Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

EEC syndrome is an autosomal dominant disorder characterized by ectrodactyly, ectodermal dysplasia, and facial clefts. We have mapped the genetic defect in several EEC syndrome families to a region of chromosome 3q27 previously implicated in the EEC-like disorder, limb mammary syndrome (LMS). Analysis of the p63 gene, a homolog of p53 located in the critical LMS/EEC interval, revealed heterozygous mutations in nine unrelated EEC families. Eight mutations result in amino acid substitutions that are predicted to abolish the DNA binding capacity of p63. The ninth is a frameshift mutation that affects the p63alpha, but not p63beta and p63gamma isotypes. Transactivation studies with these mutant p63 isotypes provide a molecular explanation for the dominant character of p63 mutations in EEC syndrome.
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PMID:Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome. 1053 33

The p53 gene is the most frequently mutated gene in human cancer. The identification of two homologues, p63 and p73, revealed that p53 is a member of a family of related transcription factors. Given that they share amino acid sequence identity reaching 63% in the DNA-binding domain, p53, p63 and p73 should have redundant functions in the regulation of gene expression. Indeed, p73 can activate p53-regulated genes and suppress growth or induce apoptosis. Moreover, p53 and p73 are both induced by DNA damage - albeit through distinct mechanisms. Other evidence, however, suggests that p63 and p73 are important for regulation of normal development. An extended C-terminal region, not found in p53, is alternatively spliced in p63 and p73. Within this C-terminal extension is a sterile &agr; motif (SAM) previously found in other proteins that regulate development. The p63-deficient mice showed developmental abnormalities. Interestingly, the human p63 gene is mutated in children who have the disease Ectrodactyly, Ectodermal dysplasia and facial Clefts (EEC) syndrome, and the disease phenotype is similar to the one of p63-deficient mice. The p63 and p73 genes are rarely mutated in human cancer, although p73 loss is observed in neuroblastoma and a subtype of T-cell lymphoma. p53, p63 and p73 appear to have overlapping and distinct functions: p53 regulates the stress response to suppress tumors; p63 is essential for ectoderm development; and p73 might regulate both the stress response and development. Because p53 and p73 are linked to different upstream pathways, this family of transcription factors might regulate a common set of genes in response to different extracellular signals and developmental cues.
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PMID:The p53/p63/p73 family of transcription factors: overlapping and distinct functions. 1076 97

Split-hand/split-foot malformation (SHFM), a limb malformation involving the central rays of the autopod and presenting with syndactyly, median clefts of the hands and feet, and aplasia and/or hypoplasia of the phalanges, metacarpals, and metatarsals, is phenotypically analogous to the naturally occurring murine Dactylaplasia mutant (Dac). Results of recent studies have shown that, in heterozygous Dac embryos, the central segment of the apical ectodermal ridge (AER) degenerates, leaving the anterior and posterior segments intact; this finding suggests that localized failure of ridge maintenance activity is the fundamental developmental defect in Dac and, by inference, in SHFM. Results of gene-targeting studies have demonstrated that p63, a homologue of the cell-cycle regulator TP53, plays a critically important role in regulation of the formation and differentiation of the AER. Two missense mutations, 724A-->G, which predicts amino acid substitution K194E, and 982T-->C, which predicts amino acid substitution R280C, were identified in exons 5 and 7, respectively, of the p63 gene in two families with SHFM. Two additional mutations (279R-->H and 304R-->Q) were identified in families with EEC (ectrodactyly, ectodermal dysplasia, and facial cleft) syndrome. All four mutations are found in exons that fall within the DNA-binding domain of p63. The two amino acids mutated in the families with SHFM appear to be primarily involved in maintenance of the overall structure of the domain, in contrast to the p63 mutations responsible for EEC syndrome, which reside in amino acid residues that directly interact with the DNA.
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PMID:Split-hand/split-foot malformation is caused by mutations in the p63 gene on 3q27. 1083 77

A human p53 homologue, p63 (p40/p51/p73L/CUSP) that maps to the chromosomal region 3q27-29 was found to produce a variety of transcripts that encode DNA-binding proteins with and without a trans-activation domain (TA- or Delta N-, respectively). The p63 gene locus was found to be amplified in squamous cell carcinoma, and overexpression of Delta Np63 (p40) led to increased growth of transformed cells in vitro and in vivo. Moreover, p63-null mice displayed abnormal epithelial development and germ-line human mutations were found to cause ectodermal dysplasia. We now demonstrate that certain p63 isotypes form complexes with p53. p53 mutations R175H or R248W abolish the association of p53 with p63, whereas V143A or R273H has no effect. Deletion studies suggest that the DNA-binding domains of both p53 and p63 mediate the association. Overexpression of wild type but not mutant (R175H) p53 results in the caspase-dependent degradation of certain Delta Np63 proteins (p40 and Delta Np63 alpha). The association between p53 and Delta Np63 supports a previously unrecognized role for p53 in regulation of Delta Np63 stability. The ability of p53 to mediate Delta Np63 degradation may balance the capacity of Delta Np63 to accelerate tumorigenesis or to induce epithelial proliferation.
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PMID:p53 associates with and targets Delta Np63 into a protein degradation pathway. 1117 34

p63 is the most recently discovered but most ancient member of the p53 family. In marked contrast to p53, p63 is highly expressed in embryonic ectoderm and in the basal, regenerative layers of many epithelial tissues in the adult. The p63-knockout mouse dies at birth and lacks limbs, epidermis, prostate, breast and urothelial tissues, apparently owing to the loss of stem cells required for these tissues. Significantly, several dominant human syndromes involving limb development and/or ectodermal dysplasia have been mapped to chromosome 3q27 and ultimately the gene encoding p63. The heterozygous p63mutations are distinct for each of the syndromes and are thought to act through both dominant-negative and gain-of-function mechanisms rather than a loss-of-function haploinsufficiency. The allele specificity of these syndromes offers unique molecular insights into the poorly understood actions of p63 in limb development, ectodermal-mesodermal interactions and stem cell maintenance.
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PMID:Mutations in the p53 homolog p63: allele-specific developmental syndromes in humans. 1187 74

The P63 gene is a recently discovered member of the p53 family. While P53 is ubiquitously expressed, p63 is expressed specifically in embryonic ectoderm and in the basal regenerative layers of epithelial tissues in the adult. Complete abrogation of P63 gene function in an animal model points to the relevance of P63 for the proper development of ectodermally derived tissues. The p63 knockout mouse dies at birth and has truncation of the limbs, as well as absence of epidermis, prostate, breast, and urothelial tissues, apparently reflecting ectodermal stem cell loss. A number of dominant human syndromes have been mapped to chromosome 3q27 and ultimately to mutations in the p63 gene. These syndromes have abnormal limb development and/or ectodermal dysplasia and include ectrodactyly, ectodermal dysplasia, clefting syndrome; ankyloblepharon, ectodermal dysplasia, clefting syndrome; acro-dermato-ungual-lacrimal-tooth syndrome; limb-mammary syndrome; as well as nonsyndromic split hand/foot malformation. The pattern of heterozygous mutations is distinct for each of these syndromes. Consistent with this syndrome-specific mutational pattern, the functional consequences of mutations on the p63 proteins also vary, invoking dominant-negative and gain-of-function mechanisms rather than a simple loss of function.
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PMID:P63 gene mutations and human developmental syndromes. 1235 72

p63 is a transcription factor structurally related to the p53 tumor suppressor. The C-terminal region differs from p53's in that it contains a sterile alpha motif (SAM) domain and is subject to multiple alternative splicings. The N-terminal region is present in the transactivation (TA) and DeltaN configurations, with the latter lacking the transcriptional activation domain 1. Single amino acid substitutions and frameshift mutations of p63 cause the human ankyloblepharon ectodermal dysplasia clefting (AEC) or ectrodactyly ectodermal dysplasia and facial clefting (EEC) syndromes. We have systematically compared the activities of the wild-type p63 isoforms and of the natural mutants in activation and repression assays on three promoters modulated by p53. We found that p63 proteins with an altered SAM domain or no SAM domain-the beta isoforms, the EEC frameshift mutant, and the missense AEC mutations-all showed a distinctly higher level of activation of the MDM2 promoter and decreased repression on the HSP70 promoter. Fusion of SAM to the GAL4 DNA-binding domain repressed a heterologous promoter. A second activation domain, TA2, corresponding to exons 11 to 12, was uncovered by comparing the activation of DeltaN isoforms on natural promoters and in GAL4 fusion systems. In colony formation assays, the AEC mutants, but not the EEC frameshift, were consistently less efficient in suppressing growth, in both the TA version and the DeltaN version, with respect to their p63alpha counterparts. These data highlight the modularity of p63, identifying the SAM domain as a dominant transcriptional repression module and indicating that the AEC and EEC frameshift mutants are characterized by a subversion of the p63 transcriptional potential.
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PMID:Complex transcriptional effects of p63 isoforms: identification of novel activation and repression domains. 1244 84

p63, a p53 family member, is required for craniofacial and limb development as well as proper skin differentiation. However, p63 mutations associated with the ankyloblepharon-ectodermal dysplasia-clefting (AEC) syndrome (Hay-Wells syndrome) were found in the p63 carboxyl-terminal region with a sterile alpha-motif. By two-hybrid screen we identified several proteins that interact with the p63alpha carboxyl terminus and its sterile alpha-motif, including the apobec-1-binding protein-1 (ABBP1). AEC-associated mutations completely abolished the physical interaction between ABBP1 and p63alpha. Moreover the physical association of p63alpha and ABBP1 led to a specific shift of FGFR-2 alternative splicing toward the K-SAM isoform essential for epithelial differentiation. We thus propose that a p63alpha-ABBP1 complex differentially regulates FGFR-2 expression by supporting alternative splicing of the K-SAM isoform of FGFR-2. The inability of mutated p63alpha to support this splicing likely leads to the inhibition of epithelial differentiation and, in turn, accounts for the AEC phenotype.
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PMID:P63 alpha mutations lead to aberrant splicing of keratinocyte growth factor receptor in the Hay-Wells syndrome. 1269 35

Lines of evidence have recently indicated a relationship between mutations in the P63 gene and ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome type 3 (EEC3). The p63 gene (P63) has homology to P53 known as a tumor-suppressor gene, but biological function of its protein has not yet been known well. There have been two reported patients who had EEC syndrome associated with malignant lymphoma. However, they did not undergo sequencing analysis of P63. Here, we present with a Japanese girl who had EEC3 and developed diffuse large B-cell type non-Hodgkin lymphoma. In this patient, we documented a heterozygous germline mutation, Asp312Gly, in P63. We speculated that p63 may exert a biological function as a tumor suppressor. Malignant lymphoma should be considered as an important complication of EEC3.
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PMID:EEC syndrome type 3 with a heterozygous germline mutation in the P63 gene and B cell lymphoma. 1283 57

The Rapp-Hodgkin syndrome (RHS, MIM 129400) corresponds to a rare form of anhydrotic ectodermal dysplasia, which shares some features with the ectrodactyly, ectodermal dysplasia and cleft lip/palate syndrome (EEC, MIM 604292) resulting from TP63 mutations. We report here, in two unrelated patients with RHS, the identification of two distinct TP63 mutations, corresponding to a novel frameshift mutation (1709DelA, exon 14) located downstream the sterile alpha motif (SAM) domain and to a missense mutation (R279H, exon 7) within the DNA binding domain. Functional analysis of the R279H mutation, which had previously been reported in several EEC families, shows that this mutation disrupted the dominant negative activity of the DeltaNp63alpha and gamma isoforms on the transcriptional activity of TP53. This report shows, on a molecular basis, that RHS is also an EEC-like syndrome resulting from mutations of the TP63 gene, and highlights the wide phenotypic spectrum associated to TP63 mutations.
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PMID:The Rapp-Hodgkin syndrome results from mutations of the TP63 gene. 1293 57


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