Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0035412 (rhabdomyosarcoma)
 6,156 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have isolated two isoforms of cDNA clones from the human PAX3 gene, a candidate gene responsible for Waardenburg syndrome type I (WSI) as well as a gene associated with development of alveolar rhabdomyosarcoma. The gene product is considered to be one of transcription factors, and the two cDNA clones isolated, termed PAX3A and PAX3B, were generated by alternative splicing. The transcripts coded 215 and 206 amino acids, respectively, and shared 196 amino acids at the NH2 end. The amino acid sequence in the common region (residues 1-196) showed a 100% identity with that of exons 1-4 of the mouse Pax-3 gene. However, both of the PAX3 cDNAs lacked the DNA sequence corresponding to the paired-type homeodomain of the mouse Pax-3 gene. Analysis of gene expression in human adult tissues by reverse transcriptase polymerase chain reaction (RT-PCR) revealed tissue-specific expression of this gene. PAX3B was expressed in most of the tissues examined, but the PAX3A type of transcript was detected only in the cerebellum, esophagus, and skeletal muscle.
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PMID:Isolation of two isoforms of the PAX3 gene transcripts and their tissue-specific alternative expression in human adult tissues. 754 13

Mutations in the human PAX3 gene have previously been associated with two distinct diseases, Waardenburg syndrome and alveolar rhabdomyosarcoma. In this report we establish that the normal human PAX3 gene is encoded by 8 exons. Intron-exon boundary sequences were obtained for PAX3 exons 5, 6, 7, and 8 and together with previous work provide the complete genomic sequence organization for PAX3. Difficulties in obtaining overlapping genomic clone coverage of PAX3 were circumvented in part by RARE cleavage mapping, which showed that the entire PAX3 gene spans 100 kb of chromosome 2. 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. This work establishes the complete structure of PAX3 and will permit high-resolution analyses of this locus for mutations associated with Waardenburg syndrome, alveolar rhabdomyosarcoma, and other phenotypes for which PAX3 may be a candidate locus.
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PMID:Genomic organization of the human PAX3 gene: DNA sequence analysis of the region disrupted in alveolar rhabdomyosarcoma. 778 66

We have determined that PAX3 (found previously to be mutated in Waardenburg syndrome) is the chromosome 2 locus rearranged by the t(2;13)(q35;q14) translocation of the paediatric solid tumour alveolar rhabdomyosarcoma. The rearrangement breakpoints occur within an intron downstream of the paired box and homeodomain-encoding regions. Upstream PAX3 sequences hybridize to a novel transcript in t(2;13)-containing lines. Cloning and characterization of this novel transcript indicate that the translocation juxtaposes the PAX3 DNA binding elements with chromosome 13 sequences, suggesting formation of a hybrid transcription factor. Therefore, PAX3 gene alterations are associated with two completely unrelated human diseases.
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PMID:Rearrangement of the PAX3 paired box gene in the paediatric solid tumour alveolar rhabdomyosarcoma. 809 85

In recent years, the discovery of Pax genes in mouse has played an invaluable role in furthering our understanding in mouse developmental processes and disorders. To date, eight murine paired box-containing genes have been cloned. Seven of these exhibit a distinct spatiotemporal expression pattern in the developing nervous system implying a role in the regional specification of the developing spinal cord and brain. The Pax genes encode for sequence-specific DNA binding transcription factors that play a key role in embryonic development. Three of these developmental control genes are altered in mutant mice and two are associated with human diseases. Disruption of these Pax genes leads to abnormalities in neural crest derivatives, neuroectoderm, sclerotome or myotome-derived tissues. Disruption of the Pax-3 gene causes the Splotch phenotype in mice and Waardenburg syndrome in humans. Pax-6 mutations result in Small eye mice and the human genetic disorder aniridia. The Pax-1 gene is mutated in undulated mice. Pax proteins can transform cells in culture which then form tumours following injection in nude mice. Consistent with this activity, PAX3 has been recently implicated in the generation of the tumour alveolar rhabdomyosarcoma.
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PMID:Pax: gene regulators in the developing nervous system. 822 63

PAX3 is a member of the paired box family of transcription factors that function during embryogenesis and cancer epigenesis. Mutations in PAX3 cause Waardenburg syndrome (types 1 and 3), Craniofacial-deafness-hand syndrome and alveolar rhabdomyosarcoma in humans and the Splotch phenotype in mice. In this study, we describe the genomic structure of PAX3, including novel coding sequences and the complete 3' UTR. Alternative transcripts of PAX3 were identified in various tissues, including human adult skeletal muscle and mouse embryos. One of the novel alternative transcripts is evolutionarily conserved in quail and can transactivate a reporter construct containing the mouse c-met promoter. The sequences and alternative transcripts reported herein extend our understanding of the function and evolution of PAX3 in vertebrates and enable a comprehensive mutation screen for individuals with Waardenburg syndrome.
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PMID:PAX3 gene structure, alternative splicing and evolution. 1052 55

Pax3 is a transcription factor crucial for normal development and tumorigenesis. Pax3 has been known to cause Waardenburg syndrome and pediatric alveolar rhabdomyosarcoma, but how Pax3 regulates transcription is not clear. Here, we report that Pax3 represses transcription and selectively interacts with heterochromatin protein 1 (HP1) and KAP1. KAP1 functions as a transcriptional corepressor by recruiting HP1 to facilitate the formation of a closed chromatin through histone deacetylation and methylation. We found that KAP1 is a corepressor for Pax3 by augmenting the repressional activity of Pax3. Unexpectedly, HP1gamma diminishes the repressional activity of Pax3. On target promoters, KAP1 and HP1gamma compete for binding with Pax3 on the N-terminal paired domain, and the C-terminal domain of Pax3 governs the subcellular localization of Pax3. Taken together, our results indicate that Pax3 represses transcription through a novel mechanism involving competition between corepressor KAP1 and the heterochromatin-binding protein HP1gamma.
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PMID:Transcriptional repression activity of PAX3 is modulated by competition between corepressor KAP1 and heterochromatin protein 1. 1694 26

The paired box genes are a family of nine developmental control genes, which in human beings (PAX) and mice (Pax) encode nuclear transcription factors. The temporal and spatial expressions of these highly conserved genes are tightly regulated during foetal development including organogenesis. PAX/Pax genes are switched off during the terminal differentiation of most structures. Specific mutations within a number of PAX/Pax genes lead to developmental abnormalities in both human beings and mice. Mutation in PAX3 causes Waardenburg syndrome, and craniofacial-deafness-hand syndrome. The Splotch phenotype in mouse exhibits defects in neural crest derivatives such as, pigment cells, sympathetic ganglia and cardiac neural crest-derived structures. The PAX family also plays key roles in several human malignancies. In particular, PAX3 is involved in rhabdomyosarcoma and tumours of neural crest origin, including melanoma and neuroblastoma. This review critically evaluates the roles of PAX/Pax in oncogenesis. It especially highlights recent advances in knowledge of how their genetic alterations directly interfere in the transcriptional networks that regulate cell differentiation, proliferation, migration and survival and may contribute to oncogenesis.
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PMID:Pax genes in embryogenesis and oncogenesis. 1862 22

The transcription regulatory protein PAX3 binds to cognate DNA sequences through two DNA-binding domains, a paired domain and a homeodomain, and has important functions during neurogenesis and myogenesis. In humans, mutations in the PAX3 gene cause Waardenburg syndrome, whereas a chromosomal translocation that generates a PAX3-FOXO1 fusion gene is associated with the development of alveolar rhabdomyosarcoma. We have determined the crystal structure of the human PAX3 homeodomain in complex with a palindromic DNA containing two inverted TAATC sequences at 1.95 A resolution. Two homeodomains bind to DNA as a symmetric dimer, inducing a 3 degrees bend in the DNA helix. The N-terminal arm of the homeodomain inserts into the minor groove and makes direct and water-mediated interactions with bases and the sugar-phosphate backbone. The recognition helix fits directly into the major groove, and an elaborate network of structurally conserved water molecules mediates the majority of protein-DNA interactions. The structure elucidates the role of serine 50 in selection of the CG sequence immediately 3' of the TAAT motif by PAX class homeodomains and provides insights into the molecular mechanisms by which certain Waardenburg syndrome-associated missense mutations could destabilize the fold of the PAX3 homeodomain whereas others could affect its interaction with DNA.
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PMID:Structural basis for DNA recognition by the human PAX3 homeodomain. 1919 74

The PAX3 gene encodes a member of the PAX family of transcription factors that is characterized by a highly conserved paired box motif. The PAX3 protein is a transcription factor consisting of an N-terminal DNA binding domain (containing a paired box and homeodomain) and a C-terminal transcriptional activation domain. This protein is expressed during development of skeletal muscle, central nervous system and neural crest derivatives, and regulates expression of target genes that impact on proliferation, survival, differentiation and motility in these lineages. Germline mutations of the murine Pax3 and human PAX3 genes cause deficiencies in these developmental lineages and result in the Splotch phenotype and Waardenburg syndrome, respectively. Somatic genetic rearrangements that juxtapose the PAX3 DNA binding domain to the transcriptional activation domain of other transcription factors deregulate PAX3 function and contribute to the pathogenesis of the soft tissue cancers alveolar rhabdomyosarcoma and biphenotypic sinonasal sarcoma. The wild-type PAX3 protein is also expressed in other cancers related to developmental lineages that normally express this protein and exerts phenotypic effects related to its normal developmental role.
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PMID:The expression and function of PAX3 in development and disease. 2973 Apr 28