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 tumor suppressor p53 is a nuclear phosphoprotein in which DNA-binding activity is increased on exposure to DNA-damaging agents such as UV or gamma radiation by unknown mechanisms. Because phosphorylation of p53 at the casein kinase (CK) II site activates p53 for DNA-binding function in vitro, we sought to determine the in vivo relevance of phosphorylation at this site after UV and gamma radiation. A polyclonal antibody was generated that binds to bacterially expressed p53 only when phosphorylated in vitro by CK II. Using this antibody, we showed that p53 is phosphorylated at the CK II site upon UV treatment of early passage rat embryo fibroblasts and RKO cells. In addition, DNA-binding assays indicated that phosphorylated p53 bound to a p53-responsive element, suggesting functional activation. However, gamma radiation, which also stabilizes p53, did not result in phosphorylation at the CK II site. These results indicate that phosphorylation at the CK II site is one of the post-translational mechanisms through which p53 is activated in response to UV radiation and that different mechanisms activate p53 after DNA damage by gamma radiation.
 ...
PMID:Functional activation of p53 via phosphorylation following DNA damage by UV but not gamma radiation. 950 Nov 76

The tumor suppressor gene p53 encodes a nuclear phosphoprotein which is critical for cell cycle control and prevention of uncontrolled cell proliferation that can lead to cancer. Previous studies have shown that cells respond to DNA damage by increasing their levels of p53, which then acts to prevent replication of damaged DNA. This study examined the effects on p53 protein levels of several different categories of chemical carcinogens. N-Methyl-N'-nitro-nitrosoguanidine and N-ethyl-N-nitrosourea, two direct-acting genotoxic (DNA-reactive) carcinogens, caused p53 induction as early as 2 h following treatment, with peak increases within 4-12 h. Aflatoxin B1 and 2-acetylaminofluorene, indirect-acting genotoxic carcinogens, caused a later induction of p53, with the peak increase appearing between 16 and 24 h following treatment. These observations demonstrate a correlation between p53 induction pattern and DNA damaging mechanism of genotoxins. Phenol, diethylstilbestrol and ethylacrylate also induced increases in cellular p53. The half-life of p53 protein was increased in cells treated with genotoxic agents. On the other hand, the epigenetic (non-DNA-reactive) carcinogens azathioprine and saccharin, as well as two substances generally considered to be non-carcinogens, dimethylsulfoxide and benzethonium chloride, had no effect on p53 protein levels of treated cells. Measurement of the cytotoxic effects of each of these chemicals led to the conclusion that p53 protein induction is not a general, non-specific consequence of the cytotoxic effect of these genotoxins. These results suggest that measurement of p53 protein induction may be an effective tool to identify environmental genotoxins.
 ...
PMID:A new approach to identifying genotoxic carcinogens: p53 induction as an indicator of genotoxic damage. 993 68

The p53 tumor suppressor gene encodes a nuclear phosphoprotein with growth inhibiting properties, which is activated in cell exposed to various forms of DNA damaging stress. The development of human cancer often involves inactivation of this suppressor through various mechanisms, including gene deletions and point mutations. Most mutations impair the specific DNA-binding capacity of p53, therefore allowing cells to proliferate in conditions where cells with intact p53 function are suppressed or eliminated. Thus, mutation of p53 may provide a selective advantage for the clonal expansion of preneoplastic or neoplastic cells. The diversity of p53 mutations provides a valuable tool to identify important sources of cancer-causing mutation in the human setting. Mutagens and carcinogens damage the genome in characteristics ways, leaving "mutagen fingerprints" in DNA. Well-characterised examples of such "fingerprints" include G: C to T: A transversions in lung cancers in association with cigarette smoke, G: C to T: A transversions at codon 249 in liver cancers in association with dietary exposure to Aflatoxin B1 (AFB1) and CC: GG to TT: AA tandem dipyrimidine transitions in skin cancers in association with UVB exposure. In addition, mutations at different codons are not functionally equivalent. The availability of crystal structures of p53 protein represents an essential development in the understanding of the functional properties of p53 mutants. In the future, it is expected that analysis of p53 mutations may provide useful information for the diagnosis, prognosis and therapy of cancer.
 ...
PMID:p53 as a sensor of carcinogenic exposures: mechanisms of p53 protein induction and lessons from p53 gene mutations. 976 47

Abnormal expression of the 53 kDa nuclear phosphoprotein produced by the p53 gene is observed in many human cancers. p53 nuclear immunoreactivity is found commonly in tumor cells. Immunohistochemistry was performed using a monoclonal antibody, DO-7 (DAKO, Denmark; cat. no. M7001; 1:100 dilution), to investigate p53 protein immunoreactivity in a group of cutaneous fibrohistiocytic tumors that are known to be locally aggressive. The study group consisted of dermatofibrosarcoma protuberans (DFSP) (n = 14) and atypical fibroxanthoma (AFX) (n = 7). Cases of dermatofibroma (DF) (n = 16) formed the benign control group. Intense nuclear immunostaining for p53 protein was observed in 71% of DFSP and 86% of AFX. None of the dermatofibromas showed strong p53 nuclear immunostaining. Statistical analyses revealed significant differences in p53 immunoreactivity between DFSP and DF (P = 0.0001, chi 2 test) and between AFX and DF (P = 0.0001, chi 2 test). In conclusion, increased p53 protein immunoreactivity is found in DFSP and AFX but not in DF. These differences in p53 immunoreactivity suggest that increased expression of the protein may be important in the pathogenesis of the more aggressive group of fibrohistiocytic tumors.
 ...
PMID:p53 protein immunoreactivity in fibrohistiocytic tumors of the skin. 977 Jan 92

Germ-line mutations in the human BRCA2 gene confer susceptibility to breast cancer. Efforts to elucidate its function have revealed a putative transcriptional activation domain and in vitro interaction with the DNA repair protein RAD51. Other studies have indicated that RAD51 physically associates with the p53 tumor suppressor protein. Here we show that the BRCA2 gene product is a 460-kDa nuclear phosphoprotein, which forms in vivo complexes with both p53 and RAD51. Moreover, exogenous BRCA2 expression in cancer cells inhibits p53's transcriptional activity, and RAD51 coexpression enhances BRCA2's inhibitory effects. These findings demonstrate that BRCA2 physically and functionally interacts with two key components of cell cycle control and DNA repair pathways. Thus, BRCA2 likely participates with p53 and RAD51 in maintaining genome integrity.
 ...
PMID:The BRCA2 gene product functionally interacts with p53 and RAD51. 981 93

The MDM2 gene is a nuclear phosphoprotein that is regulated by p53 and functions, in one capacity, to inhibit the transcriptional activity of the wild-type p53 protein. Multiple MDM2 transcripts were detected in human breast epithelial cells. In estrogen receptor-negative normal, immortal, and tumorigenic breast epithelial cells, we found a good correlation between MDM2 mRNA levels and expression of wild-type p53. When wild-type p53 was overexpressed in estrogen receptor-negative tumor cells containing a mutant or no endogenous p53, MDM2 mRNA levels increased significantly, indicating that wild-type p53 positively influences MDM2 mRNA levels in these tumor cells. Because all estrogen receptor-positive breast tumor cells had high MDM2 mRNA levels regardless of the status of their endogenous p53 protein, other factors likely influence MDM2 expression in these cells. Distinct MDM2 proteins (range, Mr 54,000-68,000 and 90,000-100,000, respectively) were differentially expressed in human breast epithelial cells. The lower molecular weight MDM2 proteins were most abundant in the normal mammary cells but present at varying levels in many of the tumor cells examined. MDM2 was a nuclear protein; however, nuclear staining intensity did not always correlate with the amount of MDM2-immunoreactive protein as determined by Western blot analysis. This discrepancy suggests that MDM2 interacts with novel cellular proteins in different kinds of breast epithelial cells.
 ...
PMID:Differential expression of multiple MDM2 messenger RNAs and proteins in normal and tumorigenic breast epithelial cells. 981 89

The MDM2 oncoprotein encodes a 90 kDa nuclear phosphoprotein capable of abrogating the growth suppressive functions of p53 and pRb tumor suppressor proteins by direct interaction. Alternative splicing of MDM2 protein coding sequences has been documented during tumor progression in human ovarian and bladder carcinomas. The aim of this study was to determine whether alternative splicing of MDM2 occurs during breast tumorigenesis in mice and humans and whether protein coding sequences were affected. Specimens representing normal and malignant breast tissues from the murine D2 mammary tumor model system and human breast carcinomas were examined. Three distinct mdm2 mRNA transcripts of 3.3, 1.6 and 1.5 kb were detected in normal and malignant murine mammary tissues by Northern blot analysis using a full-length mdm2 cDNA probe. Additional Northern blot analysis using a probe derived from exon 12 of murine mdm2 demonstrated that the 1.5 and 1.6 kb transcripts lack sequences encoding the C-terminus of the protein. No evidence of internal deletions of protein coding sequences of mdm2 was detected in any of the normal mammary tissues or D2 murine mammary tumors examined by reverse transcription PCR (RT-PCR). Three distinct MDM2 transcripts of 6.7, 4.7 and 1.9 kb were detected in malignant human breast tissue by Northern blot analysis using a cDNA probe specific for the complete open reading frame of human MDM2. However, a cDNA probe specific for the last exon of human MDM2 hybridized only to the 6.7 and 4.7 kb transcripts, demonstrating that the 1.9 kb transcript lacked protein coding sequences contained in exon 12. Similarly, no internal deletions were detected in a panel of malignant human breast tissues using RT-PCR and analogous primers within human MDM2. Therefore, breast tumors differ from other solid tumors reported previously in that no internal deletions of MDM2 protein coding sequences were observed. However, the data document the presence of multiple MDM2 mRNA transcripts in both normal and malignant breast tissues. A subset of MDM2 transcripts were shown to lack the last exon which contains sequences coding for the RING and zinc fingers and domains which are targets for caspase-3 mediated proteolytic degradation and are required to target p53 for proteosomal degradation.
 ...
PMID:Expression of MDM2 during mammary tumorigenesis. 1018 33

The nuclear phosphoprotein p53 acts as a transcription factor and is involved in growth inhibition and apoptosis. The present study was designed to examine the effect of decreasing cellular polyamines on p53 gene expression and apoptosis in small intestinal epithelial (IEC-6) cells. Cells were grown in DMEM containing 5% dialyzed fetal bovine serum in the presence or absence of alpha-difluoromethylornithine (DFMO), a specific inhibitor of polyamine biosynthesis, for 4, 6, and 12 days. The cellular polyamines putrescine, spermidine, and spermine in DFMO-treated cells decreased dramatically at 4 days and remained depleted thereafter. Polyamine depletion by DFMO was accompanied by a significant increase in expression of the p53 gene. The p53 mRNA levels increased 4 days after exposure to DFMO, and the maximum increases occurred at 6 and 12 days after exposure. Increased levels of p53 mRNA in DFMO-treated cells were paralleled by increases in p53 protein. Polyamines given together with DFMO completely prevented increased expression of the p53 gene. Increased expression of the p53 gene in DFMO-treated cells was associated with a significant increase in G1 phase growth arrest. In contrast, no features of programmmed cell death were identified after polyamine depletion: no internucleosomal DNA fragmentation was observed, and no morphological features of apoptosis were evident in cells exposed to DFMO for 4, 6, and 12 days. These results indicate that 1) decreasing cellular polyamines increases expression of the p53 gene and 2) activation of p53 gene expression after polyamine depletion does not induce apoptosis in intestinal crypt cells. These findings suggest that increased expression of the p53 gene may play an important role in growth inhibition caused by polyamine depletion.
 ...
PMID:Inhibition of polyamine synthesis induces p53 gene expression but not apoptosis. 1019 27

The product of the ATM gene, which is mutated in ataxia telangiectasia, is a nuclear phosphoprotein, and it involves the activation of the p53 pathway after ionizing radiation. Here we show that the ATM protein is constitutively associated with double strand DNA and that the interaction increases when the DNA is exposed to ionizing radiation. The ATM protein also had affinity to restriction endonuclease PvuII-digested DNA, but not to UV-irradiated DNA nor X-irradiated single-stranded DNA. The immunoprecipitation experiment detected very weak association between ATM and DNA-PK proteins, and immunodepletion of DNA-PK showed little or no effect on the interaction of the ATM protein with damaged DNA, indicating that an interaction with DNA-PK might not be required for the recruitment of the ATM protein to damaged DNA. Furthermore, the association was also confirmed in xrs-5 and xrs-6e cells, which are Chinese hamster ovary mutant cell lines defective in Ku80 function. These results indicate that the ATM protein is recruited to the site of DNA damage and it recognizes double strand breaks by itself or through an association with other DNA-binding protein other than DNA-PK and Ku80 proteins.
 ...
PMID:Recruitment of ATM protein to double strand DNA irradiated with ionizing radiation. 1046 90

BRCA1 is a nuclear phosphoprotein expressed in a broad spectrum of tissues during cell division. The inheritance of a mutant BRCA1 allele dramatically increases a woman's lifetime risk for developing both breast and ovarian cancers. A number of mouse lines carrying mutations in the Brca1 gene have been generated, and mice homozygous for these mutations generally die before day 10 of embryonic development. We report here the survival of a small number of mice homozygous for mutations in both the p53 and Brca1 genes. The survival of these mice is likely due to additional unknown mutations or epigenetic effects. Analysis of the Brca1(-/-) p53(-/-) animals indicates that BRCA1 is not required for the development of most organ systems. However, these mice are growth retarded, males are infertile due to meiotic failure, and the mammary gland of the female mouse is underdeveloped. Growth deficiency due to loss of BRCA1 was more thoroughly examined in an analysis of primary fibroblast lines obtained from these animals. Like p53(-/-) fibroblasts, Brca1(-/-) p53(-/-) cells proliferate more rapidly than wild-type cells; however, a high level of cellular death in these cultures results in reduced overall growth rates in comparison to p53(-/-) fibroblasts. Brca1(-/-) p53(-/-) fibroblasts are also defective in transcription-coupled repair and display increased sensitivity to DNA-damaging agents. We show, however, that after continued culture, and perhaps accelerated by the loss of BRCA1 repair functions, populations of Brca1(-/-) p53(-/-) fibroblasts with increased growth rates can be isolated. The increased survival of BRCA1-deficient fibroblasts in the absence of p53, and with the subsequent accumulation of additional growth-promoting changes, may mimic the events that occur during malignant transformation of BRCA1-deficient epithelia.
 ...
PMID:Growth retardation, DNA repair defects, and lack of spermatogenesis in BRCA1-deficient mice. 2773 47


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