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)

Abnormalities in the p53 gene and in expression of its protein product are among the most frequent changes demonstrated in a variety of human cancers. p53 Is a nuclear phosphoprotein that in the natural form or "wild-type" can bind to DNA and prevent cells from entering into the S phase of the cell cycle. There is an increase in wild-type p53 after exposure of the skin to UV light, which allows for DNA repair before replication that would make DNA damage permanent. A loss of this protective influence destabilizes the genome. Mutation of the p53 gene commonly causes a defective protein that is degraded more slowly and accumulates in the cell to the extent that it becomes detectable by routine immunocytochemistry. These abnormalities precede the development of cancer in some examples. Studies of precursor lesions have used mainly immunohistochemical techniques that show p53 protein overexpression. The relationship between such overexpression and actual mutation of the p53 gene is controversial because overexpression of "wild-type" p53 protein also can occur. Mutations in the p53 gene have been observed in many actinic keratoses, basal cell carcinomas, and squamous cell carcinomas, and in a small proportion of malignant melanomas. Specific types of pyrimidine transitions have pointed to a role for UV light in these mutations. Molecular analysis is needed to determine whether or not immunocytochemical staining is truly reflective of mutation or is due to some other mechanism that causes an increased expression of wild-type p53.
 ...
PMID:Abnormalities of p53 protein expression in cutaneous disorders. 830 62

The wild-type p53 gene product is a nuclear phosphoprotein that suppresses cell and tumor growth. Mutations of the p53 gene are by now the most frequently recognized genetic alterations in human malignancies and occur in many types of carcinomas as well as in astrocytomas and sarcomas. Wild-type p53 protein has a short half-life, is present in very low quantities in normal cells and cannot be detected immunohistochemically. Mutant p53 proteins have longer half-lives and are usually present in immunohistologically detectable amounts. It is generally agreed that the presence of p53 immunostaining indicates the presence of an abnormal p53 protein and is strongly suggestive of a mutation in the p53 gene. In this study, we stained paraffin sections from eight samples of gliosarcomas from seven patients with an antibody to p53. All tumors contained p53-immunoreactive nuclei in both the glial and the sarcomatous component. In five tumors, a majority of nuclei was positive in the sarcomatous component while only a minority of nuclei was positive in the glial areas. In one tumor, the reverse was seen. In another tumor, approximately half the nuclei were positive in both components and in one tumor, only a minority of nuclei were positive in either component (this lesion was the recurrence of a tumor in which the majority of the sarcoma's nuclei had been positive). These data indicate that p53 mutations may play a role in the pathogenesis of gliosarcomas and suggest an origin of both the glial and sarcomatous components from a common progenitor.
 ...
PMID:Distribution of p53 protein expression in gliosarcomas: an immunohistochemical study. 838 97

The p53 gene is contained within 16-20 kb of cellular DNA located on the short arm of human chromosome 17 at position 17p13.1. This gene encodes a 393-amino-acid nuclear phosphoprotein involved in the regulation of cell proliferation. Current evidence suggests that loss of normal p53 function is associated with cell transformation in vitro and development of neoplasms in vivo. More than 50% of human malignancies of epithelial, mesenchymal, haematopoietic, lymphoid, and central nervous system origin analysed thus far, were shown to contain an altered p53 gene. The oncoproteins derived from several tumour viruses, including the SV40 large T antigen, the adenovirus E1B protein and papillomavirus E6 protein, as well as specific cellular gene products, e.g. murine double minute-2 (MDM2), were found to bind to the wild-type p53 protein and presumably lead to inactivation of this gene product. Therefore, the inactivation of p53 tumour suppressor gene is currently regarded as an almost universal step in the development of human cancers. The current data on p53-associated tumourigenesis are briefly discussed in this minireview.
 ...
PMID:Tumourigenesis associated with the p53 tumour suppressor gene. 839 88

Several protein fusion systems have been used in recent years to study protein-protein and DNA-protein interactions. Most of them use bacterially produced proteins which have several inherent disadvantages, notably, the absence of correct post-translational modifications and the frequent insolubility of recombinant proteins. We sought to develop a system to study proteins interacting with the nuclear phosphoprotein p53, which is believed to be a tumor suppressor. To prepare fusions of p53, we developed a convenient system that permits both in vivo and in vitro production and easy affinity purification of peptides and protein fragments as glutathione-transferase fusions. We placed the coding sequence of the Schistosoma japonica glutathione S-transferase (GST) under the control of the strong CMV/T7 promoter and SV40 splice and polyadenylation signals. An extensive polylinker (MCS) at the 3' end of the GST gene is preceded by the sequence encoding the cleavage site of the site-specific protease. We cloned the complete coding sequences of human wild-type p53, as well as p53 mutants representing all four mutational hotspots (codons 141, 175, 248, and 273), into our expression vector. In vitro transcription using the upstream T7 promoter and translation in reticulocyte lysates form an easy way to produce hybrid proteins; affinity purification on a glutathione-agarose column removes proteins that are present in reticulocyte lysates. We have also studied specific in vivo interactions of human p53 with the adenoviral 55-kDa E1B protein by transfecting expression constructs of GST-p53 fusions into human Ad5-transformed 293 cells.
 ...
PMID:Specific interaction between adenoviral 55-kDa E1B protein and in vivo produced p53 fusion proteins. 840 15

The tumor suppressor p53 is a nuclear phosphoprotein with characteristics of a transcription factor. It displays sequence-specific DNA binding, contains a potent transactivation domain, and has been implicated as both a transcriptional activator and a repressor. Transcription of the human hsp70 gene is stimulated by adenovirus E1a protein. This E1a transactivation of the hsp70 promoter is mediated by CCAAT binding factor (CBF). It is demonstrated here that p53 both represses transcription from the human hsp70 promoter and also interacts with CBF. Thus, the repression of the hsp70 promoter by p53 may be mediated by direct protein-protein interaction with CBF. These results suggest that protein-protein interaction between p53 and specific transcription factors may be an additional mechanism by which p53 regulates gene expression.
 ...
PMID:Regulation of the human hsp70 promoter by p53. 841

The p53 gene is a 16-20 kb of cellular DNA located on the short arm of human chromosome 17 at position 17p13.1. This gene encodes a 375-amino acid nuclear phosphoprotein which involves in the regulation of cell proliferation. The p53 gene was originally regarded as a dominant oncogene because its overexpression resulted in the immortalization of rodent cells, and the p53 gene could transform rat embryonic fibroblasts in concert with an activated ras gene. It soon became clear, however, that many of the p53 clones that had been studied were in fact mutated versions of the gene, and the wild-type p53 actually acts as a tumor suppressor. Loss of normal p53 function has been associated with the cell transformation in vitro and the development of neoplasms in vivo. More than one-half of human malignancies derived from the epithelial, mesenchymal, hematopoietic, and lymphoid tissues, as well as the central nervous system, analyzed thus far, were shown to contain an altered p53 gene. Most p53 gene alterations are the missense mutations, giving rise to an altered protein. These mutations are most frequently located in the evolutionally conserved areas. Furthermore, it has been demonstrated that the SV40 large T antigen, the adenovirus E1B protein, and papillomavirus E6 protein can bind to wild-type p53 protein and presumably lead to inactivation of this gene product as well. Therefore, the inactivation of normal (or wild-type) p53 is currently regarded as an important genetic pathway for human carcinogenesis generated by endogenous factors and exogenous carcinogens, as well as several tumor viruses. The current data on the p53 gene and its alterations in human malignancies, particularly those in the gastrointestinal tract, are reviewed.
 ...
PMID:The p53 tumor suppressor gene as a common cellular target in human carcinogenesis. 842 17

The p53 tumor-suppressor gene encodes a nuclear phosphoprotein that arrests cell cycle progress at G1. It may facilitate DNA damage repair and is frequently mutated in many human tumors. Hodgkin disease, a malignant condition of the lymphoid system, is characterized by the presence of Reed-Sternberg cells and mononuclear variants (Hodgkin cells), whose etiology remains unknown. The large multinucleated Reed-Sternberg cells often comprise < 1% of the total cell population within a biopsy specimen and are thought to be the neoplastic component in an admixture of reactive cells. It has been shown in the large majority of cases that up to 60% of these multinucleated cells react with CM-1, an anti-p53 antibody. However, whether this "overexpression" of p53 protein reflects abnormality at the DNA level can no longer be assumed by immunocytochemistry alone. p53 from six Hodgkin disease-derived cell lines was examined by immunoprecipitation, polymerase chain reaction (PCR)-single-strand conformation polymorphism analysis, and sequencing. In one cell line, point mutations were identified in exons 5 and 8 of p53. Sequencing of cloned PCR products confirmed the mutations to be on different alleles. A strategy involving extraction of nuclei followed by enrichment by flow cytometry was used to determine whether p53 overexpression in the Reed-Sternberg cells from patient biopsy material was due to mutations in this gene. Single-strand conformation polymorphism revealed additional bands in the polyploid nuclear preparations, suggesting abnormalities, and sequence analysis confirmed the presence of point mutations.
 ...
PMID:Mutation of p53 in primary biopsy material and cell lines from Hodgkin disease. 846 94

A range of DNA-damaging agents has been shown to increase cellular levels of the nuclear phosphoprotein p53 and to induce p53-dependent processes. We examined the ability of three microtubule-active agents, taxol, vinblastine, and nocodazole, to increase p53 levels and activate p53-dependent processes. When tested using a p53 DNA-binding assay, all three agents induced p53 in a dose-dependent manner. To varying degrees, these agents also induced p21WAF1/CIP1 mRNA and transcription in a chloramphenicol acetyl transferase reporter system. These data suggest there is an additional pathway for activating p53 and subsequent p53-dependent processes.
 ...
PMID:Microtubule-active drugs taxol, vinblastine, and nocodazole increase the levels of transcriptionally active p53. 852 85

The product of the retinoblastoma tumor-suppressor gene (RB) is a ubiquitously expressed, 105-kDa nuclear phosphoprotein (pRB). The pRB protein negatively regulates the cellular G1/S phase transition, and it is at this point in the cell cycle that it is thought to play its role as a tumor suppressor. The growth-inhibitory effects of pRB are exerted, at least in part, through the E2F family of transcription factors. This chapter reviews the insights into the mechanism of action of the E2F family members that have been obtained through overexpression studies. Studies in RB-/- SAOS-2 cells have provided evidence in support of the hypothesis that the E2F family members are negatively regulated by pRB and the related protein p130. In particular, the results obtained are consistent with the earlier biochemical data which suggested that E2F1 is regulated primarily by pRB, and E2F4 by p130. Results relating to p107 are also discussed. Consistent with the proposed role of pRB and E2F1 as coregulators of entry into S phase, experiments have demonstrated that overexpression of E2F1 is sufficient to override the cell cycle arrests caused by serum deprivation of fibroblasts or transforming growth factor-beta (TGF-beta) treatment of mink lung epithelial cells. However, at least in the case of the serum deprivation induced arrest, the ultimate result of E2F1 overexpression is death by p53-dependent apoptosis. In light of this and other data, a model is discussed as to how functional inactivation of pRB and p53 might cooperate to promote tumorigenesis. A number of studies have demonstrated the oncogenic potential of E2F family members, at least under certain conditions. This is, again, in keeping with the notion that these proteins play a critical role in controlling proliferation.
 ...
PMID:The cellular effects of E2F overexpression. 857 14

p53 is a nuclear phosphoprotein whose function is classified as tumor suppression. Studies have shown that p53 functions by binding to p53 DNA recognition sequences and regulates transcription of growth-regulatory genes. Various p53 recognition sequences have recently been identified. pOST2 contained two copies of a palindromic high-affinity DNA-binding sequence for p53; the other p53 recognition sequences included p53-binding fragments found in the human ribosomal gene cluster (pRGC) region and in the murine muscle creatine kinase promoter (pMCK). The purpose of this study was to compare the abilities of various p53 recognition sequences to mediate transcription in the presence of endogenously produced wild-type (wt) or mutant p53. Three p53-responsive chloramphenicol acetyltransferase (CAT) reporter constructs (pOST2, pRGC, and pMCK) that contain one or two copies of p53 recognition sequences upstream of a herpes thymidine kinase (TK) promoter and CAT reporter cDNA were constructed. Either a p53-responsive gene or a control reporter gene was transfected into human carcinoma cell lines (having various p53 mutations) either with or without a wt or mutant p53 expression vector. CAT activity was assayed to measure transactivation through the various p53-responsive elements. We showed that pOST2 had a greater ability to mediate transactivation by p53 than either pRGC or pMCK. p53 with a mutation at either codon 175 or 248 was unable to transactivate a reporter gene with pOST2, pRGC, or pMCK. We found it interesting that pOST2, but not pRGC or pMCK, was able to mediate transactivation in cell lines that produce codon 273-mutant p53. These findings suggest that various sensitivities of the different p53-responsive elements to specific mutant and wt p53s may be an important factor in the role of p53 as a transcriptional activator both under normal physiological conditions and during carcinogenesis.
 ...
PMID:p53 transactivation through various p53-responsive elements. 864 24


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