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

Alterations of p53 have been explored in Taiwanese oral squamous cell carcinomas (OSCCs) consisting of a betel quid (BQ)/tobacco-related subgroup of 36 subjects and a tobacco-related subgroup of 13 subjects. Mutations in conserved exons were found in 12 tumors. Seven mutations were clustered in a hot-spot region mapped to a region between codons 273-282 in exon 8. The incidence of p53 mutation in BQ/tobacco tumors was 22% (8/36). The frequency of p53 allelic loss (21%, 3/14) in BQ/tobacco tumors approximates to the incidence of mutation. This is the first study demonstrating allelic deletion of p53 in such malignancies. Twenty-four of 43 samples showed positive p53 immunostaining. All tumors harboring mis-sense mutations of p53 in conserved exons exhibited nuclear protein accumulation. The incidence of mutation in conserved exons in BQ/tobacco-associated Asian OSCCs (15%) is significantly different from worldwide OSCCs (46%) related primarily to tobacco consumption (P=0.00001).
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PMID:p53 alterations in betel quid- and tobacco-associated oral squamous cell carcinomas from Taiwan. 970 75

c-Myc is a nuclear protein with important roles in cell transformation, cell proliferation, and gene transcription. It has been previously shown that a 14-amino acid (aa) modified peptide (H1-S6A,F8A) derived from the helix 1 (H1) carboxylic region of c-Myc can interfere in vitro with specific c-Myc DNA binding. Here, we have linked the above Myc-derived 14-aa peptide to a 16-aa sequence from the third helix of Antennapedia (Int). It has been repeatedly reported that this 16-aa Antennapedia peptide is able to cross mammalian cell membranes and to work as a vector for short peptides. Using fluorescent (dansylated or rhodaminated) peptides, we have shown that the fusion peptide with the Antennapedia fragment (Int-H1-S6A,F8A) but not the c-Myc derived fragment alone (H1-S6A,F8A) was capable of internalization inside MCF-7 human breast cancer cells. Int-H1-S6A,F8A and H1-S6A,F8A were the only two peptides capable of inhibiting coimmunoprecipitation of the c-Myc/Max heterodimer in vitro. We have treated (continuously for 10-11 days) MCF-7 cells with four different peptides: Int, H1-S6A,F8A, Int-H1-S6A,F8A, and Int-H1wt [a peptide differing from Int-H1-S6A,F8A by 2 aa (S6 and F8) in the H1 region]. In intact MCF-7 cells, Int-H1-S6A,F8A was the only active peptide capable of inducing the following biological effects: (a) inhibition of cloning efficiency on plates; (b) inhibition of cell growth and induction of apoptosis in subconfluent/confluent cells; and (c) inhibition of transcription of two c-Myc-regulated genes (ODC and p53). Int-H1-S6A,F8A was active in the 1-10 microM range. Int-H1-S6A,F8A may represent a lead molecule for peptidomimetic compounds that have a similar three-dimensional structure but are more resistant to peptidases and, therefore, suitable for in vivo treatment of experimentally induced tumors.
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PMID:Inhibition of cancer cell growth and c-Myc transcriptional activity by a c-Myc helix 1-type peptide fused to an internalization sequence. 972 75

To determine whether the expression of transforming growth factor alpha (TGF-alpha), its receptor (epidermal growth factor receptor [EGFr]), p53 nuclear protein, and proliferation influences prognosis of patients with liver metastases, a study was performed in 45 liver metastases and 33 corresponding primary colorectal carcinomas in patients referred for liver surgery. The expression of TGF-alpha, EGFr, p53 nuclear protein, and proliferation rate was correlated with clinicopathological characteristics and survival after partial liver resection. In liver metastases, TGF-alpha expression was low in 42%, intermediate in 35%, and high in 23%. TGF-alpha expression was higher in liver metastases derived from lymph node-positive primary carcinomas, in synchronous and in irresectable liver metastases compared with those derived from lymph node-negative primary carcinomas, metachronous, and resectable liver metastases. Nuclear p53 expression was found in 83% of primary tumors and 71% of liver metastases. p53 expression did not correlate with the various clinicopathological characteristics. Ki67 expression was not associated with clinicopathological characteristics in primary and metastatic tumors. In the 38 patients in whom a partial liver resection was performed, median survival was 25 months in patients with a higher TGF-alpha expression in the metastasis than in the primary tumor and 60 months in patients with comparable or lower TGF-alpha expression in the metastasis than in the primary tumor (P = .036). Median survival after liver resection was 21 months in patients with p53-negative liver metastases and 58 months in patients with p53-positive metastases (P = .043). By multivariate analysis, p53 and EGFr expression on liver metastases were the best predictors of disease-free survival after partial liver resection, with relative risks of 2.38 and 3.33, respectively. In patients with colorectal liver metastases, referred for liver surgery, a higher TGF-alpha expression is associated with unfavorable tumor characteristics, whereas p53 and absence of EGFr expression is associated with a better survival after partial liver resection.
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PMID:Clinical relevance of transforming growth factor alpha, epidermal growth factor receptor, p53, and Ki67 in colorectal liver metastases and corresponding primary tumors. 975 33

Atherosclerosis is a fibroproliferative disease of the arterial intima. It was recently found that wild-type p53 (wt p53) accumulates in human atherosclerotic tissue. Wt p53 is a cell cycle regulator involved in DNA repair, DNA synthesis, cell differentiation, and apoptosis and might therefore make an important contribution to the cellularity of atherosclerotic plaques. The product of the MDM2 gene is a nuclear protein which forms a complex with p53, thereby inhibiting the negative regulatory effects of wt p53 on cell cycle progression. In order to address a potential role of the interaction of p53 with MDM2 for the regulation of cellularity in atherosclerotic tissue, 22 carotid atheromatous plaques from patients undergoing endarterectomy were studied to determine the presence of p53 immunoreactivity (IR), MDM2 IR, cell proliferation as evidenced by MIB1/Ki-67 IR and DNA fragmentation by in situ terminal transferase-mediated dUTP 3' end labelling (TUNEL), as a marker for apoptosis. p53 IR localized to areas with evidence of chronic inflammation (22/22) and was observed in virtually all cell types in 68.79 +/- 7.51 per cent of the nuclei. p53 staining in the control tissue from human internal mammary arteries was present in 0.2 +/- 0.29 per cent of the cells (P < or = 0.002). MDM2 IR was present in all cases (22/22) in macrophages and smooth muscle cells (SMCs) in 60.53 +/- 8.32 per cent of the nuclei (controls: 0.8 +/- 0.65 per cent, P < or = 0.002) and co-localized with p53 IR as shown by examination of adjacent sections and by double immunofluorescence labelling. Importantly, co-immunoprecipitation and western blot analysis revealed that p53 and MDM2 were physically associated, indicating that MDM2-p53 complex formation takes place in vivo in human atherosclerotic tissue. Positive TUNEL staining and MIB1/Ki-67 IR present in 3.01 +/- 1.27 per cent of the nuclei (controls: 0 per cent, P < or = 0.002) localized to the same plaque compartments as p53 IR and MDM2 IR. Thus, the fate of cells with p53 accumulation may depend on the interaction and the stoichiometry of the p53 and MDM2 proteins. Cells were indeed found with strong p53 accumulation and nuclear morphology typical for apoptosis and there were a few MIB1/Ki-67-positive cells with co-expression of MDM2, indicating a possible role for MDM2 in reversing the negative regulatory effects of p53 for cell cycle progression. The nuclear co-localization of p53 IR with MDM2 IR and the co-immunoprecipitation assay indicate the presence of p53-MDM2 complex formation in vivo in human atherosclerotic tissue. The destiny of individual p53 and MDM2-co-expressing cells either to undergo p53-dependent apoptosis or to re-enter the cycle of cell proliferation may depend on the relative ratios of the two proteins. p53 and MDM2 may therefore play an important role in regulating cellularity and inflammatory activity in human atherosclerotic plaques.
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PMID:Co-expression of p53 and MDM2 in human atherosclerosis: implications for the regulation of cellularity of atherosclerotic lesions. 977 85

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.
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PMID:Differential expression of multiple MDM2 messenger RNAs and proteins in normal and tumorigenic breast epithelial cells. 981 89

In prostate cancer, mutation of the p53 tumor suppressor gene has been associated with locally advanced disease and hormone-resistant disease that is predominantly localized to bone. However, little is known regarding the status of the p53 gene in metastatic prostate cancer that has not been treated with hormonal manipulation. We evaluated formalin-fixed, paraffin-embedded malignant tissues from 86 patients with various stages of prostate cancer, including pathologically confined, locally advanced, and metastatic disease, to detect abnormal p53 nuclear protein accumulation using immunohistochemistry. No abnormal p53 immunostaining was detected in 18 patients with prostate cancer confined to the gland. Two tumors from 21 patients with locally advanced disease (extracapsular extension and/or seminal vesicle invasion) had abnormal nuclear p53 accumulation, and a mutation in exon 7 of the p53 gene was detected in tumor DNA from one patient using single-strand conformation polymorphism-direct sequencing analysis. Of the remaining 47 patients studied in whom tissues from the prostate gland and a metastatic site (44 lymph node, 2 bone, and 1 lung) were available, only 3 had received hormonal therapy prior to obtaining metastatic tissue. In four patients both primary and metastatic tumors demonstrated accumulation of p53 protein, whereas seven additional patients exhibited p53 accumulation only at the metastatic site. In three patients the metastatic tumors harbored missense single-base substitutions in exon 5, as detected using single-strand conformation polymorphism-direct sequencing. These results indicate that p53 abnormalities are associated with lymph node metastases derived from prostate cancer patients that had not undergone hormonal therapy.
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PMID:Association of p53 mutations with metastatic prostate cancer. 981 1

Routinely processed pathological specimens from 119 patients with stage I and II adenocarcinomas or squamous cell carcinomas were examined by immunohistochemical analysis for altered retinoblastoma (RB) and/or p53 protein expression. Absent RB nuclear staining (RB-) indicating loss of RB function occurred in 19 (16%) of the cases studied, whereas expression of a putative mutant p53 nuclear protein (p53(+)) was found in 54 (45%) of the tumors. The median survival was 39 versus 12 months for patients with RB+ and RB- tumors, respectively (P = 0.05 by log rank analysis). Similarly, the median survival was 41 months for patients whose tumors had no expression of mutant p53 (p53(-)) compared with 24 months for individuals with p53 (+) tumors (P = 0.01). These differences in survival, however, were not statistically significant by multivariate analysis. Nevertheless, individuals with RB-/p53(+) tumors had a significantly shorter median survival (12 months) than those with RB+/p53(-) tumors (41 months), as determined by both log rank and multivariate analyses (P = 0.005 and 0.03, respectively). In addition, 66 large cell carcinomas from all stages were examined. Again, a more significant difference in survival (48 versus 8 months) was found between patients with RB+/p53(-) versus RB-/p53(+) tumors (P = 0. 006). These results suggest that RB and p53 status might be used synergistically as prognostic factors in a subset of non-small cell lung carcinomas.
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PMID:Altered retinoblastoma and p53 protein status in non-small cell carcinoma of the lung: potential synergistic effects on prognosis. 981 84

p53 tumor suppression is deficient in the majority of human cancers. Efforts to understand this pathway have identified cyclin-dependent kinase (CDK) inhibitors and suggested a potential for their replacement in human cancer. In the present studies, expression of a C-terminal deletion mutant of the human p21(WAF1/CIP1) CDK inhibitor completely suppressed the growth of colon cancer cells, whereas full-length p21 only partially suppressed growth. We prepared a replication-deficient adenoviral recombinant which expresses the p21 C-terminal mutant (Ad-WAF1-341) and compared its tumor suppressive abilities with Ad-p53 and Ad-LacZ. Ad-WAF1-341- and Ad-p53-infected cancer cells, but not Ad-LacZ-infected cancer cells, expressed a nuclear protein recognized by anti-p21 antibody and were deficient in cell cycle progression. The exogenous p21 mutant interacted with CDK2 but not proliferating cell nuclear antigen following infection of p21-/- cancer cells. Ad-WAF1-341 was more potent than Ad-p53 in inhibiting DNA synthesis in human papillomavirus 16 E6-expressing cancer cells. Most importantly, the Ad-WAF1-341-infected E6-expressing cells died, whereas most of the Ad-p53-infected cells continued to proliferate. Endonucleolytic cleavage of DNA was observed in Ad-WAF1-341-infected cancer cells. These observations suggest that Ad-WAF1-341 should be evaluated in the treatment of human papillomavirus-associated neoplasia and other neoplasias resistant to p53.
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PMID:Suppression of cancer cell growth by adenovirus expressing p21(WAF1/CIP1) deficient in PCNA interaction. 981 91

Poly(ADP-ribosyl) transferase (ADPRT) is a nuclear protein that modifies proteins by forming and attaching to them poly(ADP-ribose) chains. Poly(ADP-ribosyl)ation represents an event of major importance in perturbed cell nuclei and participates in the regulation of fundamental processes including DNA repair and transcription. Although ADPRT serves as a positive cofactor of transcription, initiation of its catalytic activity may cause repression of RNA polymerase II-dependent transcription. It is demonstrated here that ADPRT-dependent silencing of transcription involves ADP-ribosylation of the TATA-binding protein. This modification occurs only if poly(ADP-ribosyl)ation is initiated before TATA-binding protein has bound to DNA and thereby prevents formation of active transcription complexes. Specific DNA binding of other transcription factors including Yin Yang 1, p53, NFkappaB, Sp1, and CREB but not c-Jun or AP-2 is similarly affected. After assembly of transcription complexes initiation of poly(ADP-ribosyl)ation does not influence DNA binding of transcription factors. Accordingly, if bound to DNA, transcription factors are inaccessible to poly(ADP-ribosyl)ation. Thus, poly(ADP-ribosyl)ation prevents binding of transcription factors to DNA, whereas binding to DNA prevents their modification. Considering its ability to detect DNA strand breaks and stimulate DNA repair, it is proposed that ADPRT serves as a molecular switch between transcription and repair of DNA to avoid expression of damaged genes.
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PMID:Regulation of RNA polymerase II-dependent transcription by poly(ADP-ribosyl)ation of transcription factors. 982 23

It is well known that DNA-ploidy is useful independent prognosticator of malignancy. However, the biological significance of polyploid cells and the relation between polyploidy and prognosis is not well understood. We analyzed DNA ploidy by flow cytometry in Meth-A cells (a cultured sarcoma cell line) after treatment with K252a, a protein kinase inhibitor, and showed induction of polyploidization. Apoptotic cell death of the high polyploid cells was verified by flow cytometry, morphological observation and gel analysis of DNA integrity. Expression of tumor-suppressor nuclear protein p53 investigated by immunohistochemistry was increased 10-fold or more in cells with 16C (C = haploid DNA content) relative to cells with 2C, suggesting that the overexpression of p53 was involved in the apoptosis. These results may be of clinical relevance since it has been known that both DNA ploidy and p53 expression have prognostic significance.
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PMID:Apoptotic cell death of high polyploid cells in a cultured sarcoma cell line. 985 16


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