paired domain or the homeodomain fail to recognize and transactivate the MITF promoter [1].
• Depending on additional symptoms, WS is classified into four types: WS1, WS2, WS3 and WS4 [1].
• WS type 1 is normally caused by mutations in PAX3 located at chromosome 2q35 and is distinguished clinically by minor facial malformations [8].
• Rearrangement of the PAX3 paired box gene in the paediatric solid tumour alveolar rhabdomyosarcoma [9].

Chemical compound and disease context of PAX3

• Substitution of a basic amino acid for asparagine at residue 47, conserved in all known murine Pax and human PAX genes, appears to have a more drastic effect on the phenotype than missense, frameshift and deletion mutations of PAX3 that cause Waardenburg syndrome type 1 [10].
• PAX3 methylation was analyzed in 15 embryonal rhabdomyosarcomas, 12 alveolar rhabdomyosarcomas, and in six normal skeletal muscle samples, using semi-quantitative PCR analysis of DNA digested with methyl-sensitive restriction enzymes [11].
• PAX3/forkhead homolog in rhabdomyosarcoma oncoprotein activates glucose transporter 4 gene expression in vivo and in vitro [12].
• Analysis of select folate pathway genes, PAX3, and human T in a Midwestern neural tube defect population [13].
• Transfection of melanoma cells with antisense PAX3 oligonucleotides additively complements cisplatin-induced cytotoxicity [14].

Biological context of PAX3

• Analyses revealed that PAX3 and SOX10 interact directly by binding to a proximal region of the MITF promoter containing binding sites for both factors [15].
• PAX3 has been shown to regulate MITF gene expression [15].
• Here we show that SOX10, in synergy with PAX3, strongly activates MITF expression in transfection assays [15].
• In our study, we investigated alternative splicing of the wild-type and fusion forms of PAX3 and PAX7 in alveolar and embryonal RMS and assessed the functional implications [16].
• Here we show that the folate metabolic enzyme ALDH1L1 is cell-specifically expressed in PAX3-negative radial glia at the midline of the neural tube during early murine embryogenesis [17].

Anatomical context of PAX3

• Here, we demonstrate that PAX3, which is often mutated in Waardenburg syndrome, is required for normal enteric ganglia formation [18].
• Although PAX3-FKHR exhibits transforming activity in immortalized fibroblast cell lines, a direct role of this fusion protein in tumorigenesis in vivo has not been shown [19].
• Among metastatic ARMS, bone marrow involvement was significantly higher in PAX3-FKHR-positive patients [20].
• Pax3 and Pax7 are specifically expressed in the dorsal neural tube and the developing somite [21].
• Loss-of-function mutations of Pax3 in Splotch mice and in Waardenburg syndrome in man revealed that Pax3 is necessary for the proper formation of caudal neural crest derivatives and for the migration of myoblasts into the limb [21].

Associations of PAX3 with chemical compounds

• The NH2-terminal paired box and homeodomain DNA-binding domains of PAX3 are fused in frame to COOH-terminal regions of the chromosome 13-derived FKHR gene, a novel member of the forkhead DNA-binding domain family [22].
• CONCLUSIONS: The results indicate that the RT-PCR assay is a reliable method for the detection of the PAX3-FKHR fusion transcript of alveolar RMS in formalin-fixed, paraffin-embedded tissue [23].
• We validated proper expression, specific DNA binding, corepressor interaction, and nuclear localization for the KRAB-PAX3-HBD protein and showed it to be a 4-hydroxytamoxifen-dependent transcriptional repressor of transiently transfected and integrated PAX3 reporters in ARMS cells [24].
• In addition, Pax3 transfectants having high PSA-NCAM show heterophilic adhesion involving polysialic acid to heparan sulfate proteoglycan and agrin [25].
• The aims of this study were to examine whether Pax3 expression is decreased in the heart of E13 E15 and E21 rats exposed to nitrofen and if vitamin A reverts this effect [26].

Physical interactions of PAX3

• In this report we demonstrate that human Daxx (hDaxx) interacts with Pax3 in vivo and with DNA-bound Pax3 in vitro [27].
• The t(2;13) chromosomal translocation in alveolar rhabdomyosarcoma tumors (ARMS) creates an oncogenic transcriptional activator by fusion of PAX3 DNA binding motifs to a COOH-terminal activation domain derived from the FKHR gene [28].

Regulatory relationships of PAX3

• Furthermore, we show that the BMP antagonist Noggin is expressed within the dorsomedial lip of the dermomyotome, where Pax3-expressing cells first initiate the expression of MyoD and Myf5 to give rise to myotomal cells in the medial somite [29].
• Through this interaction hDaxx represses the transcriptional activity of Pax3 by approximately 80% [27].
• In contrast, Pax3-negative cells in the grafted ectoderm are induced to express the epibranchial placode marker Pax2 and form neurons in the nodose ganglion that express the epibranchial neuron marker Phox2a on the same schedule as host nodose neurons [30].
• We demonstrate here that Pax3/FKHR more potently induces a MET in SaOS-2 cells than Pax3 [31].

Other interactions of PAX3

• Here we show that PAX3, a transcription factor with a paired domain and a homeodomain, transactivates the MITF promoter [1].
• FOXO1 gene is fused to PAX3 or PAX7 genes in rhabdomyosarcoma [32].
• Transcriptional regulation of IGF-I receptor gene expression by the PAX3-FKHR oncoprotein [33].
• We also observed that cell lines derived from alveolar RMS, which is characterized by recurrent PAX3- and PAX7-FKHR gene fusions and is associated with a poor prognosis, expressed higher levels of CXCR4 than lines derived from embryonal RMS [34].
• Additionally, PAX6 participates in organogenesis of the eye and the pituitary gland, and PAX3 in the development of face and neck mesenchyme [5].

Analytical, diagnostic and therapeutic context of PAX3

• In this report, we have used the published cDNA sequence to further define the genomic structure of PAX3, using inverse PCR [35].
• In one such case, RT-PCR analysis of candidate partners identified a fusion of PAX3 to AFX, which is highly similar in structure and function to FKHR [36].
• Using electrophoretic mobility shift assays, an ATTA binding site for PAX3 and PAX3/FKHR could be localized in the upstream promoter region (position -42 to -39) [37].
• Functional dissection of the gene's 5'-flanking region, which had been fused to a luciferase reporter gene and transiently expressed in rhabdomyosarcoma (RD) and cos-7 cells, indicated that the upstream region of PAX3 contains multiple positive and negative cis-acting regulatory elements [38].
• Sequence analysis of the last intron of PAX3, which contains the previously mapped t(2;13)(q35;q14) translocation breakpoints of alveolar rhabdomyosarcoma, revealed the presence of a pair of inverted Alu repeats and a pair of inverted (GT)n-rich microsatellite repeats within a 5-kb region [39].

References