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

Ectrodactyly is a congenital limb malformation that involves a central reduction defect of the hands and/or feet which is frequently associated with other phenotypic abnormalities. The condition appears to be genetically heterogeneous and recently it has been demonstrated that mutations in the p63 gene, a homologue of the tumor suppressor gene p53, are the cause of at least four autosomal dominant genetic syndromes which feature ectrodactyly: ectrodactyly, ectodermal dysplasia, and facial clefting (EEC), split hand/split foot malformation (SHFM), limb-mammary syndrome (LMS), and acro-dermato-ungual-lacrimal-tooth syndrome (ADULT). In this study, genetic analysis of the p63 gene in a group of 13 patients with ectrodactyly (syndromic and isolated) was performed. Four patients with syndromic ectrodactyly had p63 heterozygous point mutations that affect the DNA binding domain of the protein. One of these subjects exhibited the typical features of EEC syndrome as well as ankyloblepharon being, to our knowledge, the first case combining these traits. This finding supports the view of a clinical overlap in this group of autosomal dominant syndromes caused by p63 mutations and demonstrates that there are exceptions in the previously established p63 genotype-phenotype correlation.
 ...
PMID:p63 gene analysis in Mexican patients with syndromic and non-syndromic ectrodactyly. 1465 52

The p53-related p63 gene encodes six isoforms with differing N and C termini. TAp63 isoforms possess a transactivation domain at the N terminus and are able to transactivate a set of genes, including some targets downstream of p53. Accumulating evidence indicates that TAp63 plays an important role in regulation of cell proliferation, differentiation, and apoptosis, whereas transactivation-inert deltaNp63 functions to inhibit p63 and other p53 family members. Mutations in the p63 gene that abolish p63 DNA-binding and transactivation activities cause human diseases, including ectrodactyly ectodermal dysplasia and facial clefting (EEC) syndrome. In this study, we show that mutant p63 proteins with a single amino acid substitution found in EEC syndrome are DNA binding deficient, transactivation inert, and highly stable. We demonstrate that TAp63 protein expression is tightly controlled by its specific DNA-binding and transactivation activities and that p63 is degraded in a proteasome-dependent, MDM2-independent pathway. In addition, the N-terminal transactivation domain of p63 is indispensable for its protein degradation. Furthermore, the wild-type TAp63gamma can act in trans to promote degradation of mutant TAp63gamma defective in DNA binding, and the TA domain deletion mutant of TAp63gamma inhibits transactivation activity and stabilizes the wild-type TAp63 protein. Taken together, these data suggest a feedback loop for p63 regulation, analogous to the p53-MDM2 feedback loop.
 ...
PMID:DNA-binding and transactivation activities are essential for TAp63 protein degradation. 1598 26

p63 is a developmentally regulated transcription factor related to p53, which activates and represses specific genes. The human AEC (Ankyloblepharon-Ectodermal dysplasia-Clefting) and EEC (Ectrodactyly-Ectodermal dysplasia-Cleft lip/palate) syndromes are caused by missense mutations of p63, within the DNA-binding domain (EEC) or in the C-terminal sterile alpha motif domain (AEC). We show here that p63 represses transcription of cell-cycle G(2)/M genes by binding to multiple CCAAT core promoters in immortalized and primary keratinocytes. The CCAAT-activator NF-Y and DeltaNp63alpha are associated in vivo and a conserved alpha-helix of the NF-YC histone fold is required. p63 AEC mutants, but not an EEC mutant, are incapable to bind NF-Y. DeltaNp63alpha, but not the AEC mutants repress CCAAT-dependent transcription of G(2)/M genes. Chromatin immunoprecipitation recruitment assays establish that the AEC mutants are not recruited to G(2)/M promoters, while normally present on 14-3-3sigma, which contains a sequence-specific binding site. Surprisingly, the EEC C306R mutant activates transcription. Upon keratinocytes differentiation, NF-Y and p63 remain bound to G(2)/M promoters, while HDACs are recruited, histones deacetylated, Pol II displaced and transcription repressed. Our data indicate that NF-Y is a molecular target of p63 and that inhibition of growth activating genes upon differentiation is compromised by AEC missense mutations.
 ...
PMID:Mechanisms of transcriptional repression of cell-cycle G2/M promoters by p63. 1647 49

p63 is a developmentally regulated transcription factor related to p53. It is involved in the development of ectodermal tissues, including limb, skin and in general, multilayered epithelia. The DeltaNp63alpha isoform is thought to play a 'master' role in the asymmetric division of epithelial cells. It is also involved in the pathogenesis of several human diseases, phenotypically characterized by ectodermal dysplasia. Our understanding of transcriptional networks controlled by p63 is limited, owing to the low number of bona fide targets. To screen for new targets, we employed chromatin immunoprecipitation from keratinocytes (KCs) coupled to the microarray technology, using both CpG islands and promoter arrays. The former revealed 96 loci, the latter yielded 85 additional genes. We tested 40 of these targets in several functional assays, including: (i) in vivo binding by p63 in primary KCs; (ii) expression analysis in differentiating HaCaT cells and in cells overexpressing DeltaNp63alpha; (iii) promoter transactivation and (iv) immunostaining in normal tissues, confirming their regulation by p63. We discovered several new specific targets whose functional categorization links p63 to cell growth and differentiation.
 ...
PMID:New p63 targets in keratinocytes identified by a genome-wide approach. 1703 50

Development of skin appendages such as teeth, hairs and many exocrine glands, is regulated by inductive interactions between epithelial and mesenchymal tissues. At the molecular level, this interplay is mediated by conserved signaling proteins of the Wnt, FGF, TGFbeta, hedgehog and TNF families and executed by their downstream transcriptional regulators. p63, a transcription factor of the p53 family, is essential for the development of epidermis and its derivatives in vertebrates. The genomic organization of p63 is complex leading to transcription of at least six different isoforms with different, possibly even opposite functions. In humans, dominantly inherited mutations in p63 lead to a plenitude of syndromes that are featured by ectodermal dysplasia and/or craniofacial and limb malformations. In mice, lack of p63 causes a striking phenotype including severely truncated limbs, and absence of stratified epithelia and skin derivatives including teeth, hair follicles and mammary, lacrimal and salivary glands. While the significance of p63 for the morphogenesis of skin appendages is obvious, the molecular pathways regulated by p63 are only now emerging. This review discusses the current knowledge on the role of p63 in skin appendage development with emphasis on teeth and hair follicles.
 ...
PMID:p63 in skin appendage development. 1726 78

p63 is a transcription factor homologous to p53 and p73; mutations in this gene have been identified in individuals with several types of developmental abnormalities, including EEC (ectrodactyly, ectodermal dysplasia, facial clefts) syndrome and split-hand/split-foot malformation (SHFM). Several mutations in the p63 gene have previously been shown to be related to SHFM. In this study, we report on a Chinese family with intrafamilial clinical variability of SHFM that have a novel heterozygous mutation in all four affected individuals. The mutation is in exon 8 of p63, 1046G --> A, which predicts an amino acid substitution G310E. SSCP analysis of the segregation pattern of the mutation strongly suggests a causal relationship to the SHFM phenotype in p63. This mutation has not been observed in other countries in the world.
 ...
PMID:A novel mutation of p63 in a Chinese family with inherited syndactyly and adactylism. 1791 61

The congenital malformation Split Hand-Foot Malformation (SHFM, or ectrodactyly) is characterized by a medial cleft of hands and feet, and missing central fingers. Five genetically distinct forms are known in humans; the most common (type-I) is linked to deletions of DSS1 and the distalless-related homeogenes DLX5 and DLX6. As Dlx5;Dlx6 double-knockout mice show a SHFM-like phenotype, the human orthologs are believed to be the disease genes. SHFM-IV and Ectrodactyly-Ectodermal dysplasia-Cleft lip (EEC) are caused by mutations in p63, an ectoderm-specific p53-related transcription factor. The similarity in the limb phenotype of different forms of SHFM may underlie the existence of a regulatory cascade involving the disease genes. Here, we show that p63 and Dlx proteins colocalize in the nuclei of the apical ectodermal ridge (AER). In homozygous p63- (null) and p63EEC (R279H) mutant limbs, the AER fails to stratify and the expression of four Dlx genes is strongly reduced; interestingly, the p63+/EEC and p63+/- hindlimbs, which develop normally and have a normally stratified AER, show reduced Dlx gene expression. The p63+/EEC mutation combined with an incomplete loss of Dlx5 and Dlx6 alleles leads to severe limb phenotypes, which are not observed in mice with either mutation alone. In vitro, DeltaNp63alpha induces transcription from the Dlx5 and Dlx6 promoters, an activity abolished by EEC and SHFM-IV mutations, but not by Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) mutations. ChIP analysis shows that p63 is directly associated with the Dlx5 and Dlx6 promoters. Thus, our data strongly implicate p63 and the Dlx5-Dlx6 locus in a pathway relevant in the aetio-pathogenesis of SHFM.
 ...
PMID:Regulation of Dlx5 and Dlx6 gene expression by p63 is involved in EEC and SHFM congenital limb defects. 1832 38

The epidermis, the outer layer of the skin composed of keratinocytes, is a stratified epithelium that functions as a barrier to protect the organism from dehydration and external insults. The epidermis develops following the action of the transcription factor p63, amember of the p53 family of transcription factors. The Trp63 gene contains two promoters driving the production of distinct proteins, one with an N-terminal transactivation domain (TAp63) and one without (DeltaNp63), although their relative contribution to epidermal development is not clearly established. Trp63 mutations are involved in the pathogenesis of several human diseases, phenotypically characterized by ectodermal dysplasia. In this review, we summarize the current advances that have been made in understanding the role of p63 in epidermal morphogenesis.
 ...
PMID:p63 in epithelial development. 1856 Jul 58

The epidermis is a stratified epithelium which develops depending on the transcription factor p63, a member of the p53 family of transcription factors. p63 is strongly expressed in the innermost basal layer where highly proliferative epithelial cells reside. p63 functions as a molecular switch that initiates epithelial stratification or cell fate determination while regulating proliferation and differentiation of developmentally mature keratinocytes. p63 acts upstream of Dlx3 homeobox gene in a transcriptional regulatory pathway relevant to ectodermal dysplasia. Here we show that Dlx3 triggers p63 protein degradation by a proteasome-dependent pathway. Mutant DeltaNp63alpha in which Threonine397 and Serine383 were replaced with Alanine as well as C-terminal truncated versions of DeltaNp63alpha are resistant to Dlx3-mediated degradation. Transient expression of Dlx3 is associated with Raf1 phosphorylation. Dlx3 is unable to promote p63 degradation in Raf1 depleted MEF cells or upon pharmacological knockdown of Raf1. Our data support a previously unrecognized role for Dlx3 in posttranslational regulation of DeltaNp63alpha protein level, a mechanism that may contribute to reduce the abundance of DeltaNp63alpha during differentiation of stratified epithelia.
 ...
PMID:Homeodomain protein Dlx3 induces phosphorylation-dependent p63 degradation. 1934 86

Colorectal cancers with mutations in the p53 gene have an invasive property, but its underlying mechanism is not fully understood. Through the screening of two data sets of the genome-wide expression profile, one for p53-introduced cells and the other for the numbers of cancer tissues, we report here X-linked ectodermal dysplasia receptor (XEDAR), a member of the TNFR superfamily, as a novel p53 target that has a crucial role in colorectal carcinogenesis. p53 upregulated XEDAR expression through two p53-binding sites within intron 1 of the XEDAR gene. We also found a significant correlation between decreased XEDAR expressions and p53 gene mutations in breast and lung cancer cell lines (P=0.0043 and P=0.0122, respectively). Furthermore, promoter hypermethylation of the XEDAR gene was detected in 20 of 20 colorectal cancer cell lines (100%) and in 6 of 12 colorectal cancer tissues (50%), respectively. Thus, the XEDAR expression was suppressed to <25% of surrounding normal tissues in 12 of 18 colorectal cancer tissues (66.7%) due to either its epigenetic alterations and/or p53 mutations. We also found that XEDAR interacted with and subsequently caused the accumulation of FAS protein, another member of p53-inducible TNFR. Moreover, XEDAR negatively regulated FAK, a central component of focal adhesion. As a result, inactivation of XEDAR resulted in the enhancement of cell adhesion and spreading, as well as resistance to p53-induced apoptosis. Taken together, our findings showed that XEDAR is a putative tumor suppressor that could prevent malignant transformation and tumor progression by regulating apoptosis and anoikis.
 ...
PMID:XEDAR as a putative colorectal tumor suppressor that mediates p53-regulated anoikis pathway. 1954 21


<< Previous 1 2 3 4 Next >>