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)

This study has identified molecular changes characteristic of early oral cancer progression. We reported previously that acquisition of the immortal phenotype is an early event in oral cancer development (F. McGregor et al., Cancer Res., 57: 3886-3889, 1997); our current data indicate that about half of oral dysplasia cultures are immortal, and this is associated with loss of expression of retinoic acid receptor (RAR)-beta and the cell cycle inhibitor p16(ink4a) (p16), p53 mutations, and increased levels of telomerase/human telomerase reverse transcriptase mRNA. In contrast, increased expression of the epidermal growth factor receptor, known to be a characteristic of oral cancer, does not occur until after the dysplasia stage in squamous cell carcinomas. Acquisition of invasive properties as judged by an in vitro Matrigel invasion assay also does not occur until the carcinoma stage and is further increased in metastases. Interestingly, one atypical mortal dysplasia with a considerably extended life span has lost expression of RAR-beta and p16, but it still expresses only wild-type p53 (albeit at a higher level than normal) and has not activated telomerase. RAR-beta and/or p16 re-expression can be induced by treatment with 5-aza-2-deoxycytidine (Aza-C) in some immortal dysplasias, and this has been shown to be due to silencing of gene expression by promoter methylation. Aza-C treatment also down-regulated telomerase activity and human telomerase reverse transcriptase mRNA. Interestingly, with one dysplasia, Aza-C was able to reverse its immortal phenotype, as judged by morphological criteria and expression of the senescence-associated acid beta-galactosidase activity during terminal growth arrest; this immortal dysplasia was the only one in which Aza-C treatment not only down-regulated telomerase activity but also induced re-expression of both RAR-beta and p16. The possibility of reversing the immortal phenotype of some dysplasias by Aza-C may be of clinical usefulness.
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PMID:Molecular changes associated with oral dysplasia progression and acquisition of immortality: potential for its reversal by 5-azacytidine. 1218 35

In the current study, we examined the clinical characteristics and survival probability rates of 116 patients treated for squamous cell carcinoma (SCC) of the tongue. In 55 randomly selected patients these data were correlated with the immunohistological analysis of the tumor and apoptosis-related markers, p53, Bcl-2, c-erbB-2 (Her-2/neu), and to the apoptosis rate assessment by the terminal dUTP nick-end-labeling (TUNEL) method. The overall 5-year survival probability was 55%, which might be the result of the low incidence of smoking and/or alcohol consumption among the patients (21%), the early diagnosis (65% at Stages I-II) and the low histological grades (91% good-moderate). Radiotherapeutic or surgical treatment of the neck did not alter the survival probability achieved by local surgery for Stage I patients, but significantly improved survival for Stage II patients. Independent tumor-related variables which significantly worsened the probability of survival were found. Concomitant non-oral cancer was found to be a poor variable for prognosis prediction. Positive staining of p53, TUNEL (apoptosis rate), c-erbB-2 and Bcl-2 was found in 60, 48, 18 and 15% of the lesions, respectively (P<0.0001). The possible biological significance of these markers in tongue SCC is discussed in relation to the current literature, and an independent role for TUNEL and p53 is suggested.
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PMID:Squamous cell carcinoma of the tongue: the prevalence and prognostic roles of p53, Bcl-2, c-erbB-2 and apoptotic rate as related to clinical and pathological characteristics in a retrospective study. 1221 83

The loss of heterozygosity (LOH) in tumour suppressor gene loci such as p53, retinoblastoma (rb) and adenomatous polyposis coli (apc) were analyzed in oral cancer tissues with matched controls by employing polymerase chain reaction based/restriction fragment length polymorphism (PCR-RFLP), variable number of tandem repeats (PCR-VNTR) analysis and microsatellite assay. The PCR-RFLP analysis showed an infrequent LOH in rb (17%), p53 (11%) and apc (10%) loci in these cases. The microsatellite assay also revealed only a low frequency of LOH in the microsatellite markers such as TP53 (25%), D5S505 (10%) and D3S1067 (0%) in the same samples. In contrast to the present study, similar studies from Western countries have reported a high frequency of LOH in p53, rb and apc genes in oral cancer tissues. The present preliminary study indicates that the gene aberration by LOH may be an insignificant mechanism in Indian oral cancers with respect to the tumour suppressor genes examined.
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PMID:Infrequent loss of heterozygosity of the major tumour suppressor genes in Indian oral cancers. 1236 Oct 76

Recent studies suggest that several proteins can transverse biological membranes through protein transduction. The protein transduction domains of these proteins, 10-16 residues long, have been identified as critical domains for the protein transduction. Poly-arginine peptide also has the ability of protein transduction. Here, we show that the protein delivery system using 11 poly-arginine peptides (11R) is a powerful tool for the transduction of the biologically active tumor suppressor protein, p53, to suppress the proliferation of oral cancer cells. The 11R-fused p53 proteins (11R-p53) effectively penetrated across the plasma membrane of the cancer cells and translocated into the nucleus. The proteins induced the activity of the p21/WAF promoter and inhibited the proliferation of human oral cancer cells, in which the p53 gene was mutated. The effect was equivalent to that of the adenovirus-mediated p53 gene transduction system. Moreover, 11R-p53 enhanced the cisplatin-dependent induction of apoptosis of the cells. These data suggest that this protein transduction method may become a promising cancer therapy.
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PMID:Development of p53 protein transduction therapy using membrane-permeable peptides and the application to oral cancer cells. 1248 27

Deregulation of the retinoblastoma (pRB) tumor suppressor pathway and telomerase activation have been identified as rate-limiting steps for immortalization of primary human epithelial cells. However, additional molecular aberrations including p53 inactivation, ras activation, and deregulation of protein phosphatase 2A activity are necessary for full transformation of immortalized epithelial cells. Genomic instability is observed in most human tumors and constitutes an important mechanism to allow emerging tumor cells to acquire additional mutations to efficiently overcome selection barriers during carcinogenic progression. In an attempt to model oral cancer in a human cell-based system, we analyzed normal oral epithelial keratinocytes with the pRB pathway dysregulated by loss of expression of the cyclin-dependent kinase (cdk) 4/cdk6 inhibitor p16(INK4A) and/or ectopic expression of cdk4 or expression of the human papillomavirus (HPV) type 16 E7 oncoprotein. Ectopic expression of cdk4 and HPV-16 E7 was equally efficient in extending the life span of normal oral keratinocytes, and each was able to cooperate with telomerase (hTERT) to immortalize these cells. HPV-16 E7/hTERT-immortalized normal oral keratinocytes showed centrosome abnormalities, whereas populations of cdk4/hTERT-immortalized cells or hTERT-immortalized cells that had lost expression of p16INK4A showed no such abnormalities. These results demonstrate that disruption of the p16INK4A/pRB checkpoint of epithelial cell immortalization does not necessarily lead to centrosome-associated genomic instability.
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PMID:Abrogation of the retinoblastoma tumor suppressor checkpoint during keratinocyte immortalization is not sufficient for induction of centrosome-mediated genomic instability. 1254 5

We performed methylation specific PCR to explore the mechanism of inactivation of tumor suppressor genes P15, P16, P53 and VHL in 48 oral SCC. The frequencies of aberrant methylation on the promoter of the P15, the P16, the P53 and the VHL genes were 0.27 (13/48), 0.42 (20/48), 0.04 (2/48) and none, respectively. Altogether, over 50% of the samples showed the CpG-island methylation modification in at least one of the three tumor suppressor genes, indicating that the frequent inactivation of these genes may be an important step during oral cancer development, and the methylation inactivation of P15 or P16 may occur at pre-cancerous stage.
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PMID:Epigenetic changes of tumor suppressor genes, P15, P16, VHL and P53 in oral cancer. 1268 40

A cell line, AMOS-III has been established from the surgically resected specimen of an untreated primary human oral squamous cell carcinoma of the floor of mouth from a chronic smokeless tobacco consumer. Immunocytochemical analysis showed epithelial specific antigen, cytokeratins 5, 10, 13 and 16 and integrin alpha(6) markers in AMOS-III cells, confirming the epithelial lineage of the cell line. Analyses of morphology, ultrastructure, karyotype, anchorage independent growth and immunocytochemical properties of the cell line demonstrated the transformed phenotype of epithelial cells. AMOS-III cells have doubling time of 42-44 h. Giemsa-banding patterns of chromosomes confirmed the human origin of the AMOS-III cells. Molecular analysis of cancer-related gene products, p53 and p21(cip1/waf1) showed the presence of wild type p21(cip1/waf1) and truncated p53 proteins. The molecular mechanism underlying the action of retinoids in preventing the occurrence of second primary tumors in oral cancer patients remain to be clearly defined. Treatment of AMOS-III cells with all-trans retinoic acid (ATRA) at 10(-4) microM resulted in 81% cell death. ATRA treatment resulted in enhanced expression of p21(cip1/waf1), nuclear translocation of retinoic acid receptors and apoptotic cell death. Thus, this cell line provides an in vitro model for elucidating the mechanism involving p53 inactivation and p21(cip1/waf1) overexpression in smokeless tobacco-induced oral cancer. Furthermore, the ATRA responsiveness of the cell line underscores its potential utility in identifying the retinoid responsive molecular targets in oral cancer cells.
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PMID:Establishment and characterization of a cell line from smokeless tobacco associated oral squamous cell carcinoma. 1367 4

The codon 72 polymorphism of the p53 tumor suppressor gene has been investigated extensively for its association with various cancers around the world. However, its influence has not been elucidated in the Thai population. Therefore, a case-control study with 97 patients and 97 matched controls was conducted to elucidate the association between the polymorphic p53 and oral cancer risk in a Southern Thai population. The frequencies of the Arg/Arg, Arg/Pro, and Pro/Pro genotypes were 36%, 35%, and 29%, respectively in the controls and 33%, 45% and 22%, respectively in the patients. This study shows that there was no significant association between the p53 codon 72 polymorphism and oral cancer risk. There was also no link with respect to smoking or drinking habits. However, our data suggest that for individuals who were younger than 65 years old, the Pro/Pro genotype may offer some protection against oral cancer (OR = 0.13, 95%CI 0.04-1.10). This is the first report on p53 polymorphism and oral cancer in Thailand.
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PMID:The p53 codon 72 polymorphism and risk of oral cancer in Southern Thailand. 1450 41

Infection of high risk human papillomaviruses (HPVs) specifically the types 16 and 18 has been strongly implicated in the development of cervical cancer. The E6 oncoproteins of these high risk HPVs are known to bind and induce degradation of p53 tumour suppressor protein through the ubiquitin pathways. This degradation is controlled by a common polymorphism of the p53 gene encoding either a proline or an arginine at its codon 72 in exon 4. Recently, it has been demonstrated that the presence of homozygous arginine at codon 72 renders p53 about seven times more susceptible to E6-mediated proteolytic degradation as well as to cervical cancer than those with proline homozygotes or proline/arginine heterozygotes. In India, prevalence of HPV as well as cancers of the uterine cervix and the oral cavity are highest in the world. We have examined this allele-specific predisposition in cervical and oral cancer which is associated with HPV as well as in a non-HPV-linked cancer of the breast. We have carried out investigation in women comprising whole spectrum of cervical lesions with 128 HPV 16/18 positive and 35 HPV negative invasive cervical carcinomas and 34 cases of HPV (16/18) positive and 16 HPV negative cervical dysplasias (mild, moderate and severe) and 104 age-group-matched healthy women as controls. Additionally, we have analysed p53Arg-Pro polymorphism in 13 high risk HPV positive and 31 HPV negative oral cancers along with 20 normal controls and 77 breast cancers with 41 age-matched healthy controls. We observed more than two fold higher risk for homozygous arginine (chi2 = 6.3, df = 2, p = 0.04; OR = 2.3; 95% CI: 1.08-5.16) for HPV 16/18-positive cervical carcinomas when comparison was made only between HPV positive cervical cancers and normal controls but most interestingly, no significant association either in the frequency of homozygous arginine or proline alleles or their heterozygotes could be observed when all the three groups i.e. HPV-positive, HPV-negative cervical cancers and controls were considered simultaneously. No difference was also observed for either arginine or proline polymorphism between women with precancerous lesions of the uterine cervix carrying HPV 16/18 infection and controls. Similarly, increased risk of oral or breast cancer could not be correlated with the polymorphism of arginine/proline allele. Thus the interaction between HPV oncoproteins and the p53 gene polymorphism specifically, homozygous arginine at codon 72 appears to play no role in the development of either cervical or oral cancer and also it can not serve as a biomarker for early identification of cervical, oral or breast cancer.
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PMID:Polymorphism of the p53 codon 72 Arg/Pro and the risk of HPV type 16/18-associated cervical and oral cancer in India. 1457 84

The p53 mutations in betel-related oral cancer have been studied but the results may be confounded by tobacco and alcohol due to tobacco components in the quid or concomitant habits of smoking and drinking. In this study, p53 mutations in tumors from Thai betel chewers who neither smoke nor drink were studied in comparison to tumors from smokers/drinkers. PCR-SSCP analysis and direct sequencing on exon 5-8 were performed. Mutations were detected in 11.8% (8/68) of betel-related tumors and 7 of 8 mutations were G:C to A:T transitions. By contrast, mutations were found in 22.4% (13/58) of smoking/drinking-related tumors with various base substitutions. The results demonstrated different mutation profiles between the two exposed groups. The type of mutation detected in betel chewers suggested a possible role of areca-specific nitrosamine as a causative carcinogen.
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PMID:p53 mutations in betel-associated oral cancer from Thailand. 1458 Jun 80


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