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)

Myoepithelial cells (MCs) constitute the basal cell layer of normal mammary epithelia, and their identification is of particular diagnostic value because they are retained in most benign lesions while being lost in malignancy. Several MC immunocytochemical markers are currently available for diagnostic purposes, with special reference to smooth muscle-related antigens. p63 is a member of the p53 gene family, and its germline mutations are associated with severe mammary developmental defects in both rodents and humans. Different p63 isoforms have been identified, some of which (DeltaNp63) are preferentially expressed in the epithelial basal cells of different organs and have been considered as possible markers of stem cells/reserve cells. We investigated immunohistochemically 384 samples of normal and diseased human breast, including 300 invasive carcinomas, using four antibodies recognizing all p63 isoforms, or the DeltaNp63 isoforms. Twenty cytologic specimens were also investigated. Furthermore, snap-frozen tissue samples from three fibroadenomas and 10 invasive ductal carcinomas with their paired non-neoplastic tissues and three corresponding lymph node metastases were evaluated for the expression of p63 mRNA by RT-PCR. In normal breast tissue p63 immunoreactivity was confined to the nuclei of MCs. In all benign lesions p63-immunoreactive cells formed a continuous basal rim along the epithelial structures. Stromal cells, and in particular myofibroblasts, were consistently unreactive. Adenomyoepitheliomas showed nuclear staining in most neoplastic cells. A peripheral rim of p63-immunoreactive cells was retained surrounding lobular and ductal carcinoma in situ, although it was discontinuous as opposed to the normal structures. Invasive breast carcinomas were consistently devoid of nuclear p63 staining, with the exception of the two adenoid-cystic carcinomas, of the two ductal carcinomas with squamous metaplasia, and of 11 (4.6%) ductal carcinomas not otherwise specified, showing p63 immunoreactivity in a minor fraction (5-15%) of the neoplastic cells. In comparison with other MC markers, p63 was the most specific, being restricted exclusively to MCs, whereas antibodies to smooth muscle actin and, to a lesser extent, calponin also decorated stromal myofibroblasts. In the cytologic preparations p63 immunoreactivity was a consistent feature of "naked nuclei" and of a subset of cells surrounding benign epithelial clusters. RT-PCR experiments with primers specific for different p63 isoforms documented that normal tissues and fibroadenomas preferentially expressed the DeltaNp63 isoforms. Our study demonstrates that in normal and pathologic breast tissues MCs consistently express the DeltaNp63 isoforms. We suggest p63 as a reliable, highly specific, and sensitive MC marker in both histologic and cytologic preparations. Furthermore, because p63 immunoreactivity in adult epithelia is normally restricted to progenitor cells, it can be speculated that it might be a clue for the identification of the still elusive breast progenitor cells.
 ...
PMID:p63, a p53 homologue, is a selective nuclear marker of myoepithelial cells of the human breast. 1147 90

The p53 protein is the major tumor suppressor in mammals. The discovery of the p53 homologs p63 and p73 defined a family of p53 members with distinct roles in tumor suppression, differentiation, and development. Here, we describe the biochemical characterization of the core DNA-binding domain of a human isoform of p63, p63-delta, and particularly novel features in comparison with p53. In contrast to p53, the free p63 core domain did not show specific binding to p53 DNA consensus sites. However, glutathione S-transferase-fused and thus dimerized p63 and p53 core domains had similar affinity and specificity for the p53 consensus sites p21, gadd45, cyclin G, and bax. Furthermore, the fold of p63 core was remarkably stable compared with p53 as judged by differential scanning calorimetry (T(m) = 61 degrees C versus 44 degrees C for p53) and equilibrium unfolding ([urea](50%) = 5.2 m versus 3.1 m for p53). A homology model of p63 core highlights differences at a segment near the H1 helix hypothetically involved in the formation of the dimerization interface in p53, which might reduce cooperativity of p63 core DNA binding compared with p53. The model also shows differences in the electrostatic and hydrophobic potentials of the domains relevant to folding stability.
 ...
PMID:High thermostability and lack of cooperative DNA binding distinguish the p63 core domain from the homologous tumor suppressor p53. 1147 76

The p53 protein is involved in cell cycle arrest and apoptosis. To ensure that cells under non-stressed conditions are able to grow, p53 sets up a negative feedback loop by inducing Mdm2. Mdm2 is able to both inhibit the transcriptional regulation by p53 and to degrade it, thus maintaining p53 inactive until it is required. The Mdm2 related protein, Hdmx, has also been shown to inhibit the transcriptional activation of p53 but is unable to degrade it. A few years ago, the p53 family member, p63 was identified. Like p53, p63 is able to induce p53 target genes and it was shown to be able to cause cell cycle arrest and apoptosis. In this study we report that, despite the similarities between p53 and p63, neither Hdmx nor Mdm2 are able to interact with p63, to repress p63-induced transcription or to affect its half-life.
 ...
PMID:Hdmx and Mdm2 can repress transcription activation by p53 but not by p63. 1149 53

The p51/p73L/p63/p40 gene, recently identified as a p53 homolog, encodes two major isoforms, p51A and p73L, which are suggested to have similar functions synonymous with p53 and dominant-negative activity toward both p53 and p51A, respectively. We have cloned a high affinity genomic fragment bound to p51A that was assigned to be a novel retrovirus long terminal repeat. Strikingly, this fragment was found to bind to both p53 and p73L with similar affinity to p51A. Additional demonstration with known p53 response elements suggested that DNA-binding profiles of p51A and p73L were very similar but were distinct from that of p53. Consistent with this novel finding, transient cotransfection experiments in mammalian cells suggested that p73L, when it was expressed at a low level, selectively suppressed p53-dependent transactivation of p21-luc and mdm2-luc but not of cyclinG-luc and bax-luc reporters. These data raise the possibility that p73L differentially modulates the p53 function according to the distinct DNA-binding affinity between these two proteins.
 ...
PMID:Identification of a novel retrovirus long terminal repeat (LTR) that is targeted by p51A (TAp63gamma) and selective dominant-negative activity of p73L (DeltaNp63alpha) toward p53-responsive promoter activities. 1151 Nov 6

The p53 gene family, comprising p53, p63, and p73, has overlapping and distinctive functional roles. These members share structural similarities allowing for dynamic interplay in the activation of genes that are important in development and key cellular functions, such as the induction of apoptosis. Whereas p53 is a classical tumor suppressor gene, p63 and p73 do not share this feature in cancer formation and progression. The compensation in the expression level of these members in a background that is deficient for one of them has not been examined previously. Given the importance of p63 in the development and differentiation of oral-esophageal stratified squamous epithelia and the absence of oral-esophageal tumors in p53-null mice, we postulated and describe herein that p63 expression is associated with the loss of p53 in a p53-deficient background. Both full-length and amino-truncated forms of p63 are expressed and increased in oral-esophageal epithelia of p53-null mice when compared with wild-type mice, and the induction of p21 may potentially be preserved through the increase of p63.
 ...
PMID:p63 expression is associated with p53 loss in oral-esophageal epithelia of p53-deficient mice. 1152 42

The human homolog of KET, p63, bears strong homology to the tumor suppressor p53 and plays an essential role in epithelial development. CUSP, the most abundant cutaneous product of p63, has been identified as an autoantigen in chronic ulcerative stomatitis (CUS). The original report of KET expression at least partially contradicts p63 expression subsequently reported by many different groups. We have examined p63 expression by Northern analysis of RNA from multiple human tissues and by indirect immunofluorescence of rat tissue with CUS patient sera. Northern analysis reveals p63 RNA in skin, thymus, placenta, skeletal muscle, kidney, and lung, with non-transactivating p63 RNA in skin, thymus, and placenta. Reverse transcriptase polymerase chain reaction (rtPCR) assays show abundant non-transactivating p63 RNA, and little to no transactivating p63 RNA, in human basal cell carcinoma as well as in normal skin adjacent to the tumors. p63 RNA expression was not detected in brain, heart, colon, spleen, liver, or small intestine. Immunofluorescence reveals p63 expression in skin, oral epithelium, tongue, kidney, and trachea, but not in liver, large intestine, testis, skeletal muscle, or heart. Focal p63 expression within tissues, the complex array of isoforms encoded by the gene, and the specificity of the probes and antibodies utilized, may all contribute to contradictory accounts of CUSP/p63 expression.
 ...
PMID:CUSP/p63 expression in rat and human tissues. 1153 71

P73, a p53-homologue gene, has been studied for its possible role in head and neck squamous epithelium (HNSE) differentiation and carcinogenesis. P73 RNA and protein were analysed in 50 biopsies, including well- and moderately-differentiated carcinomas, and 21 matched normal adjacent tissues. P73 immunohistochemical analyses revealed intense p73 nuclear staining in basal and parabasal cells of normal squamous epithelium, in contrast with complete absence of staining in the more superficial cell layers. Moderately-differentiated carcinomas demonstrated homogeneous and diffuse staining in all tumour cells, while only basal cells were stained in well-differentiated carcinomas as in normal tissue. No correlation was observed between p73 and p53 protein expression. Immunostaining for p63, another p53-related protein previously described as being involved in HNSE morphogenesis and overexpressed in head and neck squamous cell carcinomas (HNSCC), was found to be similar to p73 labelling in carcinomas, but spread to the more differentiated layers in normal epithelium. Biallelic expression of p73 was found in tumours as well as in matched normal tissues. Comparison of p73 transcript levels between tumours and normal tissues showed decreased mRNA expression in 5/17 (30%) tumours independently of the differentiation status. Mutation and loss of heterozygosity analyses of the p73 gene revealed wild type status and no deletion. Our results strongly suggest that: (i) p73 is associated with homeostasis and control of differentiation of head and neck squamous epithelium probably in concert with p53 and p63; (ii) down-regulation of p73 expression could participate in HNSE carcinogenesis.
 ...
PMID:P73 expression in basal layers of head and neck squamous epithelium: a role in differentiation and carcinogenesis in concert with p53 and p63? 1153 43

Tumor suppressor p53 has been shown to transactivate epidermal growth factor receptor (EGFR) expression through binding to a putative p53 responsive element in the EGFR promoter between nucleotides -265 and -239 (EGFRp53RE). Isotypes of p63 gene products, recently identified as p53 relatives, have a similar function to transactivate several p53 target gene promoters. However, our results indicate that TAp63gamma has a very low ability to bind to the EGFRp53RE and surprisingly represses both basal EGFR promoter activity and endogenous EGFR expression. Transient transfection assays show that the EGFR promoter region between -348 and -293, containing two Sp1 sites, is crucial for the repression of the EGFR expression by TAp63gamma. Mutations in these Sp1 sites in the reporter constructs result in loss of the TAp63gamma repression effect. We further show that TAp63gamma directly interacts with Sp1 by immunoprecipitation analysis and that TAp63gamma impairs Sp1 binding to the target DNA site in electrophoretic mobility shift assays. These results suggest that TAp63gamma is involved in the regulation of the EGFR gene expression through interactions with basal transcription factors.
 ...
PMID:p53 Homologue p63 represses epidermal growth factor receptor expression. 1154 92

p53 gene therapy is being tested clinically for the treatment of human cancer, however, some cancer models (in vivo and in vitro) are resistant to p53. To explore the potential use of two p53 homologues, p73 and p51/p63, in cancer gene therapy, we introduced p53, p73 and p51/p63 into colorectal cancer cell lines via adenoviral vectors, and compared their effects on cell growth. Among 10 cell lines tested, six cell lines displayed a similar response following transduction of p53, p73beta or p51A/p63gamma; two lines underwent cell-cycle arrest, three lines exhibited apoptosis and one line showed no-effect following transduction. The effect on cell-cycle progression was variable in the other four cell lines. Interestingly, three cell lines were resistant to p53-mediated apoptosis, including two lines having endogenous wild-type p53 alleles, but underwent apoptosis after transduction of p73beta or p51A/p63gamma. Similar to p53, transduction of p51A/p63gamma induced extensive apoptosis when combined with adriamycin or X-radiation in SW480 cells, which are normally resistant to apoptosis. Transduction of p73beta and p51A/p63gamma also reduced the tumorigenicity of two colorectal cancer cells in vivo. These results suggest that adenovirus-mediated p73beta and p51A/p63gamma transfer are potential novel approaches for the treatment of human cancers, particularly for tumors that are resistant to p53 gene therapy.
 ...
PMID:Adenovirus-mediated transfer of the p53 family genes, p73 and p51/p63 induces cell cycle arrest and apoptosis in colorectal cancer cell lines: potential application to gene therapy of colorectal cancer. 1157 80

The tumour-suppressor protein p53 has recently been shown to belong to a family that includes two structurally related proteins, p63 and p73. This study investigated the status of p53 and its two homologues in multiple simultaneous gastric carcinomas. Expression and mutation of p53, p73 and p63 including the two major isotypes TAp63 and black triangleNp63, were examined by direct DNA-sequencing, in situ hybridization, western blotting and immunohistochemistry in 68 gastric carcinomas of 32 patients. The results obtained were correlated with pathohistological stage (according to UICC(16)) and several other histopathological factors and finally with patient survival. p53 mutations were detected in 23/68 carcinomas (34%) from 18 patients with a discordant mutation pattern. Independently of p53 mutation status, p73 transcripts and protein expression were found in 33/68 carcinomas from 24 patients. p63 positivity was found in 21 patients; 25 out of 68 tumours expressed p63. The number of cells containing p63 and their distribution depend on the degree of tumour differentiation. High grade carcinomas of the diffuse type exhibited a significantly higher p63 expression. In intestinal metaplasia and atrophic gastritis, an increase of TAp63 and black triangleNp63 staining was also observed. Specific mutations of p73 or p63 causing amino acid substitutions were not identified. Neither p53, p73 nor p63 were related to prognosis. p73 and p63 have rarely been found to be mutated in gastric carcinomas, but both proteins were expressed in only a subset of tumours. The status of these p53 homologues was discordant in all patients with multiple simultaneous gastric carcinomas. The increased expression of p63 (TAp63 and black triangleNp63) in less well differentiated gastric carcinomas may indicate that p63 can act to promote neoplastic growth in the gastric epithelium.
 ...
PMID:Expression of the p53 homologues p63 and p73 in multiple simultaneous gastric cancer. 1159 94


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