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)

The p51/p63 gene, a novel member of the p53 gene family, has recently been identified at 3q27-9. There are at least six major isotypes of p51/p63 mRNA transcripts. p51A/TAp63gamma has the potential to induce apoptosis and growth suppression in a manner similar to p53, and other isotypes may suppress the p53 and p51A1TAp63gamma genes in a dominant-negative manner. We analyzed the mutation and expression of the p51/p63 gene in 80 cases of chronic myelogenous leukemia (CML) to evaluate its role in blastic transformation. Expression of the p51/p63 gene was detected in 74 cases. The alpha isotype of p51/p63 transcripts was dominantly expressed in 72 of these 74 cases. There was no correlation between the isotypes of p51/p63 transcripts and the clinical phase. Mutations of the p51/p63 gene were found in six cases. All these mutated cases expressed p51B/TAp63 alpha. In four of the six cases, the mutations were within a limited region (codon 151-170) corresponding to the DNA-binding domain. We hypothesized that this limited region is a hot spot for mutation of the p51/p63 gene. Mutations of the p53 gene were found in four cases of CML in blastic crisis (BC). Frequencies of the p51/p63 and p53 gene mutations were higher in BC (p51/p63 gene, 11.8%; p53 gene, 7.8%) than in the chronic phase (p51/p63 gene, 1.5%; p53 gene, 0%). The p51/p63 gene mutation may act similarly to the p53 gene mutation as a genetic alteration potentially responsible for the progression of CML.
 ...
PMID:Mutation of the p51/p63 gene is associated with blastic crisis in chronic myelogenous leukemia. 1168 14

Tumor suppressor p53 has been shown to repress expression of vascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen and a key mediator of tumor angiogenesis. The p63 gene, recently identified as a p53-relative, encodes multiple isoforms with structural and functional similarities and differences from p53. In this study, we show the evidence that the two major isoforms of the p63 gene, TAp63gamma (p51A) and dNp63alpha (p73L), represses and upregulates VEGF expression, respectively, on transcription and protein levels. Transient transfection assays show that a hypoxia-inducible factor (HIF) 1 binding site within the VEGF promoter region is responsible for both upregulation and repression by dNp63alpha and by TAp63gamma, respectively, of the VEGF promoter activity. We also show that TAp63gamma targets HIF1alpha for promoting proteasomal degradation but that dNp63alpha targets HIF1alpha for stabilization. Mammalian two-hybrid assays show that HIF1alpha-dependent transcription is repressed by TAp63gamma as well as by p53, whereas it is upregulated by dNp63alpha in collaboration with a transcription coactivator p300. Our data also show that dNp63alpha acts as a dominant-negative reagent toward both p53- and TAp63gamma-mediated degradation of HIF1alpha and repression of HIF1alpha-dependent transcription. These results suggest that p63 is involved in the regulation of the VEGF gene expression and that modulation of VEGF expression by TAp63gamma and dNp63alpha is closely correlated with their distinct roles on the regulation of HIF1alpha stability.
 ...
PMID:TAp63gamma (p51A) and dNp63alpha (p73L), two major isoforms of the p63 gene, exert opposite effects on the vascular endothelial growth factor (VEGF) gene expression. 1197 Nov 80

p51(p63), a member of the p53 tumor suppressor gene family, generates multiple isoforms, including the potent and less potent transactivators p51A(TAp63gamma) and p51B(TAp63alpha), respectively, the latter poorly characterized for its protein features and functions. When constitutively expressed in 1-2-3 mouse erythroleukemic cells, p51B(TAp63alpha) appeared as a broad band with an approximate molecular mass of 85 kDa in Western blot. When cells were exposed to genotoxic stress by UV-C irradiation or by DNA-damaging drugs, including actinomycin D, bleomycin, and eptoposide, the protein accumulated intracellularly without an increase in its mRNA. Unlike p53 and p51A(TAp63gamma), however, p51B(TAp63alpha) did not activate p21(waf1) gene expression, nor did it induce apoptosis or hemoglobin production. While wild-type p53 was precipitated by an anti-MDM2 antibody, p51B(TAp63alpha) was not detectable in the MDM2 immunoprecipitates from the producer cells. After treatment with okadaic acid, a Ser/Thr phosphatase inhibitor, p51B(TAp63alpha) increased its apparent molecular mass and protein content. A 26S proteasome inhibitor, MG132 (N-CBZ-Leu-Leu-leu-al), also increased p51B(TAp63alpha) retention in an either transient or constitutive expression system. Without an interaction with MDM2, p51B(TAp63alpha) may be degraded by proteasome under normal cellular circumstances but stabilized under genotoxic stress by a posttranscriptional mechanism which might involve Ser/Thr phosphorylation.
 ...
PMID:p53 gene family p51(p63)-encoded, secondary transactivator p51B(TAp63alpha) occurs without forming an immunoprecipitable complex with MDM2, but responds to genotoxic stress by accumulation. 1202 49

We identified REDD1 as a novel transcriptional target of p53 induced following DNA damage. During embryogenesis, REDD1 expression mirrors the tissue-specific pattern of the p53 family member p63, and TP63 null embryos show virtually no expression of REDD1, which is restored in mouse embryo fibroblasts following p63 expression. In differentiating primary keratinocytes, TP63 and REDD1 expression are coordinately downregulated, and ectopic expression of either gene inhibits in vitro differentiation. REDD1 appears to function in the regulation of reactive oxygen species (ROS); we show that TP63 null fibroblasts have decreased ROS levels and reduced sensitivity to oxidative stress, which are both increased following ectopic expression of either TP63 or REDD1. Thus, REDD1 encodes a shared transcriptional target that implicates ROS in the p53-dependent DNA damage response and in p63-mediated regulation of epithelial differentiation.
 ...
PMID:REDD1, a developmentally regulated transcriptional target of p63 and p53, links p63 to regulation of reactive oxygen species. 1245 9

Based on gene sequence homologies, a p53 (TP53) gene family become apparent with the addition of the most recently identified p63 (TP73L; formerly TP63) and p73 (TP73) genes to the already known p53. The p53 gene encodes for a unique protein eliciting well-known tumor suppressor gene (TSG) properties that mediate cellular response to DNA damage, e.g., cell cycle arrest or apoptosis. In contrast, both homologues specify an array of isoforms different in their N- and C-terminal domains. Transactivating isoforms, such as TAp63/p73, show TSG properties similar to p53, while isoforms lacking N-terminal transactivating domain such as DeltaNp63/p73, induce a functional block against p53 as well as TAp63/p73 activities. Both p63/p73 types of isoforms are involved in development: p63 is critical for epithelial stem cell renewal and epithelial homeostasis, and p73 is involved in neurogenesis and natural immune response. These facts support interdependent functions for the p53 family members, which appear linked together in a complex and tight regulation network to fulfill cellular functions related to DNA damage and tissue homeostasis maintenance. The lack of p63/p73 mutations in human cancers rule out a typical TSG role for either of the p53 homologues. Nonetheless, p63 and p73 genes seem strongly involved in malignancy acquisition and maintenance process because of: 1) their tissue identities, and 2) their close interplay activities within the p53 family members, and primarily through the negative regulatory role played by DeltaNp63/p73 isoforms for cell death control and differentiation.
 ...
PMID:TP53 family members and human cancers. 1261 4

The p53 tumor suppressor gene integrates numerous signals to control cell life and death. p53 and its function-related genes consists of a complicated gene network. When a highly connected node in the network breaks down, the disruption of p53 has severe consequences. p53 gene locates in human chromosome 17q13.1. Its encoding wild-type p53 protein is composed of four parts: N-terminal activation domain, DNA-binding domain, oligomerization domain, and C-terminal regulation domain. As the gene structures of p73, p51, p63 are similar with p53, they are regarded as members of p53 gene family. p53 play an intermediate role connecting varied stress signals with the reactions of cells. DNA damage caused by ionizing radiation, aberrant growth signals, or chemotherapeutic drugs may activate the p53 network. When expression of p53 elevated, p53-mdm2 and p14(ARF)-mdm2 feedback loops can accurately regulate the expression level of p53, and the cooperation of p33ING1b gene is also needed in the process of p53 exerting normal function. Phosphorylation and acelylation are two important mechanisms to modulate p53 activity in vivo. Several dozen downstream genes are controlled directly by p53, and the activity of p53 falls into four categories: cell cycle inhibition, apoptosis, genetic stability, and inhibition of blood vessel formation. Elucidation of the function of p53 gene network will help to clarify the interaction mechanisms of p53 gene and its function-related genes.
 ...
PMID:[Research advances on p53 gene network]. 1275 23

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.
 ...
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.
 ...
PMID:The Rapp-Hodgkin syndrome results from mutations of the TP63 gene. 1293 57

p51/p63, a member of the p53 gene family, is structurally conserved among a wide range of organisms, although the transactivator (TA) and N-terminally truncated (deltaN) isotype producing property seems to vary. Since p51/p63 is thought to play important roles in skin, limb, and craniofacial development in mammals, we examined Xenopus laevis larval and adult tissues for expression of p51/p63. Temporal analyses indicated enhanced transcription of the deltaN form of p51/p63 in premetamorphosis phase (at stage 44-48). p51/p63-positive cells in the inner layer of larval skin expanded to the suprabasal layers during the stratification. The epithelium of limb buds and the maxillofacial ectodermal tissues in tadpoles had a high level expression of p51/p63. The cloned deltaN-A/gamma type Xenopus p51/p63 exhibited a dominant-negative activity against the human TA-A/gamma isotype in a reporter assay. These results suggest that tissue-specific p51/p63-inducing mechanism and isotype-specific transcriptional regulator activities of p51/p63 are conserved between mammals and frogs.
 ...
PMID:Evolutionarily conserved expression pattern and trans-regulating activity of Xenopus p51/p63. 1468 51

This study was conducted to evaluate the frequency and prognostic impact of TP53 alterations stratified for the TP53 codon 72 polymorphism (c.215G>C, p.Arg72Pro) in a cohort of 109 patients with advanced ovarian carcinomas. TP53 sequence variants were observed in 80 of the 109 (73.4%) tumors and were significantly associated with grade of differentiation (P=0.001). A tendency towards higher frequency of sequence variants in tumors with higher FIGO stages was seen (P=0.05). The type of TP53 sequence variant (transition A:T>G:C vs. G:C>A:T at CpG dinucleotides, and transversion G:C>T:A) had significant correlation with patients' age (P=0.04) with more A:T>G:C in patients over 60 years old. No significant associations were found between frequency of sequence variants and age at diagnosis, histological type, size of residual tumor after primary surgery, or long-term survival. Analyses of the codon 72 polymorphism in tumor DNA gave a higher frequency of homozygosity/hemizygosity than expected from the population frequency, particularly for the Pro allele. Tumors homozygous or hemizygous for the Pro allele had significantly higher frequency of TP53 sequence variants, particularly of the nonmissense type (P=0.002), and patients with these types of alterations had significantly shorter survival (P=0.04). TP53 protein accumulation, determined by immunohistochemistry (IHC), was found in 67.9% (74 out of 109) of the tumors, was significantly more common among serous than nonserous ovarian carcinomas (P=0.008), and had a significant effect on progression-free survival (P=0.03). p63 (TP73L; formerly TP63) and p73 (TP73) protein accumulation detected by IHC was seen in 67.9 and 0% of the tumors, respectively. A significantly higher frequency of p63-positive cases was seen among serous tumors (P=0.008) and tended to increase with increasing FIGO stages (P=0.05), but had no significant effect on survival. No association between p63 protein accumulation and TP53 protein accumulation was seen.
 ...
PMID:Effect of the codon 72 polymorphism (c.215G>C, p.Arg72Pro) in combination with somatic sequence variants in the TP53 gene on survival in patients with advanced ovarian carcinoma. 1522 86


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>