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)

Gene therapy of oral cancer will require expression of genes by promoters that are both powerful and relatively tumor specific. We compared the level of expression of a reporter gene from promoters of human cytomegalovirus (CMV), SV40 virus, mouse mammary tumor virus (MMTV), human papillomaviruses (HPV) types 16 and 18, and the human multi-drug-resistance gene (mdr1), in several lines of oral cancer cells. In the oral cancer cell line 686LN the rank order of expression levels was: CMV > SV40 > HPV > mdr1 > MMTV. Unlike in previous reports the mdr1 promoter was no more active in two cancer cell lines with mutations in the p53 gene than in two other lines with wild-type p53, and its expression level could not be increased by either doxorubicin or taxol. On the other hand, expression from the MMTV promoter was increased over 10-fold by the presence of 1 microM dexamethasone. Thus, by an appropriate choice of promoter and inducer a wide variety of expression levels, over a 3-log range, could be attained in 686LN cells. The oral cancer-specificity of each promoter was judged by comparing expression in the neuroblastoma line IMR32. The most specific promoters were those from papillomaviruses, which were up to 45 times more active in the oral cancer cells, and the least specific was the CMV promoter. In order to find if an HPV-derived promoter was sufficient to produce expression of a suicide phenotype the 686 promoter was cloned adjacent to the thymidine kinase gene of herpes simplex and the construct was expressed from an adenovirus vector. The vector reduced the growth of 686LN cells over a 5-day period by up to 32% when optimal concentrations of virus and ganciclovir were used. These data will be valuable in the design of new constructs for gene therapy of oral cancer.
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PMID:Strength and specificity of different gene promoters in oral cancer cells. 1074 75

This study was carried out to elucidate whether apoptosis and p53 can be used to stratify oral cancer patients into groups with a favorable or unfavorable response to preoperative radiation therapy. Thirty-two patients were evaluated. The apoptosis index was 1.7+/-0. 9% in the ineffective cases, and it was significantly lower than effective cases (3.2+/-1.2%). While 14 of 16 effective cases (86.7%) did not express p53, 13 of 16 ineffective cases (81.3%) overexpressed p53. These results suggest that mutated p53 in tumors is associated with a poor response to radiation which may be related to evasion of apoptosis in oral cancer.
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PMID:Apoptosis and p53 are associated with effect of preoperative radiation in oral squamous cell carcinomas. 1079 41

The cyclin-dependent kinase inhibitor gene p21(Waf1/Cip1) plays a central role in inducing cellular growth arrest, terminal differentiation, and apoptosis. Alterations in this gene may adversely affect regulation of these processes and increase susceptibility for cancer. We have recently reported a novel polymorphism in the p21(Waf1/Cip1) gene in the Indian population and its association with esophageal cancer. An A-->G transition at codon 149 resulted in amino acid substitution from aspartate to glycine in the proliferating cell nuclear antigen binding COOH-terminal domain of p21(Waf1/Cip1) that may affect PCNA-p21(Waf1/Cip1) interactions, thereby affecting regulation of cellular proliferation, and may increase susceptibility for development of cancer. In a parallel study in our laboratory, we searched for putative p21(Waf1/Cip1) mutations in oral premalignant and malignant lesions. No somatic mutation was detected in exon 2 of p21(Waf1/Cip1). Interestingly, a codon 149 polymorphism variant (A-->G) was identified in 11 of 30 (37%) premalignant lesions (7 of 19 hyperplastic lesions and 4 of 11 dysplastic lesions) and 11 of 30 (37%) squamous cell carcinomas (SCCs). This codon 149 variant was also identified in paired lymphocytes of all of the patients with premalignant lesions and SCCs harboring the variant allele, suggesting the occurrence of a polymorphism. Lymphocyte DNA isolated from 50 unrelated age- and gender-matched healthy subjects was screened for this polymorphism. Seven of 50 (14%) normal controls harbored the A-->G codon 149 variant allele. Immunohistochemical analysis of p21(Waf1/Cip1) protein expression showed immunoreactivity in 19 of these 30 (63%) oral premalignant lesions and 16 of 30 (53%) SCCs. The most intriguing features of the study were: (a) the significant increase in frequency of this polymorphism not only in patients with oral SCCs (P = 0.038), but also in patients with premalignant lesions (P = 0.038), compared with normal controls; and (b) the significantly higher frequency of p21(Waf1/Cip1) variants (codon 149) in oral premalignant lesions (10 of 11 cases) and SCCs (11 of 11 cases) with wild-type p53 (P = 0.045) than in lesions with p53 mutations, suggesting that this polymorphism affects the p53 pathway and may play a vital role in oral tumorigenesis. Furthermore, overexpression of p21 protein in oral lesions harboring missense mutations in the p53 gene suggest a p53-independent role for p21 in the pathogenesis of oral cancer.
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PMID:Association between polymorphism in p21(Waf1/Cip1) cyclin-dependent kinase inhibitor gene and human oral cancer. 1087 97

Oral cancer has increased recently in Australia, and overall survival rates have not improved in the past 30 years. Dentists are uniquely well placed to screen their patients at regular recall examinations and detect cancers or pre-cancerous lesions at an early curable stage. Although the major risk factors--tobacco smoking and alcohol abuse--have been identified, only a minority of patients at-risk will develop oral cancer. Molecular analysis has now detected an accumulation of genetic lesions in oral cancer, but the earliest molecular changes in the oral epithelium in the progression to malignancy in at-risk patients has not yet been determined. These changes could if known be exploited for screening purposes. How long human oral carcinogenesis takes to progress from the initiated cell to an invasive tumour, and whether molecular biology can be used to identify the minority of patients who will develop cancer from the large population exposed to the risk factors, are other important unanswered questions. p53 tumour suppressor gene mutations are the most frequently found genetic errors in oral cancer and the p53 gene is a likely target for tobacco and alcohol.
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PMID:A general review of the p53 gene and oral squamous cell carcinoma. 1089 14

MDM2, a critical element of cellular homeostasis mechanisms, is involved in complex interactions with important cell-cycle and stress-response regulators including p53. The mdm2-P2 promoter is a transcriptional target of p53. The aim of this study was to determine the association between mdm2-P2 transcripts and the status of the p53 gene in betel- and tobacco-related oral squamous cell carcinomas (SCCs) to understand the mechanism of deregulation of MDM2 and p53 expression and their prognostic implications in oral tumorigenesis. Elevated levels of MDM2 proteins were observed in 11 of 25 (44%) oral hyperplastic lesions, nine of 15 (60%) dysplastic lesions, and 71 of 100 (71%) SCCs. The intriguing feature of the study was the identification and different subcellular localization of three isoforms of MDM2 (ie, 90 kd, 76 kd, and 57 kd) in oral SCCs and their correlation with p53 overexpression in each tumor. The hallmark of the study was the detection of mdm2-P2 transcripts in 12 of 20 oral SCCs overexpressing both MDM2 and p53 proteins while harboring wild-type p53 alleles. Furthermore, mdm2 amplification was an infrequent event in betel- and tobacco-associated oral tumorigenesis. The differential compartmentalization of the three isoforms of MDM2 suggests that each has a distinct function, potentially in the regulation of p53 and other gene products implicated in oral tumorigenesis. In conclusion, we report herein the first evidence suggesting that enhanced translation of mdm2-P2 transcripts (S-mdm2) may represent an important mechanism of overexpression and consequent stabilization and functional inactivation of wild-type p53 serving as an adverse prognosticator in betel- and tobacco-related oral cancer. The clinical significance of the functional inactivation of wild-type p53 by MDM2 is underscored by the significantly shorter median disease-free survival time (16 months) observed in p53/MDM2-positive cases as compared to those which did not show co-expression of these proteins (median time, 26 months; P = 0.02).
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PMID:Induction of MDM2-P2 transcripts correlates with stabilized wild-type p53 in betel- and tobacco-related human oral cancer. 1093 61

This study identified that the carcinogenesis of hamster buccal pouch (HBP) induced by 7,12-dimethylbenz[a]anthracene (DMBA) was greatly enhanced (18 folds) by a combination treatment with Taiwanese betel quid (BQ) extract. A new cell line, HCDB-1, has been established from induced carcinomas. The cultured monolayer cells were epithelioid in shape with irregular nuclei. They demonstrated abundant cytokeratin and tonofilaments; however, ultrastructural well-organized desmosomes were lacking. The HCDB-1 cell exhibited population doubling in 19 h and was highly tumorigenic in nude mice. A C-->T transition at codon 141 (Ala to Val) of the p53 gene was detected in this cell. This mutation is equivalent to a specific temperature-sensitive mouse p53Ala135Val mutant that causes transformation by shifting to 37.5 degrees C. HCDB-1 is the first cell line established from the HBP model of oral carcinogenesis induced by DMBA/Taiwanese BQ extract. It might be valuable for exploring the molecular pathogenesis of oral cancer.
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PMID:Establishment and characterization of a cell line (HCDB-1) derived from a hamster buccal pouch carcinoma induced by DMBA and Taiwanese betel quid extract. 1094 46

We studied the p53 mutational spectra of 34 lip and 60 intra-oral squamous-cell carcinomas and examined possible etiological and prognostic correlations for these tumor sites. For the p53 analysis of exons 5-8, we used PCR/TGGE screening followed by DNA sequencing. Mutations were found in 18/34 (53%) lip and 22/60 (38%) intra-oral carcinomas. The p53 mutational spectrum of the intra-oral carcinomas comprised transitions and transversions in nearly equal frequency (11 to 10). In comparison, transitions were 3.5 times more frequent than transversions (14 to 4) in carcinomas of the lip. The predominant types of base change found in intra-oral tumors were G:C-to-T:A transversions and G:C-to-A:T transitions (32% each), while in lip tumors G:C-to-A:T transitions (70%) were the most frequent. The rate of lip tumors with mutations was higher in non-smokers (8/13) than in smokers (9/20). In contrast, p53 mutations in intra-oral tumors clustered in smokers (18/47 vs. 2/10). G:C-to-T:A transversions, regarded as tobacco smoke-associated in lung cancer, were found in 2 moderate and 4 heavy smokers with intra-oral cancer. This base substitution was found in none of our lip cancers. In lip tumors, a high rate of mutations occurred at dipyridine sites (13/18); among these were 8 C-to-T transitions and 1 CC-to-TT tandem base transition. These changes are characteristic of DNA damage caused by UV light. The presence of mutational events at the DNA-binding surface of the p53 protein may correlate with poor clinical outcome. However, we could not find any statistically significant correlations between p53 status and survival. Only the recurrence-free interval was significantly shortened in cases with mutations affecting residues of the DNA-binding surface of the p53 protein.
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PMID:p53 mutational spectra are different between squamous-cell carcinomas of the lip and the oral cavity. 1096 43

The CDKN2 gene encodes two structurally different proteins: a cyclin-dependent kinase inhibitor called p16, which regulates retinoblastoma protein (pRb)-dependent G1 arrest, and a cell cycle inhibitor designated p14ARF, which arrests cell growth in G1-S and also in G2-M. Whereas inactivation of p16 has been described as a frequent event in various cancers, including oral cancer, the current function of p14ARF is still poorly understood. A physical association between p14ARF and MDM2 blocks MDM2-induced p53 degradation, resulting in increased levels of p53, which in turn leads to cell cycle arrest. The present study immunohistochemically examined the expression of p16 and p14ARF together with pRb, MDM2 and p53 status in a series of oral cancers. The results showed that p14ARF was frequently absent in the oral cancers (15/37, 41%) as was p16 immunostaining. Concomitant immunopositivity for p14ARF and MDM2 overexpression was frequently observed in a subset of the cancers, whereas an inverse correlation between p14ARF and MDM2 expression and the diffuse staining of p53 was clearly detected. Moreover, the results showed that in most cases of oral cancer (35/37, 95%) at least one protein was altered, and lymph node metastasis was more frequent in the tumors with alterations in both the p16/pRb and p14ARF/p53 pathway (8/16, 50%) than in the tumors with one or no alteration of these two major pathways.
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PMID:Immunohistochemical inactivation of p14ARF concomitant with MDM2 overexpression inversely correlates with p53 overexpression in oral squamous cell carcinoma. 1101 84

This paper examines the genetic defects associated with inherited cancer syndromes and their relevance to oral cancer. Tumour suppressor genes are now thought of as either gatekeepers or caretakers according to whether they control cell growth directly by inhibiting cell proliferation and/or promoting cell death (gatekeepers) or whether they maintain the integrity of the genome by DNA repair mechanisms (caretakers). In disorders such as xeroderma pigmentosum, ataxia telangiectasia, Bloom syndrome and Fanconi's anaemia, where there are defective caretaker genes, there is an increased incidence of second primary malignancies, including oral cancer. By contrast, with the exception of Li Fraumeni syndrome, abnormalities of gatekeeper genes do not predispose to oral cancer. Not only do Li Fraumeni patients develop second primary malignancies, but defects of the p53 pathway (p53 mutation, MDM2 over-expression, CDKN2A deletion) appear to be a ubiquitous feature of sporadic oral cancer as it occurs in the West. The findings suggest that genetic instability is of fundamental importance in the pathogenesis of oral cancer.
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PMID:A review of inherited cancer syndromes and their relevance to oral squamous cell carcinoma. 1185 72

The p53 tumour suppressor gene is inactivated in various types of human cancers, and has been implicated as an early event in several cancers. A p53 Pro/Arg polymorphism at exon 4 codon 72, has been suggested to be involved in susceptibility to cancers as well. Hence, in the current study, we investigated p53 exon 4 codon 72 polymorphism using Proline or Arginine specific primers from the peripheral blood cells (PBC) representing constitutional DNA from 72 oral cancer patients. PBC from 153 normal healthy individuals were used to determine the frequency of the p53 genotypes, Pro/Pro, Arg/Arg and Pro/Arg, in the Indian population. The frequency of distribution of genotypes in the normal healthy individuals was, Pro/Pro - 0.20 (31/153), Arg/Arg -- 0.14 (22/153) and Pro/Arg -- 0.65 (100/153); and in the oral cancer patients was, Pro/Pro -- 0.19 (14/72), Arg/Arg -- 0.08 (6/72) and Pro/Arg -- 0.72 (52/72). Thus, we observed an equidistribution of the genotypes in normal control and oral cancer patients (chi(2)= 1.77, df = 2, 0.3 <P< 0.5). Further, DNA from corresponding tumours from the 72 oral cancer patients were examined for loss of heterozygosity in the p53 gene. Allelic loss was observed in 8 of 52 (15%) heterozygous informative oral cancer patients. Our data indicates an equidistribution of the genotypes and absence of over-representation of either Pro/Pro or Arg/Arg genotypes in the oral cancer patients as compared to the normal healthy controls. Hence, association of the p53 genotypes with susceptibility to oral cancer, was not observed.
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PMID:Determination of p53 genotypes in oral cancer patients from India. 1125 85


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